Chronopharmacokinetics: Implications for Drug Treatment

Institut für Pharmakologie & Toxikologie, Ruprecht-Karls-Universität Heidelberg, Fakultät für Klinische Medizin, Mannheim, Germany.
Journal of Pharmacy and Pharmacology (Impact Factor: 2.26). 09/1999; 51(8):887-90. DOI: 10.1211/0022357991773294
Source: PubMed


Nearly all functions of the human body are organized across the 24 hours of the day. This is also true for functions involved in the regulation of pharmacokinetics such as gastric absorption and emptying, gastro-intestinal perfusion, and liver and kidney functions. Several clinical studies, performed in a cross-over design, have provided evidence that the pharmacokinetics of mainly lipophilic drugs can be circadian phase-dependent. These studies show that after oral dosing, peak drug concentration (Cmax) is, in general, higher or time-to-peak (tmax) shorter after morning, compared with evening application. A few studies performed with both immediate-release and sustained-release preparations (isosorbide-5-mononitrate, nifedipine) gave evidence that only the immediate-release formulation displayed circadian time-dependent pharmacokinetics, but not the sustained-release form. Most importantly, pharmacodynamic studies performed in parallel revealed that the effects, as well as the dose-response relationship, can be circadian phase-dependent, an observation which has an impact on pharmacokinetic/pharmacodynamic modelling. Moreover, this can be of relevance because the onset of certain diseases (e.g., bronchial asthma, coronary infarction, angina pectoris, rheumatic complaints) is not randomly distributed across the 24-h scale. In conclusion, there is now convincing evidence that the time-of-day has to be taken into account both in clinical pharmacokinetic and pharmacodynamic studies.

