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Pharmacokinetics of the Transdermal Reservoir Membrane System Delivering β-Estradiol: In Vitro/In Vivo-Correlation
Abstract
Purpose. The aim of our study was to investigate the high fluctuations of Estradiol (E2) plasma levels transdermally delivered in postmenopausal women by a commercially available membrane controlled reservoir system (MCRS).
Methods. The transdermal E2 flux either out of a complete MCRS or across its membrane out of defined ethanol water mixtures was determined, as well as E2 plasma profiles in 6 postmenopausal women produced by a MCRS.
Results. The transdermal in vitro E2 flux rate out of a complete MCRS, claimed to deliver 25 g/day, increased steadily, reaching a maximum value of 2.06 0.58 (g/h at 30 to 40 hours and decreased to a rate of about 0.5 (g/h from 60 to 90 hours. No statistically significant differences between plasma profiles calculated from the in vitro investigation and derived from a clinical study could be identified. The E2 flux in defined ethanol/water mixtures across MCRS-membrane, adhesive and skin layer increased with increasing ethanol concentrations up to a maximum of 227 34 ng/cm2/h at an ethanol concentration of 62.5% (V/V) and decreased with further increase in the volume fraction of ethanol.
Conclusions. In vitro as well as in vivo investigations showed high fluctuation of E2 plasma profiles in postmenopausal women produced by the MCRS. These fluctuations are caused by a non-constant input rate of E2 which may be due to changing ethanol concentrations in the reservoir of the MCRS.
... Indeed, although the in vitro permeation data do not always fit the expected one-to-one relation with the in vivo data ( Franz et al., 2009), a certain proportionality between the in vitro and in vivo fluxes is maintained. Therefore a direct in vitro-in vivo correlation of the biopharmaceutical performances has been postulated and well established, either for local ( Minghetti et al., 2000) and systemic administration ( Rohr et al., 1998). ...
Transdermal patches and medicated plasters are designed to sustain efficacious systemic or loco-regional drug concentrations, respectively. In both cases, drug skin permeation is a critical attribute from the early stage of the pharmaceutical development. In 2014, the EMA introduced the guideline "on the quality of transdermal patches", in which the importance of equivalence of drug fluxes in vitro skin permeation study was particularly emphasized to generic or abridged applications for the marketing authorization or manage dossier variations during the product cycle life. Moving from experimental data, this work provides information on the set-up of such studies and on the statistical evaluation of obtained fluxes. In particular, the impact of the inter-sample variability on the equivalence assessment was deeply investigated by using two formulation pairs containing propranolol, diclofenac or nitroglycerine. The main outputs of the work were attributable to the definition of the acceptability interval and number of replicates to be performed. As an example, the equivalence of two propranolol patches (flux variability lower than 25%) can be assessed using six replicas and a confidence limit with-in the 0.8-1.25 range (α = 0.05; power 90%). In contrast, the equivalence of diclofenac plasters, which exhibit a variability near the 50%, can be demonstrated increasing the number of replicas (i.e., 20 skin samples) for each formulation and widening the acceptance range according to a statistical approach proposed in the work.
... As is evident from this study, unsaturated 4-HT solution in 66.66% alcohol showed significantly lower penetration compared to saturated 4-HT solution in 66.66% alcohol. The proportion of ethanol used in this study is similar to the ethanol used in the commercial transdermal patches (41). However, given that the nipple is a sensitive area, the effects of repeated topical application of high alcohol concentration on the nipple need further investigation. ...
Majority of breast cancers originate from epithelial cells in the duct and lobules in the breast. Current systemic treatments for breast cancer are associated with significant systemic side effects, thus warranting localized drug delivery approaches. The aim of this study was to investigate the influence of hydroalcoholic vehicle on topical delivery of 4-hydroxy tamoxifen (4-HT) through the mammary papilla (nipple). The in vitro permeability of 4-HT through porcine mammary papilla was studied using different hydroalcoholic vehicles (0, 33.33, and 66.66% alcohol). Nile red was used as a model lipophilic dye to characterize the drug transport pathway in the mammary papilla. The penetration of 4-HT through the mammary papilla increased with increase in alcohol concentration in the vehicle. The solubility of 4-HT was enhanced by increasing alcohol concentration in the vehicle. On the other hand, the epidermis/vehicle partition coefficient decreased with increase in alcohol concentration. The mammary papilla served as a depot and slowly released 4-HT into the receptor medium. Highest drug penetration was observed with saturated drug solution in 66.66% alcohol, and 4-HT levels were comparable to IC50 value of 4-HT. Results from this study demonstrate the possibility of using mammary papilla as a potential route for direct delivery of 4-HT to the breast.
Studies examining the quantitative relationship between data obtained from an in vitro permeation test (IVPT) with excised human skin and data obtained in living humans have shown an excellent in vitro–in vivo correlation (IVIVC) when the protocols for the in vitro and in vivo studies are well harmonized. Independently, IVPT studies in which the bioavailability of a number of test and reference products was shown to be equivalent have had their in vitro results verified by in vivo results (i.e. studies comparing clinical outcomes [endpoints] in human patients or a pharmacodynamic vasoconstrictor [VC] assay in human subjects), and the test products were subsequently approved by the FDA. A substantial body of data now exists demonstrating that the in vitro measurement of percutaneous absorption through excised human skin is a valid method by which to predict absorption in vivo in humans.
In vitro fertilization (IVF) was developed for women with diseased or absent Fallopian tubes. Rapidly however, the clinical successes witnessed in IVF opened in their wake the doors to the until-then uncharted realm of oocyte exchanges. Together with its variant for male factor infertility – intracytoplasmic sperm injection (ICSI) – IVF is now called the assisted reproductive technology (ART). Logically, therefore, we refer to oocyte donation – with either IVF or ICSI – as donor-egg ART (DE-ART).
Using donated oocytes for women whose ovaries have failed – in DE-ART – implied however that endometrial receptivity may be attained through the prescribed use of exogenous hormones. At the outset, at a time when results of general IVF were relatively meager, the need to rely solely on artificially prepared endometrium in recipients tarnished any prospect that DE-ART would be successful. Hence, the improbable and rapid unraveling that placed the results of DE-ART not only at par but most often above those of the corresponding regular ART programs was certainly a surprise
Transdermal delivery system was the best alternative to oral dosage forms. Methotrexate was formulated in transdermal patches with different ratios of Ethyl cellulose and Hydroxy propyl methyl cellulose E15. Different chemical enhancers Tween-80, Span-80, Di-methyl sulphoxide, and Isopropyl myristate are used to enhance the drug delivery and its mechanism. The formulations were evaluated for In vitro release, Ex-vivo permeation studies. Further albino rats are used to study the skin irritation and pharmacokinetic parameters for optimized formulations. The mechanism of drug release follows the Higuchi kinetics and shows significance (p<0.01) with in the test formulations so, the drug release be both diffusion and erosion controlled rate release. DMSO shows prominent 7 fold increase of flux than the patches without enhancer. From the pharmacokinetic study it was observed that the bioavailability of patches significantly improved due to low elimination rateconstant and high mean residence time of MTX (p<0.01).
