The clinical impact of cytochrome P450 polymorphisms on anti-epileptic drug therapy
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概要
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The goal of pharmacogenetics is to deliver safe and effective drug therapy. Genetic polymorphisms in cytochrome P450 (CYP) enzyme genes are implicated in the inter-individual variability in pharmacokinetics of anti-epileptic drugs (AEDs). However, the clinical impact of CYP polymorphisms on AED therapy remains controversial. Previous studies have shown that the defective CYP2C9 alleles affect the required dose of phenytoin and the risk of its toxicity. We have reported that the CYP2C19-deficient genotype is associated with the serum concentration of an active metabolite of clobazam, N-desmethylclobazam, and with the clinical efficacy of clobazam therapy. We determined also the influence of polymorphisms in CYP genes on the population pharmacokinetic parameters of AEDs using a non-linear mixed effect modeling program, which enables us to define relevant genetic factors together with other factors, and the magnitude of the effect on variation in pharmacokinetics in patients. The defective alleles of CYP2C9 and CYP2C19 were found to have significant effects on the inter-individual differences in clearance of phenobarbital and zonisamide, respectively. Based on these recent findings, we discuss the clinical significance of AED dose adjustment according to both genetic and non-genetic factors that affect CYP activity.
著者
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Yoshida Shuichi
Department of Neuropsychiatry, Hirosaki University Graduate School of Medicine
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Kaneko Sunao
Department Of Neuropsychiatry Hirosaki University
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Yoshida Shuichi
Department Of Neuropsychiatory Hirosaki University Graduate School Of Medicine
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Kaneko Sunao
Department of Neuropsychiatry, Hirosaki University Graduate School of Medicine
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Saruwatari Junji
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University
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Ishitsu Takateru
Kumamoto Saishunso National Hospital
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Seo Takayuki
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University
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Shimomasuda Masatsugu
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University
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Okada Yusuke
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University
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Goto Shuji
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University
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Nagata Rie
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University
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Takashima Ayaka
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University
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Yoshida Shiho
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University
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Yasui-Furukori Norio
Department of Neuropsychiatry, Hirosaki University Graduate School of Medicine
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Nakagawa Kazuko
Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University
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