Kim Kyoung-Ah, Shon Ji-Hong, Park Ji-Young, Yoon Young-Ran, Kim Min-Jung, Yun Doo-Hee, Kim Moon-Kyung, Cha In-June, Hyun Myung-Ho, Shin Jae-Gook
Department of Pharmacology, Inje University College of Medicine and Clinical Pharmacology Center, Pusan Paik Hospital, and the Department of Chemistry, Pusan National University, Pusan, South Korea.
Clin Pharmacol Ther. 2002 Jul;72(1):90-9. doi: 10.1067/mcp.2002.126176.
To evaluate the enantioselective disposition of lansoprazole in relation to the genetic polymorphism of CYP2C19.
A single oral dose of racemic lansoprazole (30 mg) was administered to 6 extensive metabolizers and 6 poor metabolizers whose genotypes were determined by use of polymerase chain reaction-restriction fragment length polymorphism. The pharmacokinetic parameters were estimated from the plasma concentrations of lansoprazole racemate, its enantiomers, and metabolites, which were measured for 24 hours after drug administration. The unbound fraction of lansoprazole enantiomers was determined by means of ultrafiltration of fresh human serum spiked with racemic lansoprazole.
The plasma concentrations of R(+)-lansoprazole were consistently higher than those of the S(-)-enantiomer in both extensive and poor metabolizers of CYP2C19, and the mean area under the plasma concentration-time curve of the (+)- and (-)-enantiomers showed 4.3- and 5.8-fold differences between poor and extensive metabolizers, respectively. The (+)/(-) ratios of lansoprazole clearance were not significantly different between poor and extensive metabolizers (0.19 +/- 0.07 and 0.05 +/- 0.08, respectively). The values for volume of distribution of the (-)-enantiomer were 3- and 10-fold greater, respectively, than those of the (+)-enantiomer in poor and extensive metabolizers, which was related to a 2-fold higher unbound fraction of the (-)-enantiomer.
The effect of CYP2C19 genetic polymorphism on the enantioselective disposition of lansoprazole seems to be less significant than the effect on omeprazole and pantoprazole. The disposition of lansoprazole enantiomers appears to be influenced by enantioselective protein binding and by enantioselective metabolism of lansoprazole.
评估兰索拉唑对映体的处置与CYP2C19基因多态性的关系。
对6名代谢正常者和6名代谢不良者口服单剂量消旋兰索拉唑（30 mg），其基因型通过聚合酶链反应-限制性片段长度多态性方法确定。根据给药后24小时测量的兰索拉唑消旋体、其对映体和代谢物的血浆浓度估算药代动力学参数。通过超滤加入消旋兰索拉唑的新鲜人血清来测定兰索拉唑对映体的游离分数。
在CYP2C19代谢正常者和代谢不良者中，R(+)-兰索拉唑的血浆浓度始终高于S(-)-对映体，(+)-和(-)-对映体的血浆浓度-时间曲线下平均面积在代谢不良者和代谢正常者之间分别显示出4.3倍和5.8倍的差异。兰索拉唑清除率的(+)/(-)比值在代谢不良者和代谢正常者之间无显著差异（分别为0.19±0.07和0.05±0.08）。在代谢不良者和代谢正常者中，(-)-对映体的分布容积值分别比(+)-对映体大3倍和10倍，这与(-)-对映体高2倍的游离分数有关。
CYP2C19基因多态性对兰索拉唑对映体处置的影响似乎比对奥美拉唑和泮托拉唑的影响小。兰索拉唑对映体的处置似乎受对映体选择性蛋白结合和兰索拉唑对映体选择性代谢的影响。
