R L Dedrick's research while affiliated with National Institutes of Health and other places
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Publications (170)
Background:
The pyrimidine analogue gemcitabine (2', 2'-difluorodeoxycitidine, dFdC) is active against pancreatic cancer, and its high clearance (CL(tb)) and low incidence of local toxicity make it an excellent candidate for evaluation as intraperitoneal (IP) therapy. We designed a dosing schema that used multiple sequential exchanges of a periton...
This chapter discusses allometry, physiological pharmacokinetics (PK), and the use of in vitro systems to predict drug metabolism in experimental animals and human study participants. Allometric principles are used to answer a variety of questions relevant to the application of preclinical PK data to the design of dose regimens for humans. Allometr...
Sustained-release intravitreal drug implants for posterior segment diseases are associated with significant complications. As an alternative, subconjunctival infusions of drug to the episclera of the back of the eye have been performed, but results in clinical trials for macular diseases showed mixed
To improve understanding of transscleral drug de...
This revised second edition covers the pharmacologic principles underlying the individualization of patient therapy and contemporary drug development, focusing on the fundamentals that underlie the clinical use and contemporary development of pharmaceuticals. Authors drawn from academia, the pharmaceutical industry and government agencies cover the...
In vivo microdialysis relies principally on diffusion as the mechanism for solute exchange between the tissue and the probe perfusate. Mathematical models for describing microdialysis have been formulated based on known concepts of diffusion through tissue and the membranes with which probes are currently constructed. The models predict that the ra...
Rituximab is a monoclonal antibody directed against the CD20 B-cell antigen and is approved for the treatment of B-cell lymphoma. We investigated the pharmacokinetics of rituximab following intravitreal administration to assess the feasibility of treating primary intraocular lymphoma. Intravitreal injections of rituximab 0.1 ml (1 mg) were performe...
The activity of gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter, is reduced in the hippocampus in patients with complex partial seizures from mesial temporal sclerosis. To provide preliminary safety and distribution data on using convection-enhanced delivery of agents to treat complex partial seizures and to test the effic...
Convection-enhanced delivery (CED), the delivery and distribution of drugs by the slow bulk movement of fluid in the extracellular space, allows delivery of therapeutic agents to large volumes of the brain at relatively uniform concentrations. This mode of drug delivery offers great potential for the treatment of many neurological disorders, includ...
Regional delivery of drugs can offer a pharmacokinetic advantage in the treatment of localized tumors. One method of regional delivery is by intra-arterial infusion into the basilar/vertebral artery network that provides local access to infratentorial tumors, which are frequent locations of childhood brain cancers. Proper delivery of drug by infuse...
A finite-element (FE) method is used to numerically solve a pharmacokinetic model that describes the uptake of systemically administered antibody (mAb) in a prevascular spherical tumor nodule embedded in normal tissue. The model incorporates plasma kinetics, transcapillary transport, lymphatic clearance, interstitial diffusion in both the normal ti...
We measured zidovudine concentrations in blood, muscle, and brain extracellular fluid (ECF) by microdialysis and in serum ultrafiltrate and cerebrospinal fluid (CSF) samples during a continuous intravenous infusion (15 mg/kg/h) and after bolus dosing (50-80 mg/kg over 15 min) in nonhuman primates to determine whether CSF drug penetration is a valid...
We have developed a pharmacokinetic model for monoclonal antibodies (mAb) to aid in investigating protocols for targeting small primary tumors or sites of metastatic disease. The model describes the uptake of systemically-administered antibody by a prevascular spherical tumor nodule embedded in normal tissue. The model incorporates plasma kinetics,...
We examine the theoretical basis for calibrating microdialysis probes in vivo for pharmacokinetic experiments in which the extracellular analyte concentrations vary in time.
A software package, MICRODIAL. was used to simulate microdialysis for illustrative transient situations with linear concentration dependence.
For a constant distant extracellul...
The current mortality rate for lung cancer exceeds 85%, as it has for the last 3 decades. This statistic reflects the utility of the major diagnostic tool that has been used during this period to diagnose lung cancer: the chest X-ray. The overwhelming majority of new cases of lung cancer that are detected with chest X-rays involve individuals who a...