A review. Measurement of skin permeation in vitro and in vivo can play a major role in the optimization of formulations for dermal and transdermal drug delivery. The good correlation between in vitro and in vivo measurements adds support to the usefulness of the former option. In addn. to the pharmaceutical considerations, regulatory concern about potential dermal absorption leading to possible local or systemic effects, is now a major concern for the cosmetic and chem. industries. [on SciFinder(R)]
A novel reservoir-type transdermal system of TMP was developed containing eucalyptus oil as a penetration enhancer. The single and multiple-dose pharmacokinetic profiles of TMP administrated by TMP transdermal patch were characterized in healthy volunteers using an in vivo, randomized, open-label, two-way crossover design. TMPP oral tablets were chosen as reference. Following single/multiple oral administration of 200/100 mg TMPP tablets, a TMP Cmax of 1284/613.5 ng/ml was observed within 0.75 h. Single/multiple applications of the TMP patch yielded mean Cmax of 309/325 ng/ml at a median Tmax of 5/4 h, with steady state achieved at second application. The mean Cmin of the patch was 131 ± 30.38 ng/ml, contrasting to nearly zero for the tablet. Multiple applications of patch produced an accumulative effect over single application. At steady state 250 mg/20 cm(2) TMP patch given daily provided comparable exposure to 100 mg TMPP tablets three times daily (3753.91 versus 3563.67 ng·h/ml). TMP tablets and patch yielded similar steady-state plasma concentrations: Cav (148.48 ± 51.27 and 156.41 ± 40.31 ng/ml). The results demonstrated that TMP patch can achieve a therapeutic effect that is comparable to oral administration, exhibited prolonged and sustained plasma levels, fewer drug fluctuations, lower adverse effects, more convenience, and improved patient compliance. In-vitro permeation through human skin demonstrated zero-order kinetics with the flux of 364 μg/cm(2)/h. The predicted Cav (163.9 ng/ml) was in agreement with the observed Cav (156.4 ng/ml).
The present study was aimed to develop Eudragit-based matrix system for transdermal delivery of methotrexate, an immunosuppressant drug for rheumatoid arthritis. Drug release followed zero order rather than first order or Higuchi type release kinetics. FT-IR, DSC and X-RD studies indicated no interaction between drug and polymer. The in-vitro dissolution rate constant, dissolution half life, and pharmacokinetic parameters (Cmax, tmax, AUC(s), t1/2, Kel, and MRT) were evaluated statistically by two-way ANOVA. A significant difference was observed between test products but not within test products. Statistically, a good correlation was found between percent of drug absorbed from patches versus Cmax, and AUC(s). Percent of drug dissolved at a given time versus serum drug concentration was correlated statistically. The results of this study indicate that the polymeric matrix films of methotrexate hold potential for transdermal.
The present study was aimed to develop a matrix-type transdermal formulation of pentazocine using mixed polymeric grades of Eudragit RL/RS. The possible interaction between drug and polymer used were characterized by FTIR, DSC and X-RD. X-RD study indicates a change of state of drug from crystalline to amorphous in the matrix films prepared. The matrix transdermal films of pentazocine were evaluated for physical parameters and in vitro dissolution characteristic using Cygnus' sandwich patch holder. Irrespective of the grades of Eudragit polymer used, the thickness and weight per patch were similar. In vitro dissolution study revealed that, with an increase in the proportion of Eudragit RS (slightly permeable) type polymer, dissolution half life (t(50%)) increases and dissolution rate constant value decreases. Selected formulations were chosen for these pharmacokinetic studies in healthy rabbits. The relevance of difference in the in vitro dissolution rate profile and pharmacokinetic parameters (C(max), t(max), AUC((s)), t(1/2,) K(el), and MRT) were evaluated statistically. In vitro dissolution profiles (DRC and t(50%)) and pharmacokinetic parameters showed a significant difference between test products (P < 0.01). Quantitatively good correlation was found between the percentage of drug absorbed from the transdermal patches and AUC((s)).
Purpose. The aim of our study was to investigate the kinetics of -estradiol (E2) metabolism in the human keratinocyte cell line HaCaT and to estimate the effect of the potential inhibitor ethanol on the biotransformation reaction.
Methods. The formation rates of estrone (E1) in dependence on substrate concentrations were determined in HaCaT cells using tritium labelled E2. Experiments were conducted with and without addition of dehydroepiandrosterone (DHEA) and ethanol. Possible toxic effects on the cells due to ethanol were investigated by cytotoxicity tests.
Results. The metabolism of E2 in HaCaT cells exhibited Michaelis-Menten kinetics with Km and Vmax values of 3.5 M and 216 pmol mg–1 protein h–1, respectively. The reaction was inhibited by DHEA and ethanol. The alcohol showed a reversible competitive inhibition mechanism for concentrations of 4 to 8% (v/v). Lower ethanol concentrations had no effect, whereas levels 10% significantly decreased cell viability leading to a different inhibition mechanism.
Conclusions. The HaCaT cell line seems to be a suitable model for studying enzyme kinetics equivalent to the human skin. The concentration dependent inhibitory effect of ethanol observed in this cell line may be relevant for the transdermal E2 application in patients.
Purpose. The aim of our study was to clarify the kinetic performance of a membrane controlled reservoir system (MCRS) for -estradiol (E2) under in vitroconditions by determination of the role of membrane and adhesive layer on E2flux control.
Methods. E2and ethanol fluxes across EVA membrane or membrane coated with adhesive from saturated solutions in defined ethanol/PBS mixtures were measured in the symmetric and asymmetric configuration. Physicochemical parameters of the EVA membrane were determined.
Results. The E2flux across the 9% EVA membrane steadily increased with increasing ethanol concentrations in both configurations, due to enhanced uptake of E2by the polymer and increasing membrane diffusivity. Permeation across the EVA membrane coated with an adhesive layer in the symmetric and asymmetric configuration increased up to maximum values of 0.80 0.14 (g cm–2 h–1and 0.37 0.02 g cm–2 h–1, respectively, at 62.5% (v/v) ethanol. The fluxes then decreased with further increase in the volume fraction of ethanol due to a dramatically reduced permeability of the adhesive layer. For the asymmetric case, a linear dependence of E2on ethanol fluxes was observed.