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Available from: Björn Lemmer, Jul 26, 2015
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    • "Chronotherapeutics refers to a clinical practice of synchronizing drug delivery in a manner consistent with the body's circadian rhythm including disease states to produce maximum health benefit and minimum harmful effects. Particular rhythms in the onset and extent of symptoms were observed in diseases such as, bronchial asthma, myocardial infarction, angina pectoris, rheumatic disease, ulcer, diabetes, attention deficit syndrome, hypercholesterolemia, and hypertension (Lemmer, 1999). All these acted as a push for the development of pulsatile drug delivery systems. "
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    ABSTRACT: Pulsatile drug delivery of enalapril maleate is one such system that, by delivering drug at the right time, right place and in right amounts, holds good promises of benefit to the patients suffering from hypertension. The basic design involves the preparation of cross linked hard gelatin capsules using formaldehyde. Then the drug diluent mixtures were prepared and loaded which was separated by using hydrogel plug of polymers of different grades such as HPMC 50 cps, HPMC 100 cps, HPMC K4M, HPMC K15M, HPMC K100M, xanthan gum, carbopol 971 and sodium CMC at different amount (100 and 120 mg). Prepared formulations were subjected to evaluation of various physical parameters and in vitro drug release studies. Dissolution tests were performed using the USP type I basket method at 50 rpm in 6.8 phosphate buffer. From the in vitro dissolution studies it was found that by increasing the amount of polymers, release rate was decreased. Here, 100 mg of HPMC K100M showed 80% drug release in 8 hours whereas 120 mg showed 78.87% drug release in 10 hours. Similar decrease in the release rates were found with the increase of other polymers used in this study. The release data was fitted to various mathematical models such as zero order, first order, Higuchi, Korsmeyer Peppas and Hixson Crowell cube root law. The drug release follows mixed order kinetics and mechanism was found to be non-Fickian diffusion.
    Full-text · Article · Jan 2015
    • "Pulsatile drug release may be an optimal approach for the treatment of several diseases including bronchial asthma, hypertension, rheumatic disease, and myocardial infarction as well for controlling the body functions like blood pressure and hormonal levels influenced by circadian rhythms.[123] Pulsatile release may also be a useful tool for the targeting the drugs that irritate the stomach or degrades in gastric environment as well for drugs developing biological tolerance or undergoes first-pass metabolism extensively.[12] Such pulsatile drug delivery systems (DDS) are either single unit or multiparticulate systems characterized by a rapid drug release after a predetermined lag time.[3] "
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    ABSTRACT: Alginates can be tailored chemically to improve solubility, physicochemical, and biological properties and its complexation with metal ion is useful for controlling the drug release. Synthesized N,O-dimethyl, N-methyl, or N-Benzyl hydroxylamine derivatives of sodium alginate were subsequently complexed with zinc to form beads. Hydroxamation of sodium alginate was confirmed by Fourier transform infra-red spectroscopy (FTIR) and differential scanning calorimetry (DSC). The synthesized polymeric material exhibited reduced aqueous, HCl and NaOH solubility. The hydroxamated derivatives demonstrated pulsed release where change in pH of the dissolution medium stimulated the atenolol release. Atenolol loaded Zn cross-linked polymeric beads demonstrated the sustained the plasma drug levels with increased half-life. Although the synthesized derivatives greatly altered the aqueous solubility of sodium alginate, no significant differences in in vitro and in vivo atenolol release behavior amongst the N,O-dimethyl, N-methyl, or N-Benzyl hydroxylamine derivatives of sodium alginate were observed.
    No preview · Article · Mar 2013
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    • "The CTS also controls main pathways responsible for drug pharmacokinetics and modifies absorption, distribution, metabolism, and elimination (and toxicity)—ADME(T)—of drugs during the 24 h. It is well documented that the pharmacokinetic profiles of many drugs may vary depending upon their administration time, and circadian changes in metabolic activities appear to be its major cause (Bruguerolle, 2008; Lemmer, 1999; Lévi et al., 2000, 2010). Studies on rats and mice involving drug metabolism revealed a higher metabolic activity during the night period (Belanger et al., 1997; Furukawa et al., 1999; Gachon et al., 2006; Martin et al., 2003). "
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    ABSTRACT: The circadian timing system (CTS) governs the 24-h rhythm of the organism and, hence, also main pathways responsible for drug pharmacokinetics. P-glycoprotein (P-gp) is a drug transporter that plays a pivotal role in drug absorption, distribution, and elimination, and temporal changes in its activity may affect input, output, activity, and toxicity profile of drugs. In the current study, the influence of different circadian stages on the overall intestinal permeability (Peff) of the P-gp substrates talinolol and losartan was evaluated in in situ intestinal perfusion studies in rats. Additionally, in vivo studies in rats were performed by employing the P-gp probe talinolol during the day (nonactive) and night (active) period in rats. Effective intestinal permeabilities of talinolol and losartan were smaller in studies performed during the night (p<.05), indicating that P-gpdependent intestinal secretion is greater during the nighttime activity span than daytime rest span of the animals. P-gp modulators vinblastine and PSC833 led to a significant decrease of talinolol and losartan exsorption in the intestinal segments as compared with control groups. Strikingly, the permeability-enhancing effect of vinblastine and PSC833 was higher with night perfusions, for both talinolol and losartan. In vivo studies performed with talinolol revealedconsistent with the in situ studies (Peff day>night)a day vs. night difference in the oral availability of talinolol in the group of male rats in terms of the area under the curve (AUC) data (AUCday>AUCnight). The P-gp modulator vinblastine significantly increased talinolol AUCday (p<.05), whereas only a weak vinblastine effect was seen in night. According to the in situ data, the functional activity of P-gp was regulated by the CTS in jejunum and ileum, which are major intestinal segments for energy-dependent efflux. In conclusion, circadian rhythms may affect carrier-mediated active efflux and play a role in the absorption process. In addition to daily rhythms in P-gp activity in rat intestine, the in vivo studies indicate that absorption-, distribution-, metabolism-, and elimination-relevant rhythms may be involved in the circadian kinetics of the drug, besides transporter-dependent efflux, such well-known aspects as metabolic or renal clearance or motility. Since this also holds true for a potentially interacting second compound (modulator), modulator effects should be evaluated carefully in transporter related drug-drug interactions. (Author correspondence: [email protected] /* */)
    Full-text · Article · Apr 2012 · Chronobiology International
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