Due to physiological barriers within the eye, which limit penetration of many drugs from the systemic circulation into the vitreous, the most common method of treating retinal disease is direct intravitreal injection. However, this common procedure may be inappropriate for a wide range of drugs as it may lead to highly variable concentrations poten...
Purpose:
Our previous work had shown that retinoic acid (RA) inhibits cell growth and induces apoptosis in estrogen receptor-positive (ER-positive) MCF-7 and T-47D human breast carcinoma cells, but not in ER-negative human breast carcinoma cells MB-231 and MB-453. The purpose of this work was to determine whether these differences might be due to...
A wide variety of therapeutic drugs are administered into the peritoneal cavity as a portal of entry to the body and as a localized treatment. Because of intravenous access problems in neonates, transfusion of packed red blood cells was one of the earliest uses of intraperitoneal (i.p.) therapy [1, 2]. Insulin is often placed in the dialysate in or...
Because intraperitoneal (i.p.) therapy may provide a therapeutic advantage and because hyperthermia enhances carboplatin (CBDCA) cytotoxicity, we evaluated the feasibility, toxicity, and pharmacokinetics of CBDCA given via continuous hyperthermic peritoneal perfusion (CHPP) in patients with small-volume residual ovarian cancer. Patients and
Six pat...
Monoclonal antibodies (MAbs), produced for specific tumor antigens, can be linked with radioisotopes or metabolic toxins and administered intraperitoneally (i.p.) to treat metastatic cancer located on the peritoneum. Despite their specific binding properties, these proteins distribute to the serosal surface of all tissues surrounding the cavity in...
Currently, most new lung cancers are found only after symptoms or signs reflect the occurrence of regional or distant metastases. Delayed awareness of lung cancer accounts for its 87% five year mortality rate. New insights may lead to improved methods of early lung cancer detection. Experimental intervention proposed for early cancer management gen...
The goals of this clinical trial of intraventricular 454A12-rRA therapy were to identify dose-limiting toxicities, to evaluate the pharmacokinetics of single-dose intraventricular 454A12-rRA, and to detect antitumor activity.
We performed a pilot study of intraventricular therapy with the immunotoxin 454A12-rRA in eight patients with leptomeningeal...
Measurement of intracellular drug levels in cell culture systems can be of predictive value in establishing rational clinical dosage schedules. Such in vitro measurements carried out with anti-HIV agents of the 2',3'-dideoxynucleoside (ddN) class have shown that many of the pharmacologically active ddNTP metabolites of these agents have relatively...
Both theory and clinical studies demonstrate that drug concentrations in the peritoneal cavity can greatly exceed concentrations in the plasma following intraperitoneal administration. This regional advantage has been associated with clinical activity, including surgically documented complete responses in ovarian cancer patients with persistent or...
Hyperosmolar blood-brain barrier disruption (HBBBD), produced by infusion of mannitol into the cerebral arteries, has been used in the treatment of brain tumors to increase drug delivery to tumor and adjacent brain. However, the efficacy of HBBBD in brain tumor therapy has been controversial. The goal of this study was to measure changes in vascula...
Regional delivery of suitable drugs by intra-arterial infusion may offer a therapeutic advantage. High concentrations in the tumor are sought with reduced systemic toxicity. Adequate mixing of drug solutions with perfusing blood is essential to provide uniform distribution of drug to tumor-bearing tissue distal to the infusion site. Using a glass m...
A technique is described for plasma sampling by continuous membrane plasmapheresis performed on blood flowing through an extracorporeal arteriovenous shunt. The plasmapheresis sampler in the shunt employs replaceable commercial planar membranes 2.5 cm in diameter. Validation tests were conducted for 0.6-micron pore diameter microporous membranes wi...
The origin and magnitude of potential errors in whole-blood sampling are predicted on the basis of a mathematical model. The model describes the kinetics of solute metabolism, breakdown, and interphase distribution (i.e., partitioning and exchange between formed elements and plasma) within a blood sample during sample withdrawal and storage. The mo...
We present a physiological pharmacokinetic model that describes the plasma and cerebrospinal fluid (CSF) concentrations of topotecan [(S)-9-dimethylaminomethyl-10-hydroxyamptothecin hydrochloride, SK&F 104864-A, NSC 609699] following i.v. and intraventricular administrations in monkeys. The model consists of three physical spaces: the CSF, the plas...