Conclusions. The E2flux from MCRS is strictly dependent on reservoir ethanol concentrations, whereas the adhesive layer represents the rate controlling barrier at high ethanol levels (>70% v/v).
This article systematically reviews the status of in vitro and in vivo percutaneous permeation of selected compounds reported in the literature
and attempts to relate these permeation data to formulations and biochemical changes occurring in human skin, animal skins and skin equivalents.
A substantial portion of the article is dedicated in reviewing the status of commercially available drugs and their delivery methods. Information
on permeation modifier compounds and in vivo/in vitro (IVIVC) correlations is also provided in order to obtain a complete picture of the research
status in the dermatopharmaceutical field.
With the exception of topical glucocorticoids, demonstrating bioequivalence between generic and reference topical products entails conducting clinical end-point trials which are both lengthy and expensive. Considerable effort has been channeled towards development and validation of alternative approaches to demonstrate bioequivalence of topical and transdermal products. The critical opportunity pathways identified by the FDA for the industry for topical bioequivalence include the following surrogate methods: in vitro studies, dermatopharmacokinetic method, dermal microdialysis and near infrared spectroscopy. This review provides an update of recent advances in these methodologies.
The present study aimed to develop hydroxypropyl methylcellulose based transdermal delivery of pentazocine. In formulations containing lower proportions of polymer, the drug released followed the Higuchi kinetics while, with an increase in polymer content, it followed the zero-order release kinetics. Release exponent (n) values imply that the release of pentazocine from matrices was non-Fickian. FT-IR, DSC and XRD studies indicated no interaction between drug and polymer.The in vitro dissolution rate constant, dissolution half-life and pharmacokinetic parameters (C(max), t(max), AUC(s), t(1/2), Kel, and MRT) were evaluated statistically by two-way ANOVA. A significant difference was observed between but not within the tested products. Statistically, a good correlation was found between per cent of drug absorbed from patches vs. C(max) and AUC(s). A good correlation was also observed when per cent drug released was correlated with the blood drug concentration obtained at the same time point. The results of this study indicate that the polymeric matrix films of pentazocine hold potential for transdermal drug delivery.
The aim of this study was to investigate the systemic bioavailability and plasma profiles of 17beta-estradiol (E2) after the application of three matrix patches for the transdermal delivery of E2: Menorest, Tradelia, and Estraderm MX claiming to deliver a dosage of 50 microg E2/day. All three patches were each worn randomly by 21 postmenopausal women volunteers over a 4-day period (i.e. 96 h). Each of the three treatment periods were separated by an at least 7 day wash out period according to a randomized, 3-way crossover design. Blood samples were taken from the antecubital vein before and 3, 6, 9, 12, 24, 28, 33, 48, 57, 72, 81, and 96 h after application. E2 plasma values were determined by a specific direct radioimmunoassay method. The following pharmacokinetic parameters were evaluated: AUC0-96h, Cmax, Tmax, Cmin, C(average). The time to reach the maximal E2 value of 32 h was the only pharmacokinetic parameter which was identical for all three patches. Menorest produced the highest E2 bioavailability judged by the AUC0-96h = 3967.8 +/- 1651.8 pg/ml, C(average) = 41.3 +/- 21.3 pg/ml, Cmin = 36.8 +/- 8.6 pg/ml. Tradelia showed statistically not significantly smaller C(average) = 38.9 +/- 17.0 pg/ml, AUC0-96h = 3737.9 +/- 1637.6 pg/ml x per h, and Cmin = 33.8 +/- 26.7 than Menorest. Estraderm MX showed lowest E2 plasma profiles Cmax = 38.9 +/- 25.1 pg/ml, C(average) = 33.2 +/- 17.1 pg/ml, AUC0-96 = 3192.1 +/- 1646.0 pg/ml per x h. Menorest showed the smallest fluctuation over the entire test period, similar to Estraderm MX, while Tradelia showed the highest E2-fluctuation (P < 0.01): Tradelia exhibited the highest Cmax = 48.0 +/- 20.3 pg/ml. When E2 baseline levels, prior to patch application are subtracted individually from the produced E2 plasma level, Estraderm MX is not bioequivalent to Menorest (P < 0.05). A circadian curve pattern of the E2 plasma level was observed for all patches: in the evening higher E2 plasma level were always detected compared with the morning, however, less pronounced with Estraderm MX. Individual comparison of AUC0-96h of each patch exhibited a large interindividual variability of 2000-8000 pg/ml per h for all three patches but relatively small individual variability: women with high E2 bioavailability (high responders) maintained high bioavailability in all applied patches, women identified as low and medium responders remained the same regardless of the applied patch. Menorest produced in 2/3 of all postmenopausal women with the highest E2 bioavailability (AUC0-96h), Tradelia was found in less than 1/3 (28.6%), and Estraderm MX in only one postmenopausal woman. Menorest only produced the highest reduction in postmenopausal symptoms together with Tradelia. Estraderm MX produced a smaller reduction in postmenopausal symptoms compared to Menorest and Tradelia. The observed side-effects were approximately equal in all three patches, with a maximum value after 72 h. It can be concluded that the three patches for the transdermal delivery of E2 claiming to deliver 50 microg E2/day differed from each other in their pharmacokinetic performance, although statistically not significant: Menorest exhibited the highest C(average), AUC and Cmin, and the lowest fluctuation, followed by Tradelia and Estraderm MX.
