Kodaira Chise, Sugimoto Mitsushige, Nishino Masafumi, Yamade Mihoko, Shirai Naohito, Uchida Shinya, Ikuma Mutsuhiro, Yamada Shizuo, Watanabe Hiroshi, Hishida Akira, Furuta Takahisa
First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Eur J Clin Pharmacol. 2009 Jun;65(6):593-600. doi: 10.1007/s00228-009-0625-8. Epub 2009 Feb 24.
The effect of multidrug resistance transporter gene 1 (MDR1) on the bioavailability and kinetics of several substrates has not yet been fully elucidated. We evaluated the influence of MDR1 C3435T polymorphism on the pharmacokinetics and pharmacodynamics of lansoprazole in Japanese subjects.
Fifteen healthy volunteers with the rapid extensive metabolizer genotype of CYP2C19 were classified into three MDR1 C3435T genotype groups: C/C (n = 5), C/T (n = 5), and T/T (n = 5). Lansoprazole 30 mg was administered orally for 15 days. The intragastric pH and plasma lansoprazole levels were determined on days 1 and 15.
On day 1, the mean C(max) of lansoprazole in the T/T group was significantly higher than that in the C/C or C/T groups (T/T 1,248, C/C 618, C/T 607 ng/ml; P = 0.038). On day 15, similar MDR1 genotype-dependent differences were observed in the C(max) of lansoprazole, although smaller than the differences observed on day 1. In contrast, the intragastric pH attained after lansoprazole administration did not differ among MDR1 genotype groups on either day 1 or day 15.
Although the sample size was small, our study demonstrated that the MDR1 C3435T polymorphism influenced the pharmacokinetics, but not the pharmacodynamics (i.e., intragastric pH), of lansoprazole in rapid metabolizers of CYP2C19.
多药耐药转运蛋白基因1（MDR1）对几种底物的生物利用度和动力学的影响尚未完全阐明。我们评估了MDR1 C3435T基因多态性对日本受试者中兰索拉唑药代动力学和药效学的影响。
15名具有CYP2C19快速广泛代谢基因型的健康志愿者被分为三个MDR1 C3435T基因型组：C/C（n = 5）、C/T（n = 5）和T/T（n = 5）。口服兰索拉唑30 mg，持续15天。在第1天和第15天测定胃内pH值和血浆兰索拉唑水平。
在第1天，T/T组兰索拉唑的平均C(max)显著高于C/C或C/T组（T/T 1248、C/C 618、C/T 607 ng/ml；P = 0.038）。在第15天，兰索拉唑的C(max)中观察到类似的MDR1基因型依赖性差异，尽管比第1天观察到的差异小。相比之下，在第1天和第15天，兰索拉唑给药后达到的胃内pH值在MDR1基因型组之间没有差异。
尽管样本量较小，但我们的研究表明，MDR1 C3435T基因多态性影响了CYP2C19快速代谢者中兰索拉唑的药代动力学，但不影响其药效学（即胃内pH值）。
