Influence of CYP2C19 Polymorphism and Concomitant Antiepileptic Drugs on Serum Clobazam and N-Desmethyl Clobazam Concentrations in Patients With Epilepsy
| Autor: | Yukiko Mogami, Tokito Yamaguchi, Katsumi Imai, Kiyohito Terada, Kazumi Matsuda, Rumiko Takayama, Yoshiyuki Kagawa, Yoshiaki Yamamoto, Risa Kasai, Kou Miyakawa, Yushi Inoue, Hiroko Ikeda, Yukitoshi Takahashi, Shigeko Nishimura |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Male Drug Clobazam Adolescent media_common.quotation_subject CYP2C19 Pharmacology Sensitivity and Specificity Benzodiazepines Young Adult Epilepsy Asian People Japan Humans Medicine Drug Interactions Pharmacology (medical) In patient Active metabolite media_common Polymorphism Genetic Dose-Response Relationship Drug business.industry Desmethyl medicine.disease Cytochrome P-450 CYP2C19 Phenotype Concomitant Regression Analysis Anticonvulsants Female Aryl Hydrocarbon Hydroxylases business medicine.drug |
| Zdroj: | Therapeutic Drug Monitoring. 35:305-312 |
| ISSN: | 0163-4356 |
| Popis: | The aims of this study were to identify the factors influencing the metabolism of clobazam (CLB) and its active metabolite [N-desmethyl clobazam (NCLB)] and to evaluate the NCLB concentration as an indicator for CYP2C19 polymorphism in epileptic patients.A total of 302 serum samples from 238 Japanese patients were evaluated. The ratios of the serum CLB and NCLB concentrations to the CLB dose (CD ratios) were calculated and compared with CYP2C19 phenotypes.The mean CD ratio of NCLB in extensive metabolizers (EM: *1/*1), intermediate metabolizers (IM: *1/*2 or *1/*3), and poor metabolizers (PM: *2/*2, *3/*3, or *2/*3) was 3.1, 4.9, and 21.6 (μg/mL)/(mg/kg), respectively. In the EM and IM groups, the concomitant use of hepatic enzyme inducers (phenytoin and carbamazepine) reduced the CD ratio of CLB and increased that of NCLB. In the PM group, these inducers also decreased the CD ratio for CLB but did not elevate the CD ratio for NCLB. Using multiple regression analysis, body weight showed a positive correlation with an increased CD ratio for NCLB. The concomitant use of zonisamide and stiripentol also elevated the CD ratio for NCLB in the EM and IM groups, but that of the PM group was almost unchanged. When the cut-off value of the CD ratio for NCLB was set as 10.0 (μg/mL)/(mg/kg) for predicting the CYP2C19 PM status, the sensitivity and specificity were 94.4% and 95.7%, respectively.The interaction between NCLB and other antiepileptic drugs showed marked differences among CYP2C19 phenotypes. Measurement of the serum NCLB concentration is clinically useful for identifying the PM phenotype. |
| Databáze: | OpenAIRE |
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