The pharmacokinetic performance of a matrix system for transdermal beta-estradiol (E(2)) delivery after multiple consecutive dosing in postmenopausal women undergoing hormone replacement therapy was investigated. The E(2) plasma profiles determined during the third application in 16 postmenopausal women were compared with results obtained in a published clinical study using the same patch in 24 postmenopausal women without E(2) pretreatment; they were compared with a theoretical diffusion/pharmacokinetic model. A conventional theoretical model with constant model parameter (CPM) obtained from in vitro mass balance experiments in a Franz cell type set up described successfully the transdermal E(2) bioavailability parameter AUC(0-96h) (4341.9 +/- 1513.1; calculated 4250.8) and C(average) (45.0 +/- 13.2; calculated 41.2). Also, experimentally, there was no significant drop in E(2) plasma values after patch removal and reapplication; this was corroborated by calculations. Accumulation of E(2) did not occur when several patches were applied consecutively over a period of 3 weeks. Steady state was achieved following application of the first patch. However, the differences between recorded E(2) plasma profiles and theoretical results detected at specific measurement points cannot be explained by the CPM model. Experimentally obtained plasma profiles were always lower in the morning and higher in the evening than predicted on the basis of the model. Measurements of in vivo skin temperature in the postmenopausal women showed oscillating temperature profiles in the form of a cosinor function: The temperature mesor of untreated postmenopausal women was 34.8 degrees C with an acrophase at 17.0 o'clock (95% CI: 14.30-19.30) and an amplitude of +/- 0.4 degrees C (p = 0.1). During the application of the patch the average temperature next to a patch rose 0.3 degrees C, which was statistically significant (p = 0.1). In the skin under the application of the matrix patch a mesor temperature was detected as 35.6 degrees C with an amplitude of +/- 0.5 degrees C with an acrophase at 17.51 o'clock (95% CI: 14.30-21.00) (p = 0.05). The temperature period was 24 h for all measurements and the maximum temperature was observed at about 16.30 h, and a minimum at about 5.00 h. A linear dependency was detected in in vitro experiments between the log of E(2) permeability and the temperature for stripped skin, epidermis/dermis layer, as well as for the matrix. Modeling of E(2) plasma profiles with oscillating diffusion coefficients (ODM1) with a sine wave function results in this equation: D(1) = D(0x) + Da(x).sin(k.t). D(0x) is the diffusion coefficient determined at 35.6 degrees C, k is 1/24 h, D(a) is the diffusion coefficient of the temperature amplitude, h is hour, and x stands for the respective diffusion layer. It was shown that the experimental E(2) plasma profile variations are more pronounced than can simply be explained by skin temperature variations alone (ODM1 model). A simplex fit with an oscillating diffusion coefficient in the form of a sine wave function for the stratum corneum (ODM2 model) resulted in a temperature amplitude of 1.1 degrees C, about twice as high as was determined in the in vivo measurements (ODM2 model). Therefore, other circadian parameterlike blood flow might superimpose the temperature profile. The improvement in data analysis by incorporating oscillating diffusion coefficients (ODM1 and 2) over CPM was judged from a comparison of experimental data with the calculated plasma profiles with the AIC, Akaikes model selection criterion, which allows ranking between models because it is independent of the scaling of the data points. ODM1 and ODM2 improved the data analysis over CPM by allowing better calculation of experimental C(max), t(max), the time to reach to C(max), and the fluctuation, f. No difference between CPM, ODM1, or ODM2 was found for the bioavailability parameter C(average) and AUC(0-96h).
N-Methyl-2-pyrrolidone (NMP) increased the skin permeation of estradiol (E2) in Yucatan micropig epidermis using a modified Franz-type diffusion cell. The addition of NMP significantly increased the fluxes of E2 from water and soybean oil. The flux and skin concentration of E2 were higher from soybean oil than from water and increased with increasing NMP concentrations in soybean oil. Correlation was observed with E2 flux and skin concentration (R(2) = 0.804) NMP enhanced E2 skin permeation because NMP made E2 skin concentration higher. Thus, NMP (10%) was added to the oily gel made by isocetyl isostearate and hydrogenated phospholipid. E2 permeation from the gel without NMP was the same as that from soybean oil suspension. The flux of E2 from the gel with NMP was 0.6 microg/h per cm(2) and might be sufficient for estrogen replacement therapy.
Drug development in dermatotherapy and also development of transdermal therapeutic systems (TTS) demand high-predictive in vitro models to estimate drug levels in skin and systemic uptake. Here we compare three ready-to-use models, reconstructed human epidermis, split porcine skin and the perfused porcine forelimb. 17beta-Estradiol (E(2)), which is highly metabolized by skin cells, serves as model drug since E(2) application is of high relevance in hormone replacement therapy while topical E(2) may promote wound healing. E(2) TTS, gel and an ethanolic solution were investigated for cutaneous penetration, permeation and metabolism.
E(2) TTS enabled an E(2) uptake of 42.9% of the applied dose accompanied by a high percentage of E(2) metabolism (30% of the penetrated dose) in the perfused porcine forelimb. In Franz cell experiments with reconstructed human epidermis and split porcine skin, the gel allowed an E(2) uptake of 41.7 and 22.9% of the applied dose accompanied by a high E(2) metabolism (42.6 and 28.6% of the penetrated dose). Due to toxic effects of the vehicle, this was not true with an ethanolic solution, then E(2) permeation and metabolism were clearly diminished. Most importantly, the in vitro models proved to be predictive with respect to the E(2)/estrone ratio in female plasma under transdermal hormone replacement therapy.
In vitro tests should reduce the need for both animal and human studies for cutaneous uptake and metabolism in the future.
The purpose of this investigation was to study the effect of some penetration enhancers on in vitro permeation of glibenclamide and glipizide through mouse skin. Ethanol in various concentrations, N-methyl-2-pyrrolidinone, transcutol, propylene glycol and terpenes like citral, geraniol and eugenol were used as penetration enhancers. The in vitro skin permeation experiments were conducted by both simultaneous application of drug and enhancer solution and by pretreatment of the skin with neat enhancer. At the end of the experiment drug retained in the skin was estimated. The flux values (μg/cm2/h) of both drugs significantly (p < 0.05) increased in the presence of penetration enhancers, except transcutol and propylene glycol. The glibenclamide flux values ranged from 1.42 ± 0.09 without enhancer, to 18.25 ± 1.21 in a combination of 50% ethanol and 5% eugenol. Glipizide flux values ranged from 3.21 ± 0.51 without enhancer, to 57.21 ± 5.25 in a combination of 50% ethanol and 5% eugenol. Skin retention and solubility of both drugs increased with all penetration enhancers compared to control (except propylene glycol). As the target permeation rates for glibenclamide and glipizide were calculated to be 193.8 and 184.8 μg/h respectively, the present study showed that the required permeation rates for both drugs could be achieved with the aid of enhancers by increasing the area of application in an appreciable range.
Peer Reviewed http://deepblue.lib.umich.edu/bitstream/2027.42/41513/1/11095_2004_Article_306362.pdf
The article provides an overview of in vitro evaluation of transdermal drug delivery systems. A simple in vitro release methodology applicable to all transdermal systems is described which can be used as a quality control test.
