Update on the Genetic Polymorphisms of Drug-Metabolizing Enzymes in Antiepileptic Drug Therapy 英文参考文献.docVIP

Pharmaceuticals 2010, 3, 2709-2732; doi:10.3390/ph3082709 OPEN ACCESS pharmaceuticals ISSN 1424-8247 /journal/pharmaceuticals Review Update on the Genetic Polymorphisms of Drug-Metabolizing Enzymes in Antiepileptic Drug Therapy Junji Saruwatari 1, Takateru Ishitsu 2 and Kazuko Nakagawa 1,3,* 1 Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Oe-honmachi 5-1, Kumamoto 862-0973, Japan; E-Mail: junsaru@gpo.kumamoto-u.ac.jp (J.S.) 2 Kumamoto Saishunso National Hospital, Kumamoto, Suya 2659, Koshi, Japan; E-Mail: ishitsu@bf7.so-net.ne.jp (T.I.) 3 Center for Clinical Pharmaceutical Sciences, Kumamoto University, Oe-honmachi 5-1, Kumamoto 862-0973, Japan * Author to whom correspondence should be addressed; E-Mail: kazukon@gpo.kumamoto-u.ac.jp; Tel./Fax: +81-96-371-4545. Received: 31 May 2010; in revised form: 10 August 2010 / Accepted: 17 August 2010 / Published: 20 August 2010 Abstract: Genetic polymorphisms in the genes that encode drug-metabolizing enzymes are implicated in the inter-individual variability in the pharmacokinetics and pharmaco- dynamics of antiepileptic drugs (AEDs). However, the clinical impact of these polymorphisms on AED therapy still remains controversial. The defective alleles of cytochrome P450 (CYP) 2C9 and/or CYP2C19 could affect not only the pharmacokinetics, but also the pharmacodynamics of phenytoin therapy. CYP2C19 deficient genotypes were associated with the higher serum concentration of an active metabolite of clobazam, N-desmethylclobazam, and with the higher clinical efficacy of clobazam therapy than the other CYP2C19 genotypes. The defective alleles of CYP2C9 and/or CYP2C19 were also found to have clinically significant effects on the inter-individual variabilities in the population pharmacokinetics of phenobarbital, valproic acid and zonisamide. EPHX1 polymorphisms may be associated with the pharmacoki