Monoclonal antibody (MAb) transport in peritoneal tissue is dominated by convection, which is dependent on the net driving force of i.p. hydrostatic and osmotic pressure. To test the hypothesis that the i.p. osmolality has significant effects on IgG delivery to the tumor during the acute period after injection, solid tumors (FEMX-II) were transplan...
Peritoneal dialysis (PD) is dependent on the transport of water and solutes from the blood capillaries within the tissues that surround the peritoneal cavity. Because of their large blood supply and surface area, the viscera have been considered the most important tissues for PD transport. In animals, however, removal of the gastrointestinal tract...
We have developed a pharmacokinetic model for the analysis of a protocol that involves injection of a biotinylated monoclonal antibody followed at a later time by radiolabeled streptavidin. Three distinct physiological spaces are described: an avascular tumor nodule, the normal tissue surrounding the tumor, and the plasma. The model incorporates pr...
![FIG. 3. Redistribution of "'1In-Tf (A) and [14C]sucrose (B) after...](profile/Richard-Bobo/publication/15065605/figure/fig1/AS:878491125968898@1586460014566/Redistribution-of-1In-Tf-A-and-14Csucrose-B-after-infusion-Artificial-CSF-300_Q320.jpg)
For many compounds (neurotrophic factors, antibodies, growth factors, genetic vectors, enzymes) slow diffusion in the brain severely limits drug distribution and effect after direct drug administration into brain parenchyma. We investigated convection as a means to enhance the distribution of the large and small molecules 111In-labeled transferrin...
High-flow microinfusion provides a means for delivering macromolecules to large volumes of brain in easily obtainable time intervals. Slowly degraded approximately 180-kDa macromolecules, delivered at a constant volumetric flow rate of 3 microliters/min into homogeneous brain tissue (e.g., gray matter), would penetrate to a 1.5-cm radius in 12 h. T...
The concentration profiles of [14C]3'-azido-3'-deoxythymidine (AZT) emanating from an acutely implanted microdialysis probe were measured in rat caudate putamen by quantitative autoradiography for infusions of 14 min and 1 and 2 h. A mathematical model which simulated diffusive solute transport, unaffected by the processes of microvascular exchange...
Two-step imaging and treatment protocols involve injecting a suitably prepared monoclonal antibody that can bind both to a specific tumor antigen and to a second reagent which carries a drug or radionuclide. The second component is injected later, after the antibody has distributed throughout the target tumors and been largely cleared from the plas...
Immunotoxins have been suggested as possible therapeutic agents in patients with leptomeningeal carcinomatosis. The pharmacokinetics, stability, and toxicity of immunotoxins injected into the i.t. space were examined in rats and rhesus monkeys. Monoclonal antibodies specific for the human (454A12 and J1) and rat (OX26) transferrin receptors were co...
The spatial distribution of i.v. administered immunotoxins in s.c. human rhabdomyosarcoma RD2 xenografts was studied. The toxin and immunotoxins were: (a) diphtheria toxin (DT); (b) a binding-deficient form of DT (CRM107) linked to a monoclonal IgG1 antibody (454A12) directed against the human transferrin receptor (454A12-107); (c) the binding-defi...
We describe a physiological pharmacokinetic model for methyl mercury and its metabolite mercuric mercury in the growing rat. Demethylation appears to occur in both host tissues and gastrointestinal flora with elimination dominated by biliary secretion of inorganic mercury and by transport of methyl mercury into the gut lumen followed by substantial...
Hair taken from rats dosed with 203Hg-labeled methylmercury was fed to previously untreated rats in order to determine if the organomercurial was available for release from the hair matrix within the gut lumen and for subsequent systemic absorption. Cumulative fecal excretion data were consistent with an absorption of about 80% of the ingested meth...
Protein transport occurs between the blood and the peritoneal cavity during clinical procedures, but events within the surrounding tissue space are poorly understood. We used quantitative autoradiography to examine the tissue concentration profiles of immunoglobulin G (IgG) in regions surrounding the peritoneal cavity. We have varied the route of a...
Alkylating agents are known to produce second tumors in cancer patients treated for their primary cancer. Since therapeutic doses are high and the pharmacokinetics of the drugs are thoroughly studied, these agents provide a unique opportunity to compare intrinsic carcinogenic potency between experimental animals and humans. We have examined the car...