The aim of this study was to compare the bioavailability and plasma profiles of estradiol and estrone after repeated applications of 2 types of estradiol transdermal systems: a new adhesive matrix system (Menorest®) compared with a reference membrane/reservoir system (Estraderm®) and to evaluate their short term safety. This was an open, randomised, crossover study, with 2 treatment periods of 10.5 days separated by a 10-day washout period and with a 1-week follow-up. Participants were studied at Institut Aster, Paris, and Association de Recherche Thérapeutique (ART), Lyon, France, and included 31 healthy postmenopausal women, all volunteers aged between 49 and 67 years (mean 58 years). Each transdermal system was applied for three successive 3.5 day-wear periods (10.5 days) on the lower abdominal skin. Plasma estradiol and estrone concentrations were measured at steady-state, before and after the third application of each transdermal system at regular intervals over 106 hours. Cutaneous tolerance was assessed after each transdermal system removal. Although the extent of availability [area under the plasma concentration-time curve (AUC) and average plasma concentration (Cav)] was similar with both transdermal systems, their pharmacokinetic profiles were different, with Menorest® producing less fluctuating and more sustained plasma estradiol levels than the reference system. The mean estradiol to estrone Cav ratio was similar with the 2 transdermal systems and in the physiological range of premenopausal status. The incidence of adverse events was similar for both treatments, but a lower incidence of local erythema was observed with Menorest® (8.9%) than with the reference system (18.3%). In conclusion, during the entire wear period, Menorest® produced more sustained plasma estradiol levels with less fluctuations (40 to 72 ng/L) than the reservoir/ membrane system (18 to 102 ng/L). Menorest® gave estradiol plasma levels approximating the concentrations observed during the early to mid-follicular premenopausal stage, with a 2-fold lower incidence of erythema than with the reservoir/membrane system.
The successful introduction of nitroglycerin transdermal delivery systems for the prophylactic treatment of angina pectoris has spawned an explosion of interest in this route of drug delivery in the field of pharmaceutics. Since that time, we have gained a great deal more knowledge concerning the design of membrane controlled delivery systems. This route of administration has been proposed and investigated in a number of disease states using several drugs. We would like to report our experience in investigating the transdermal route for long term treatment of postmenopausal symptoms using estradiol replacement therapy.The rationale for the development of a transdermal estradiol system is associated with the metabolic and pharmacological effects of orally administered estrogen replacement in post-menopausal women. Because estradiol is metabolized almost completely on first pass through the liver, orally administered estrogens result in nonphysiologic levels of the estrogenic metabolites of the natural ovarian hormone. Transdermal delivery of estradiol successfully by-passes the first pass effect and results in a more normal estrogen blood profile. The results of several biopharmaceutics studies demonstrate the characteristics of the membrane controlled delivery system which was designed around pharmacologic principles. In addition, a number of clinical trials have shown that total required doses of estradiol provided transdermally are only a fraction of those required by the oral route. We will also discuss problems associated with adequately defining total drug input from transdermal devices when working in these very small dosing ranges.
Peer Reviewed http://deepblue.lib.umich.edu/bitstream/2027.42/41577/1/11095_2004_Article_305246.pdf
To evaluate the effects of vehicle supplementation on serum estradiol (E2) delivery pharmacokinetics from the Ciba-Geigy (Summit, NJ) 0.1-mg Estraderm Patch.
Postmenopausal women were randomized to a 28-day crossover treatment protocol separated by a 14-day wash out period.
Normal human volunteers were studied in an academic research environment.
The subject pool included eight healthy postmenopausal women between 32 and 60 years of age.
In treatment A, a 0.1-mg Estraderm Patch was worn for 7 days; in treatment B, and identical patch was worn into which 0.6 mL of ethanol was injected on day 3 of use.
Serum E2 levels were measured in both groups.
Although E2 absorption showed characteristic interpatient variability, addition of ethanol significantly extended the mean time for serum E2 levels to return to baseline, without increasing peak absorption. The mean extension was 50 hours.
The addition of ethanol to the Estraderm Patch increased the duration of elevated serum E2 levels measured in menopausal women, thus potentially increasing the effective life span of the transdermal therapeutic system.
Women's views on the menopause and hormone replacement therapy were explored using a questionnaire given to women attending one general practice who were having hormone replacement therapy under the supervision of their doctor. Sixty four women (67%) responded. Although only 5% of women had requested hormone replacement therapy from their general practitioner the majority of women indicated that they had been helped by hormone replacement therapy. Eight per cent of women were using hormone replacement therapy primarily to treat menopausal symptoms with only 6% of women using it primarily as prophylaxis against osteoporosis. Many women were correctly informed about the effects of hormone replacement therapy but mistaken beliefs about its side effects may indicate the need for further health education. The desire for further information was striking: 59% of women wanted further information about hormone replacement therapy, and 80% of women would have liked to have had more information about the menopause before its onset. The media appeared to be an important source of information about health matters: 61% of women obtained information about hormone replacement therapy from either the television, magazines or newspapers. The role of the media and health workers in health education is discussed.
Estrogen-replacement therapy is important for the prevention of postmenopausal osteoporosis. However, oral synthetic and conjugated estrogens increase biliary cholesterol saturation index and risk of gallstone disease. To examine whether transdermal estrogen administration could avoid these adverse effects, 17 postmenopausal women were treated with transdermal estradiol (Estraderm TTS; Ciba-Geigy, Arnhem, The Netherlands), 100 μg/day for 4 weeks, and after 1 month without therapy, with oral estradiol (Progynova; Schering, Weesp, The Netherlands), 2 mg/day for 4 weeks. The increase in the serum estradiol level was much higher during transdermal than oral estradiol administration. On the contrary, the increase in the serum estrone level was much more pronounced during oral treatment. Both modes of treatment led to a similar reduction of urinary calcium excretion. A highly significant decrease in serum phosphate levels was found during transdermal therapy. Biliary cholesterol saturation index did not change during transdermal therapy (mean ± SEM, 1.25 ± 0.06 before and 1.22 ± 0.07 at the end of transdermal therapy; P = NS). A slight increase in cholesterol saturation index that did not reach statistical significance was found during oral therapy (1.28 ± 0.09 before and 1.36 ± 0.09 during oral treatment). However, the subgroup of women with strong increases in serum estrone levels during oral estradiol therapy (>0.5 pmol/mL; n = 8) generally had increased biliary cholesterol saturation index, a decrease in relative percentage chenodeoxycholic acid in bile, and increased serum sex hormone-binding globulin levels during oral treatment. Cholesterol monohydrate crystals were never found in duodenal biles during either treatment. This study indicates that transdermal estradiol does not induce lithogenic bile. On the contrary, oral estradiol leads to lithogenic bile in a subgroup of women with strong increases in serum estrone levels during oral treatment.
