Circadian variation of Valproic acid pharmacokinetics in mice

https://doi.org/10.1016/j.ejps.2013.05.009Get rights and content

Abstract

Valproic acid (VPA) is currently one of the most commonly used antiepileptic drugs. This study aims to investigate whether VPA pharmacokinetics varied according to circadian dosing-time. A single dose of VPA (350 mg kg−1) was administered by intraperitonally (i.p.) route to a total of 132 mice synchronized for 3 weeks to 12 h light (rest span) and 12 h dark (activity span). Four different circadian times (1, 7, 13 and 19 HALO) of drug injection were used (33 mice/circadian time). At each circadian time, blood samples were withdrawn at (0 h) and at 0.083, 0.166, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2 and 3 h after VPA injection. Plasma VPA concentrations were determined by an EMIT method.

There were no significant differences in Tmax of VPA whatever the circadian-time of injections (Tmax = 0.166 h). However, there were relevant differences in Cmax between the four circadian groups (p < 0.005), it varied between 386 ± 30.86 mg L−1 in mice treated at 7 HALO and 824 ± 39.85 mg L−1 in mice treated at 19 HALO. The AUC0–∞ was significantly two times higher when VPA was administered at 19 HALO as compared to the injection at 7 HALO. Drug dosing at 7 HALO resulted in highest ClT value: 0.405 ± 0.006 L h−1 kg−1, whereas ClT was significantly slower when VPA was administered at 19 HALO (0.157 ± 0.009 L h−1 kg−1) (p < 0.0001). The AUC0–∞ was significantly 2-fold higher when VPA was administered at 19 HALO (2216.65 ± 138.91 mg h−1 L−1) as compared to the injection at 7 HALO (864.09 ± 16.82 mg h−1 L−1) (p < 0.0001).

Cosinor analysis showed circadian rhythm in different pharmacokinetic parameters. Cmax and AUC0–∞ have a significant circadian rhythm with an acrophase located at 20.16 HALO ± 0.16 h (the middle of the active span) (p < 0.001), whereas ClT and Vd showed a significant circadian rhythm with an acrophase located respectively at 7.86 HALO ± 0.57 h and 6.13 HALO ± 0.07 h (the middle of the rest span) (p < 0.001).

The large circadian variation of VPA pharmacokinetic processes might be involved in the mechanisms of circadian rhythm in murine toxicity since the optimal tolerance corresponded to the time which induces lowest Cmax and AUC values.

Introduction

Circadian rhythms are an inherent property of living systems and constitute an essential part of their internal and external temporal order (Reinberg, 1992). The appearance of reproducible and stable circadian rhythms of high amplitude, and with a characteristic phasing with respect to other biological processes and the external environment, is believed to guarantee an optimal functioning of the biological system, with maximum efficiency, performance and welfare (Smolensky and D’Alonzo, 1993). In mammals, daily rhythms in behavior and physiology are regulated by the circadian timing system, which includes a master pacemaker in the suprachiasmatic nuclei (SCN) (Liu et al., 1997).

Chronopharmacology is the study of the influences of biological rhythms on medications and the effect of medications on biological rhythms (Lemmer, 1996). The term “chronopharmacokinetic” refers to administration time-dependent differences in the absorption, distribution, metabolism, and elimination of chemical agents due to rhythms in biological functions and processes (Bélanger, 1993, Bruguerolle and Lemmer, 1993). The safety of many drugs varies depending on dosing time associated with 24 h rhythms of biochemical, physiological and behavioral processes under the control of the circadian clock (Lemmer, 1995). The results of numerous investigations indicate that the pharmacokinetics and/or the effects of various drugs vary, sometimes markedly, as a function of the time of the day when they are administered, and a number of drugs have been shown to exhibit significant variations in their pharmacokinetics with respect to the biological time of administration (Bélanger, 1993). The kinetics circadian variations could be due to parallel changes in the physiological functions and variables involved in the distribution, metabolism and excretion of the drug. The factors influencing drug distribution in a specified species are blood flow to various organs, binding of the drug to plasma proteins and membrane permeability to the drug (Bélanger, 1993, Bruguerolle and Lemmer, 1993, Bruguerolle, 1998).

Chronotherapy based on experimental chronopharmacological investigations has been applied in the treatment of a number of diseases, e.g. cancer, asthma and cardiovascular disorders (Lévi, 2000). Currently, Valproic acid (VPA) is the most commonly used antiepileptic drug in the treatment of generalized epilepsy, and it is also effective in partial epilepsy. It is a short-chained branched fatty acid and its structure differs from all other clinically used antiepileptic drugs since it has no cyclic compounds (Walton and Treiman, 1992, Perucca, 2002). VPA mechanism of action is probably due to a combination of several effects in the central nervous system because of its wide spectrum of activity against different types of seizures (Walton and Treiman, 1992, Peterson and Naunton, 2005). During the last decades, VPA has also shown its effectiveness in several other neurological and psychiatric disorders (Nalivaeva et al., 2009). VPA is rapidly and completely absorbed since it has a pKa of 4.7; it is highly ionized at the blood pH. VPA is extensively metabolized in the liver. These biotransformations depend on the enzymatic activity of the hepatocytes which undergoes temporal changes too (Bolaños and Medina, 1997, Perucca, 2002).

The objective of this study was to investigate the time-dependent pharmacokinetic changes of VPA after an intraperitoneal (i.p.) administration of a 350 mg kg−1 dose at four circadian times 1, 7, 13 and 19 HALO using mice as an animal model.

Section snippets

Animals and synchronization

A total of 132 ten-week-old male Swiss albino mice (SIPHAT, Tunisia) were used in this study. All mice were synchronized for at least 3 weeks prior to the beginning of experiments. During this period, the animals were entrained in two air-conditioned rooms specially designed for chronobiological investigations under a lighting regimen consisting of an alternation of 12 h of light (L) and 12 h of darkness (D) (LD 12:12). The light–dark cycle regime was inversed between the 2 rooms (Room 1: L from

Mice synchronization

The rectal temperature was used as a marker of circadian synchronization of animals. In this study, a circadian rhythm in rectal temperature (computed for the combined data of the different HALO groups) was validated by the cosinor analysis on day 1 (p < 0.0001). The acrophase of this 24 h rhythm occurred as usual at the mid-half of the dark-activity span (Ø = 18.6 HALO ± 0.3 h). The characteristics of the 24 h pattern in rectal temperature confirmed the physiological entrainment of mice to the

Discussion

Circadian rhythms affect the time-dependent therapeutic efficacy and toxicity of drugs by influencing both the pharmacokinetics and pharmacodynamics (Smolensky and D’Alonzo, 1993). Knowledge of drug chronopharmacokinetics may be clinically relevant since it may have implications in drug prescription by modulating the distribution of the total daily dose along the 24-h’ scale (Lemmer and Bruguerolle, 1994, Lemmer, 1996, Lévi, 2000).

Optimizing drug dosing-time has been suggested to be an

Competing interests

The authors declare that they have no competing interests.

Acknowledgments

The authors would like to thank Mr. Adel Rdissi for proof reading this article.

This work was supported by “Le ministère de l Enseignement Supérieur et de la Recherche Scientifique”.

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