Spatial solute concentration profiles resulting from in vivo microdialysis were measured in rat caudate-putamen by quantitative autoradiography. Radiolabeled sucrose was included in the dialysate, and the tissue concentration profile measured after infusions of 14 min and 61.5 min in an acute preparation. In addition, the changes in sucrose extract...
Protein transport to and from fluid in the peritoneal cavity is observed during clinical procedures. Dialysate osmolality is a major determinant of net fluid flux into the cavity. We carried out experiments in rats to determine the plasma, peritoneal, and tissue concentrations of immunoglobulin (Ig) G resulting from either intravenous (iv) or intra...
The uptake and binding of monoclonal antibodies (MAbs) in solid tumors after a bolus i.v. injection are described using a compartmental pharmacokinetic model. The model assumes that MAb permeates into tumor unidirectionally from plasma across capillaries and clears from tumor by interstitial fluid flow and that interstitial antibody-antigen interac...
The time-dependent (5 min-72 h) localization of 3 radiolabeled anti-melanoma monoclonal antibodies (MAbs 436, IND1, and 9.2.27) was studied in paired label experiments in small (4-12 mg) s.c. human melanoma xenografts (SK-MEL-2 and M21) in athymic nude mice. MAb 436 recognizes a Mr 125,000 cell surface melanoma-associated glycoprotein antigen (125...
This chapter discusses overall concepts of quantitative microdialysis, including some difficulties of application. The major factors that may influence the proper quantitative use of the microdialysis probe include: (1) microdialysate concentrations obtained in vitro depend strongly on microvascular transport and metabolism in the extracellular spa...
The behavior of a microdialysis probe in vivo is mathematically described. A diffusion-reaction model is developed that not only accounts for transport of substances through tissues and probe membranes but also accounts for transport across the microvasculature and metabolism. Time-dependent equations are presented both for the effluent microdialys...
Intra-arterial carotid artery chemotherapy for malignant gliomas is limited by focal injuries to the eye and brain which may be caused by poor mixing of the drug with blood at the infusion site. This inadequate mixing can be eliminated in animal models with diastole-phased pulsatile infusion (DPPI) which creates 1-ml/sec spurts during the slow bloo...
The delivery of cell-specific protein toxins to the interstitium of solid tumors was examined in athymic mice bearing s.c. human rhabdomyosarcoma (TE671) tumors. The toxins are diphtheria toxin (DT), Mr = 60,000, and an immunotoxin, Mr = 210,000. The immunotoxin is a chemical conjugate of a mutant DT defective in binding and a monoclonal antibody s...
A model was developed to determine whether protein-based chemotherapeutic agents can cross the blood-brain barrier and successfully treat brain tumors. The human small-cell lung carcinoma N417D was grown as a solid tumor in the nude rat brain, and diphtheria toxin (DT) was administered intravenously as therapy. Because rat cells lack functional DT...
A mathematical framework was developed to provide a quantitative basis for either in vivo tissue or in vitro microdialysis. Established physiological and mass transport principles were employed to obtain explicit expressions relating dialysate concentration to tissue extracellular concentration for in vivo applications or external medium concentrat...
A physiological pharmacokinetic model for the disposition of the antineoplastic drug cis-diamminedichloroplatinum(II) (cisplatin or DDP) in several mammalian species is reviewed. The significance of the model's key parameters and of their interspecies relationships is discussed. Methods for estimating two of these parameters (the rate constants for...
The pharmacokinetic theory of intra-arterial drug administration has been clearly articulated. It provides a useful guide
to the development and interpretation of preclinical studies and clinical trials. Despite the clarity and usefulness of the
theory, there are misunderstandings of its implications and technical problems associated with its imple...
Physiologic pharmacokinetic models are a useful interface between exposure models and risk assessment models by providing a means to estimate tissue concentrations of reactive chemical species at the site of action. The models utilize numerous parameters that can be characterized as anatomical, such as body size or tissue volume; physiological, suc...
Focal injury to the brain or retina is a frequent complication of drug delivery to the internal carotid artery (ICA) and may be due to poor mixing of the drug with blood at the infusion site. Rhesus monkeys were studied to determine whether phased drug delivery during diastole from a modified pulsatile angiographic injector would improve drug mixin...
