Influence of stress and dexamethasone on plasma levels of antiepileptic drugs and theophylline in rats
Abstract
Elevation of plasma glucocorticoids (GCs) during stress and GCs treatment in different diseases can modify the liver enzymes activity, biotransformation and the effectiveness simultaneously used medications. Recently the effect of GCs, especially of dexamethasone (DEX) – a synthetic GCs receptor agonist on cytochrome P450 enzymes was described. The aim of the present study was to investigate whether the pharmacokinetc of the selected antiepileptic drugs: phenytoin (PHT), vaproate magnesium (VPL), phenobarbital (PB) or theophylline (THEO) could be modified in the rats subjected to acute or chronic stress, and in those treated with DEX, too. All drugs were injected at a single dose 48 h or 1 h after the last stress session of the chronic unpredictable stress (a variant of Katz et al.). Acute stress was an electric footshock. 1 h later all drugs were injected. Additionally, an experiment was conducted on the rats that were first treated with DEX at a single dose and then 3 h later with all drugs. The control group of animals was treated with drugs alone. 30 (VLP and THEO), 60 (PB) or 120 min (PHT) later, the blood of rats was taken to estimate the level of drugs by immunofluorescence. In the rats subjected to chronic and acute stress and also after DEX treated a decrease of the free plasma levels of PHT and VPL was observed. The total plasma level of THEO was significantly decreased in rats with only acute stress or treated with DEX. However, the free plasma level of PB was significantly increased in rats injected with DEX. These date obviously indicate that each kind of stress as well as GCs (e.g. DEX) may change the metabolism of drugs and it should be taken into consideration during pharmacotherapy.
References
1. Coe Ch. L., Lubach G. R.: Developmental consequences of antenatal dexamethasone treatment in nonhuman primates. Neurosci. Biobehav. Rev., 29, 227, 2005.
2. Iber H., Sewer M. B. et al.: Modulation of drug metabolism in infectious and inflammatory diseases. Drug. Metab. Rev., 31, 29, 1999.
3. Katz R. J., Roth K. A., Caroll B. J.: Acute and chronic stress effect of open field activity in the rat: Implication for a model of depression. Neurosci. Biobehav. Rev., 5, 247, 1981.
4. Kouronakis P. N., Rekka E.: Induction of drug metabolism can be a homeostatic response. Arch. Pharm. (Weinheim), 324, 161, 1991.
5. Liddle Ch., Goodwin B.J. et al.: Separate and interactive regulation of cytochrome P450 3A4 by triiodothyronine, dexamethasone, and growth hormone in cultured hepatocytes. J. Clin. Endocrinol. Metab., 83, 7, 24411, 1998.
6. Shaw P. M., Adesnik M. et al.: The phenobarbital-induced transcriptional activation of cytochrome P-450 genes blocked by the glucocorticoid-progesterone antagonist RU486. Mol. Pharmacol., 44, 775, 1993.
7. Soga Y., Nishimura F. et al.: CYP2C polymorphisms, phenytoin metabolism and gingival overgrowth in epileptic subjects. Life Sci., 74, 827, 2004.
8. Tong V., Chang T. K. H. et al.: The effect of valproic acid on hepatic and plasma levels of 15-F2t-isoprostane in rats. Free Radical Biol. Med., 34, 1435, 2003.
9. Volk B., Meyer R. P. et al.: Localization and characterization of cytochrome P450 in the brain. In vivo and in vitro investigations on phenytoin- and phenobarbital-inducible isoforms. Toxicol. Lett., 82/83, 655, 1995.
10. Watkins P. B., Murray S. A. et al.: Erythromycin breath test as an assay of glucocorticoid-inducible liver cytochromes P-450. J. Clin. Invest., 83, 688, 1989.
11. Watkins P. B., Wrighton S. A. et al.: Identification of an inducible form of cytochrome P-450 in human liver. Proc. Natl Acad Sci USA, 82, 6310, 1985.
12. Wrigton S. A., Schuetz E. G. et al.: Demonstration in multiple species of inducible hepatic cytochromes P-450 and their mRNAs related to the glucocorticoid-inducible cytochrome P-450 of the rat. Mol. Pharmacol., 28, 312, 1985.
13. Żebrowska-Łupina I., Ossowska G., Klenk-Majewska B.: Chronic stress reduces fighting behavior of rats: The effect of antidepressants. Pharmacol. Biochem. Behav., 39, 293, 1991.
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