The pharmacokinetics of three transdermal estradiol (E2) replacement regimens were studied following establishment of steady-state dynamics. Oestrogel 3.0 mg, Oestrogel 1.5 mg, and Estraderm transdermal delivery system 4 mg (0.05 mg/day) were administered for 14 days each to 15 postmenopausal volunteers, with a 14-day washout period between each regimen. The percutaneous E2 pharmacokinetics were compared with an oral micronized E2 preparation. Venous samples were obtained at 0, 1, 2, 4, 8, 12, and 24 hours on 3 sequential days 11 days after initial application of the Oestrogel and the transdermal delivery system, and at the same times after oral E2 ingestion. All three percutaneous regimens provided nearly constant serum E2 and estrone (E1) levels throughout their use. The mean serum E2 levels were 102.9 +/- 39.9, 68.1 +/- 27.4, and 41.1 +/- 13.5 pg/mL for Oestrogel 3.0 mg, Oestrogel 1.5 mg, and Estraderm, respectively. Oral E2 resulted in a mean serum E2 level of 114.0 +/- 65.2 pg/mL with marked peak and nadir values. The E1/E2 ratio was comparable with all three percutaneous regimens (1.08-1.33) and was significantly lower than that found with oral Estrace (5.05).
The estradiol transdermal therapeutic system is a cutaneous delivery device which delivers estradiol into the systemic circulation via the stratum corneum at a constant rate for up to 4 days. Physiological levels of estradiol (the major estrogen secreted by the ovaries in premenopausal women) can therefore be maintained in postmenopausal women with low daily doses because first-pass hepatic metabolism is avoided. In short term clinical studies, the beneficial effects of transdermal estradiol on plasma gonadotrophins, maturation of the vaginal epithelium, metabolic parameters of bone resorption and menopausal symptoms (hot flushes, sleep disturbance, genitourinary discomfort and mood alteration) appear to be comparable to those of oral and subcutaneous estrogens, while the undesirable effects of oral estrogens on hepatic metabolism are avoided. As with oral or injectable estrogen replacement therapy, concomitant sequential progestagen is recommended for patients with an intact uterus during transdermal estradiol administration, in order to reduce endometrial stimulation. Transdermal estradiol has been well tolerated in clinical trials, with local irritation at the site of application being the most common adverse effect. The incidence of systemic estrogenic effects appears to be comparable to that observed with oral therapy. Thus, transdermal estradiol offers near-physiological estrogen replacement in postmenopausal women in a convenient low-dose form which may avoid some of the complications of higher dose oral therapy. Long term epidemiological studies are warranted to determine whether transdermal estradiol therapy provides protection against osteoporosis and fractures and cardiovascular disease equivalent to that offered by oral and injectable estrogens. However, despite the importance of such data, it seems reasonable to conclude at this stage of its development that transdermal estradiol represents an important advance in hormone replacement therapy.
The in vitro release profiles of two sizes of estradiol patches were determined by the paddle method, where the patch was held in position at the bottom of the dissolution vessel by sandwiching it between a watch glass and an aluminum wire mesh or Teflon screen, and also by the manufacturer's paddle-over-disk method. The estradiol content of test aliquots of the dissolution medium was determined by HPLC. The release profiles by both procedures were comparable and showed that approximately 10% of the labeled drug was released in 4 days.
To determine whether post-menopausal oestrogen use affects the risk of dying from stroke.
Postal questionnaire survey to elicit details of oestrogen replacement therapy and potential risk modifiers.
Californian retirement community.
All 22,781 residents of community (white, affluent, well educated) contacted by mail and phone; 13,986 (61%, median age 73) responded, including 8882 women. These formed cohort for mortality follow up, using health department death certification. Only 13 lost to follow up, apparently not deceased, but 34 excluded because no information on oestrogen use.
None.
Mortality rate from stroke compared in women who did and did not receive oestrogen replacement treatment.
Age adjusted mortality rates were computed using internal standard and four age groups. By January 1987 there had been 1019 deaths in the cohort. Twenty out of 4962 women who used oestrogen replacement treatment died from stroke compared with 43 out of 3845 women who did not use oestrogen replacement treatment: relative risk 0.53, 95% confidence interval 0.31 to 0.91. Protection was found in all age groups except the youngest and was unaffected by adjustment for possible confounding factors (hypertension, smoking, alcohol, body mass index, exercise).
Oestrogen replacement treatment protects against death due to stroke.
The metabolism of estrone sulfate has been studied in normal, young males by single injections of 6,7-³H-estrone sulfate (9 subjects); by constant infusions of 6,7-³H-estrone sulfate (8 subjects), 6,7-³H-estrone (5 subjects), and 6,7-³H-estradiol (5 subjects); and by the measurement of the concentration of radioactivity in plasma as estrone sulfate, estrone, and estradiol.
The disappearance of radioactivity as estrone sulfate following the single injections of 6,7-³H-estrone sulfate can be described as a function which is the sum of two exponentials. The initial rapid component (T½ = 3 min) represents spread into and transfer from a space, with a volume of 7.2 rh 0.6 (se) L. The mean value for the rate constant of total removal (reversible and irreversible) from this space is 266 ± 2 7 (se) units/day of which 11.1 ± 2.4 (se) % is irreversible. The mean metabolic clearance rate (MCR R) is 105 ± 20 (se) L/day/m²
Using the constant infusion technique the mean MCRr is 80 ± 10 (se) L/day/m². The overall mean MCR of estrone sulfate is 90 ± 10 (se) L/day/m².
The mean transfer constant or fraction of ³H-estrone sulfate infused which is measured as estrone in the blood is 0.15 with 95% confidence limits of 0.12 to 0.18. In the two subjects in whom ³H-estradiol was measured the was 0.022 and 0.044.
For the infusion of ³H-estrone and ³H-estradiol the mean and (95% confidence limits) were 0.40 (0.21 to 0.81) and 0.42 (0.30 to 0.58).
Using the available data for and [ρ]bb values, it is probable that most of the estrone sulfate entering the blood each day does so as a result of conversion from the free estrogens and little, if any, arises as a result of direct secretion.
We have attempted to measure the metabolic clearance rates (MCR) and the transfer factors of estradiol (E(2)) and estrone (E(1)) during 2-hr and 12-hr infusions. When estradiol-(3)H was infused for 2 hr, apparent equilibrium was reached at 70 min; the 12-hr infusions showed that plasma estradiol-(3)H levels increased slowly throughout the infusion. When estrone-(3)H was infused, constancy of estrone-(3)H levels was not attained in either the 2-hr infusions or in the two 12-hr infusions. The tritium level in the metabolite of the infused estrogen did not become constant in 50% of the short infusions and increased during all the long infusions. Thus, the conversion ratios C(E1E2) and C(E2E1) continually changed and transfer factors could not be calculated. The apparent "MCR'S" calculated on the basis of the 2-hr studies expressed as liters/24 hr per m(2) +/-SD were: "MCR(E1)" (women) 980 +/-94, (men) 1170 +/-95; "MCR(E2)" (women) 615 +/-17, (men) 830 +/-30. The estradiol "MCR's" differed significantly between men and women. "MCR(E2)" was the same using either estradiol-(14)C or -(3)H and was unchanged by the infusion of 170 mug of estradiol daily. Postmenopausal women had estrogen "MCR's" in the same range as premenopausal women. Excess glucocorticoids increased the "MCR(E2)."