During cancer chemotherapy toxicity to normal tissues often limits the tolerable dose. To increase drug delivery to tumor while maintaining tolerable systemic exposure, regional treatments, such as intraarterial drug delivery, have been used. Despite intraarterial delivery, systemic toxicity often remains the dose-limiting sensitivity. If systemic...
A flow-limited physiologic pharmacokinetic model is presented for the analysis of the distribution and disposition of some polychlorinated biphenyl congeners in several animal species. Analysis of the pharmacokinetic parameters in the model gives insight into congener-to-congener and species-to-species comparisons. For example, the partition coeffi...
Calculation of the pharmacokinetic advantage of regional drug administration requires knowledge of the relevant intercompartment transport parameter. In a lumped model this is the blood (or plasma) flow rate for intra-arterial drug infusion or the permeability-area product for intraperitoneal or intrathecal administration. It is suggested that the...
Techniques have been developed for isolated perfusion of chemotherapeutic agents in patients with glioblastoma. Three catheters that facilitate crossing the carotid siphon have been developed; two are based on an everting or toposcopic principle, and one uses microjets for deflectability and improved mixing. Blood from the ipsilateral jugular vein...
A physiological pharmacokinetic analysis of cis-dichlorodiammineplatinum(II) (DDP) is presented for the rabbit, dog, and human. The results are compared to a previous analysis for the rat. DDP binds irreversibly to low-molecular weight nucleophiles and macromolecules to form mobile and fixed metabolites at rates which are tissue-specific. The rate...
A physiological pharmacokinetic analysis of cis-dichlorodiammineplatinum(II) (DDP) is presented for the rabbit, dog, and human. The results are compared to a previous analysis for the rat. DDP binds irreversibly to low-molecular weight nucleophiles and macromolecules to form mobile and fixed metabolites at rates which are tissue-specific. The rate...
Sporadic instances of retinal damage and of focal brain toxicity have been observed following intracarotid artery infusions of chemotherapeutic agents (such as BCNU and cis-platinum) for the treatment of glioblastomas. The episodic nature of these toxicities is consistent with the possibility that the drug solutions were streaming from the catheter...
Treatment of brain tumors by intra-arterial (IA) chemotherapy is occasionally complicated by sites of focal toxicity in the brain and retina. A possible cause of focal toxicity is non-uniform drug delivery due to intravascular drug streaming. To investigate this phenomenon in vivo , the authors examined the distribution of drug delivery after inter...
Concepts elucidated from preclinical pharmacology studies have made a substantial impact on the clinical use of anticancer drugs. However, the majority of animal pharmacology results have not been available until after drugs have entered clinical trials. Since clinical pharmacokinetic measurements are already part of many phase I trials, human data...
The post-microinfusion transport of cis-diamminedichloroplatinum(II) (cisplatin) in rat brain has been modeled as a linear diffusion-reaction-permeation process. The model has been used to analyze the experimental data of Kroin and Penn to obtain the macromolecular binding constant of cisplatin in the brain, k = 0.0050 +/- 0.0023 min-1, and the cap...
A simplified distributed model of peritoneal solute transport is described, and found to agree with several observations in mammalian species. The model enables prediction of peritoneal transport from measurements of diffusivity in tissue, capillary permeability and capillary surface area.
We have presented data quantifying both the absorption of fluid and solutes from the peritoneal cavity and the effective lymph flow rate of these substances to the blood. Peritoneal loss rate of macromolecules is dependent on IP pressure while the effective lymph flow rate has a much smaller value than the loss rate and is independent of IP pressur...
Four patients with malignant cerebral gliomas received 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) into the internal carotid artery (ICA) while the ipsilateral jugular drainage was pumped extracorporeally through a hemoperfusion cartridge containing a nonionic adsorbant resin. Each patient received 220 mg/sq m BCNU, infused over 45 minutes through...
Circulation of blood in the ipsilateral jugular vein through an extracorporeal circuit for drug removal during intracarotid chemotherapy has recently been reported to decrease the systemic drug exposure. The reduced systemic exposure achieved by the use of this technique should permit a several-fold increase of the intracarotid dose of chemotherapy...
During cancer chemotherapy by intra-arterial drug administration, systemic toxicity often limits the tolerable dose. We evaluated the pharmacokinetic advantage obtained by infusing carmustine (BCNU) into the internal carotid artery during BCNU removal from the blood from the perfused region by hemoperfusion. A hemoperfusion column (XR-010, Extracor...
