Lee SeungHwan, Kim Bo-Hyung, Nam Won-Seok, Yoon Seo Hyun, Cho Joo-Youn, Shin Sang-Goo, Jang In-Jin, Yu Kyung-Sang
Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
J Clin Pharmacol. 2012 Feb;52(2):195-203. doi: 10.1177/0091270010395510.
The current study assessed the influence of the CYP2C19 genotype on the pharmacokinetics and tolerability of voriconazole after single and multiple oral doses in healthy volunteers. Six subjects for the CYP2C19 homozygous extensive metabolizer (EMs), 6 for heterozygous extensive metabolizer (HEMs), and 6 for poor metabolizer (PMs) were enrolled, and their CYP2C9, CYP3A5, and MDR1 genotypes were analyzed. After a single intravenous infusion or single and multiple oral doses of 200 mg of voriconazole, plasma concentrations of voriconazole were measured. Bioavailability was not significantly different among the CYP2C19 genotypes. Voriconazole exposure in PMs was approximately 3 times higher compared with EMs after a single intravenous or oral dose. At steady state, the plasma concentration just before the next dosing and area under the concentration-time curve from dosing to the time point of the next dosing for PMs were about 5 times and 3 times higher than EMs, respectively. These results suggest that the CYP2C19 genotype is the major determinant of the wide PK variability of voriconazole.
本研究评估了CYP2C19基因型对伏立康唑在健康志愿者单次及多次口服给药后的药代动力学和耐受性的影响。纳入了6名CYP2C19纯合子广泛代谢者（EMs）、6名杂合子广泛代谢者（HEMs）和6名慢代谢者（PMs），并分析了他们的CYP2C9、CYP3A5和MDR1基因型。在单次静脉输注或单次及多次口服200 mg伏立康唑后，测定伏立康唑的血浆浓度。CYP2C19各基因型间的生物利用度无显著差异。单次静脉或口服给药后，PMs中伏立康唑的暴露量比EMs高约3倍。在稳态时，PMs在下一次给药前的血浆浓度以及从给药到下一次给药时间点的浓度-时间曲线下面积分别比EMs高约5倍和3倍。这些结果表明，CYP2C19基因型是伏立康唑药代动力学广泛变异的主要决定因素。