To determine whether the nonoral administration of estradiol (E2) might provide physiologic replacement without alteration of hepatic function, 20 postmenopausal women were studied before and after 3 weeks of treatment with either E2-containing transdermal therapeutic systems or placebo. Twenty premenopausal women were also studied. With E2-containing systems, serum E2 and estrone levels were restored to the premenopausal range. Variable responses of the different biochemical and biologic markers of the actions of E2 were observed. The most sensitive marker was vaginal cytology, with the E2 dosage reverting the maturation index to premenopausal values. Hot flashes, measured objectively, were reduced in frequency but not abolished. Serum levels of follicle-stimulating hormone and luteinizing hormone were lowered but remained higher than the premenopausal range. No significant changes were noted in urinary calcium/creatinine and hydroxyproline/creatinine ratios, which were used as markers of bone resorption. With active systems, no significant changes were noted in the concentrations of the hepatic proteins renin substrate and thyroxine-binding globulin or in the binding capacities of cortisol-binding globulin and sex hormone-binding globulin. These results indicate that transdermal E2 administration may be used to provide estrogen replacement while exerting limited effects on hepatic function.
To describe the efficacy, safety, and wearability of estrogen replacement therapy of a 7-day estradiol transdermal system (Climara), developed using new drug-in-adhesive technology.
The pharmacokinetics of the 7-day system were investigated in single- and multiple-dose studies, a relative bioavailability study of the two patch sizes, and comparative studies with the twice-weekly transdermal system (Estraderm). Safety and efficacy in the treatment of vasomotor symptoms compared with conjugated equine estrogens (Premarin) and placebo were evaluated in two 11-week, randomized, double-blind, multicenter trials in 603 women; the data are combined in this report. Irritation and adhesion were also evaluated in comparative studies with Estraderm, Micropore (an inert once-weekly tape), and placebo controls.
Blood levels were sustained for the full 7 days of patch wear, there was no drug accumulation, and a physiologic estrone to estradiol ratio was maintained. Pharmacokinetics studies showed dose proportionality of the 0.05 and 0.1 mg/day patches. Both patch sizes significantly decreased the frequency of hot flushes compared with placebo and were comparable with conjugated equine estrogens. There was a statistically significant difference between the two patch sizes. The mean overall decline in the hot flush rate was 74.6% for the 0.1 mg patch versus 64.5% for the 0.05 mg patch (p < or = 0.05). The combined data also showed that the onset of efficacy is within 1 to 2 weeks after the start of therapy and that efficacy is fully sustained during the 7-day patch wear period with some diminution of effect during the treatment-free week of each cycle. Treatment was well tolerated. Adverse events led to withdrawal from the studies in 8.9% of subjects. In most of these (6.8% of subjects), the cause was adverse skin reactions. Skin irritation was similar to Estraderm in comparative studies, whereas adhesion was significantly better with Climara.
The Climara patch delivers estradiol for a full 7 days. Clinical efficacy of both patch sizes is comparable with currently accepted therapy and is sustained for the entire week of patch wear. A significant difference in response between the two doses supports dose titration. The patch is well tolerated and has excellent adhesion.
Circumstantial evidence links endogenous estrogens to increased risk of breast cancer in women, but direct epidemiologic support is limited. In particular, only a few small prospective studies have addressed this issue.
Our purpose was to assess breast cancer risk in relation to circulating levels of the two major endogenous estrogens, estrone and estradiol, measured before the clinical onset of the disease.
The association between serum levels of estrogens and the risk of breast cancer was examined in a prospective cohort study of 14,291 New York City women, 35-65 years of age, who received screening for breast cancer at the time of blood sampling and who had not been diagnosed with breast cancer. During the first 5 1/2 years of study, we identified 130 breast cancers among the postmenopausal group (7063 women, 35,509 person-years). The case subjects and twice as many postmenopausal control subjects were included in a case-control study nested within the cohort. Biochemical analyses for percent free estradiol, percent estradiol bound to sex hormone-binding globulin (SHBG), total estradiol, estrone, and follicle-stimulating hormone were performed on sera that had been kept at -80 degrees C since sampling.
For increasing quartiles of total estradiol, the odds ratio (ORs) of breast cancer, as adjusted for Quetelet index (weight in kilograms divided by the square of the height in meters), were 1.0, 0.9, 1.8, and 1.8 (P value for trend = .06); the ORs for increasing quartiles of estrone were 1.0, 2.2, 3.7, and 2.5 (P value for trend = .06). For increasing quartiles of free estradiol, defined as the fraction of estradiol that is not bound to proteins, the Quetelet index-adjusted ORs of breast cancer were 1.0, 1.4, 3.0, and 2.9 (P value for trend < .01). When we considered the percent of estradiol bound to SHBG, the Quetelet index-adjusted ORs were 1.0, 0.70, 0.40, and 0.32 (P value for trend < .01), thus suggesting a strong protective effect. These associations persisted or became even stronger when analyses were restricted to women whose samples had been drawn 2 or more years before breast cancer diagnosis.
These data represent the first confirmation in a large prospective epidemiologic study of a link between circulating estrogens and breast cancer risk. Although estrogen levels appeared to fall within the conventional limits of normality in all women under study, those who subsequently developed breast cancer tended to show higher levels of estrone, total estradiol, and free estradiol, and a lower percent of estradiol bound to SHBG than women who remained free of cancer.
Factors that increase endogenous estrogen production or reduce the binding of estradiol to SHBG may increase a woman's risk of developing breast cancer later in life.
The report differentiates between dermatological and transdermal products, identifies and discusses the principles involved in the development and optimization of topical drug products. The regulatory concerns in the evaluation of topical dermatological products with respect to bioequivalence and quality control are also discussed.