Peritoneal dialysis transport studies were carried out in anesthetized rats. Injections of [14C]EDTA were made by intravenous bolus or intraperitoneal dialysis solution, and blood and peritoneal fluid samples were collected for 1 h. After death and rapid freezing of the animal, transverse sections through the abdominal cavity were cut for quantitat...
Transport of uncharged, water-soluble substances (ranging in molecular weight from 180 to 5,000) between the fluid in the peritoneal cavity and plasma was studied in anesthetized female Sprague-Dawley rats. In certain experiments the effect of fluid shifts on the transport was observed by manipulating the effective osmotic pressure or the hydrostat...
A physiological model has been developed to describe the disposition of cis-dichlorodiammine-platinum(II) (DDP) following i.v. dosing in the female rat bearing the Walker 256 carcinoma. The model simulates concentrations of DDP and its mobile and fixed metabolites in plasma, liver, gut, skin, muscle, tumor, carcass, and kidney, and DDP and mobile m...
The exchange of fluorescein isothiocyanate-labeled dextrans ranging in weight-averaged molecular weight from 19,400 to 160,000 and 125I-bovine serum albumin (BSA) between dialysis fluid (5% BSA in Krebs-Ringer solution) in the peritoneal cavity and the plasma was studied in anesthetized female Sprague-Dawley rats. Plasma and peritoneal samples were...
Transport experiments of 125I-human serum albumin from the peritoneal cavity to the plasma were conducted in 200-g female rats. Blood and peritoneal samples were collected at intervals over 2-3 h. After death and rapid freezing of the animal, transverse sections were cut in a cryomicrotome from several tissues surrounding the peritoneal cavity, and...
A physiological model has been developed to describe the disposition of cisdichlorodiammine-platinum(II) (DDP) following i.v. dosing in the female rat bearing the Walker 256 carcinoma. The model simulates concentrations of DDP and its mobile and fixed metabolites in plasma, liver, gut, skin, muscle, tumor, carcass, and kidney, and DDP and mobile me...
Physiologic pharmacokinetic analysis of 4,4'-dichlorobiphenyl, 2,2',3,3',6,6'-hexachlorobiphenyl, and 2,2',4,4',5,5'-hexachlorobiphenyl is presented for the dog and monkey, and the results are compared with previous similar analyses for the rat and mouse. The normalized clearances (ml/min/kg body weight) vary considerably between the dog and the mo...
Transport of water-soluble substances between the peritoneal cavity and the plasma was modeled with a distributed approach. The model includes diffusion and convection through tissue as well as membrane transport across blood capillaries, which are assumed to be distributed uniformly in the tissue. Lymphatic uptake via the diaphragm is also include...
The pharmacokinetic advantage of intra-arterial drug administration can be improved if blood from the infused region is perfused through a suitable extracorporeal device. The extent of improvement depends on the blood flow to the device, the fraction of the vascular drainage that can be obtained, and the drug extraction by the device. A relatively...
The pharmacokinetics of PCBs are complicated by numerous factors, not the least of which is the existence of up to 209 different chlorinated biphenyls. Whereas all PCB congeners are highly lipophilic and most are readily absorbed and rapidly distributed to all tissues, PCBs are cleared from tissues at very different rates, and the same congeners ma...
Measurements of drug concentration in cerebrospinal fluid (CSF) provide the most accessible index of drug delivery to the brain. Our perception of the blood-brain barrier has been largely shaped by these measurements. A crucial question for the interpretation of these data is the nature of the relationships between drug concentration in CSF and the...
A flow-limited physiological model was developed to describe the time course of 2,3,7,8-tetrachlorodibenzofuran (TCDF) in the blood and tissues of rats, mice, and monkeys. The liver showed the greatest tendency to concentrate the material with tissue-to-blood distribution coefficients ranging from 30 in the monkey to 130 in the mouse. TCDF was also...
The rate of disappearance of fluorouracil from peritoneal fluid has been experimentally measured and mathematically modeled. The experimental data were obtained following the instillation of 50 ml of dialysis fluid which contained an initial fluorouracil concentration ranging from 24 microM to 12 mM. The rate of disappearance was strongly dependent...