The permeabilities of many steroids through human skin have been previously measured and reported in the literature. Analysis of these data reveals that significant discrepancies exist between the measurements of Scheuplein et al. and those of other groups. Six of the 14 steroids which were examined by Scheuplein et al., aldosterone, corticosterone, estradiol, hydrocortisone, progesterone, and testosterone, have also been examined by other groups. For each of these steroids, the permeability measurements of Scheuplein et al. are lower than those reported by other groups by factors of between 5.0 and 77. Eight independent measurements of the permeability of estradiol are in good agreement with one another, but are greater than the value reported by Scheuplein et al. by factors of between 11 and 20. Several possible sources of experimental error, including the variability of the skin samples, the differences in the experimental temperature, the establishment of steady-state conditions, the use of radiolabeled drugs, and the skin preparation technique, have been considered and do not appear to account for the magnitude of the observed discrepancies nor for the fact that the data of Scheuplein et al. are consistently lower than those reported by other groups.
The bioavailability of estradiol (CAS 50-28-2; E2) from a new "matrix type" estradiol transdermal patch (Dermestril; Test patch) was compared to that of the widely used "liquid-reservoir, membrane-controlled type" transdermal patch (Reference patch) in a two-way randomized cross-over study on 28 healthy postmenopausal women, during a single 4-day application of 2 patches (total content 8 mg E2, total nominal release rate 100 micrograms E2 in 24 h). Evaluated from the AUC0-96h, the extent of bioavailability was practically the same for the two patch types. Conversely the rate of bioavailability was significantly different, because from the Reference patch the release rate is fast in the first 24 h, leading to an E2 peak at 8 h and to a Cmax in average at 23 h. But after the 2nd day the release/absorption rate declines markedly, leading to E2 serum concentrations at the 3rd and 4th days possibly below the effective threshold. From the Test patch the release/absorption rate of E2 is more constant, leading to sustained E2 concentrations during the 4 days of application, with smaller fluctuations than during application of the Reference patch. In conclusion the Test patch can be considered practically bioequivalent to the Reference patch with regard to the extent of absorption, but not with regard to the rate of absorption, because the E2 concentrations in serum are more constant during the application of the Test transdermal patch than during the application of the Reference.
The aim of this study was to investigate the systemic bioavailability and plasma profiles of 17 beta-estradiol (CAS 50-28-2, E2) after the application of two types of matrix patches for the transdermal delivery of E2: MenorestTM (the test patch) with delivery rates of 37.5, 50 and 75 micrograms E2/day and a reference patch with a delivery rate of 50 micrograms E2/day. All 3 test patches were identical in composition, achieving different transdermal E2 delivery rates by variations in the surface area (11.0, 14.5 and 22.5 cm2). All 4 patches were each worn by 24 postmenopausal women over a 4-day period (i.e. 96 h), each of the 4 treatment periods being separated by a 7-day wash-out period according to a randomized, 4-way crossover design. Blood samples were collected before and 3, 6, 9, 12, 24, 34, 48, 58, 72, 84, and 96 h after each patch application. Plasma E2 concentrations were determined by a specific direct radioimmunoassay method. The following pharmacokinetic parameters were evaluated: AUC0-96h; Cmax, tmax, Cmin, Caverage. The course of the E2 plasma levels over the total test period (96 h) was relatively constant for all patches. For the test patch, a linear relationship between the pharmacokinetic parameters and the different patch areas (i.e. dosages of 37.5, 50, 75 micrograms E2/d) could be shown (correlation coefficient 0.99). The resulting Cmax values for the patch were: 44.2, 58.3, and 92.1 pg E2/ml, corresponding to Caverage values of 39.5, 45.5, and 70.6 pg E2/ml. The reference patch and the test patch, at a dose of 50 micrograms E2/d, were similar in terms of Cmax, while the Caverage, AUC0-96h and Cmin were significantly higher with the test patch. The systemic bioavailability of the reference patch was comparable to that of the test patch at a dose of 37.5 micrograms E2/d: AUC0-->96h 3017.5 +/- 1312.4 pg/ml.h for the reference patch and 3375.9 +/- 1254.7 pg/ml.h for the test patch. A physical model for the calculation of the course of the E2 levels was used to describe the experimentally determined data. However, in the evening, periodically higher E2 plasma levels were observed for all patches than in the morning. From these results it can be concluded that E2 plasma profiles produced by the test patch are reproducible, and in the physiological range consistent with the early to mid follicular level in the premenopausal woman over 4 days (96 h), correlating with the doses administered (37.5-50-75 micrograms E2/d). Additionally, the systemic bioavailability of the test patch at a dose of 37.5 micrograms E2/d is comparable to that of the reference patch at a dose of 50 micrograms E2/d.
The continuous infusion of (3)H-6,7-estrone and (3)H-6,7-estradiol has been used to study the metabolic clearance rate (MCR), the interconversions, and the red cell uptake of these steroids in normal males and females. The whole blood MCR of estrone is 1,990 +/- 120 liters per day/m(2) (SE) in males and 1,910 +/- 100 liters per day/m(2) in females. The whole blood MCR of estradiol is 1,600 +/- 80 liters per day/m(2) in males and 1,360 +/- 40 liters per day/m(2) in females. The values in females do not vary significantly when studied in the follicular or luteal phase of the cycle. At least 35% of the total estrone metabolism in both sexes is extrasplanchnic and at least 25% of the total estradiol metabolism in males, and 15% in females is extrasplanchnic. The [rho](BB) (2,1) [transfer constant of estradiol to estrone, which is equivalent to the fraction of the precursor (estradiol) converted to the product (estrone) when both the infusion of the precursor and the measurement of the product are in peripheral blood] is 15%; and the [rho](BB) (1,2) [transfer constant of estrone to estradiol, which is equivalent to the fraction of the precursor (estrone) converted to product (estradiol) when both the infusion of the precusor and the measurement of the product are in peripheral blood] is 5% in both males and females. Our findings concerning the radioactivity in whole blood, as measured by our procedure, were the following: 15-20% of estrone in both sexes and 15% of estradiol in males is associated with red cells. Only 2% of the whole blood radioactivity of estradiol in females is associated with red cells. Changes in the distribution of radioactivity between plasma and red cells will influence the MCR as calculated from plasma, but not as calculated from whole blood.
New delivery systems for hormone replacement therapy
- J S Frazer
Comparative efficacy and tolerability of transdermal Estradiol and conjugated estrogens,-a double blind multi center study
- W L E H Nachtigall
- Utian
Compliance of postmenopausal women under ERT
- S A Campbell
- Crawford
Kinetik eines neuen Pflaters zur transdermalen Applikation von 17-β-Estradiol
- C U D Rohr
- A M Nauert
- Ehrly
In vitro model for intramuscular drug bioavailability I: Can membranes mimic muscle capillary wall permeability
- U G D Schmittmann
- T Rohr
- Kissel
Physical chemical analysis of percutaneous absorption process from creams and ointments
- T Higuchi