Miura Masatomo, Tada Hitoshi, Yasui-Furukori Norio, Uno Tsukasa, Sugawara Kazunobu, Tateishi Tomonori, Suzuki Toshio
Department of Pharmacy, Akita University Hospital, Akita, Japan.
Chirality. 2005 Jun;17(6):338-44. doi: 10.1002/chir.20159.
The aim of this study was to examine the effect of clarithromycin, a CYP3A4 inhibitor, on the enantioselective disposition of lansoprazole among three different CYP2C19 genotype groups in healthy Japanese subjects. These subjects included 6 each of homozygous extensive metabolizers (homEMs), heterozygous extensive metabolizers (hetEMs), and poor metabolizers (PMs). In the EMs of CYP2C19, clarithromycin markedly increased Cmax and the AUC0-infinity of (S)-lansoprazole and (S)-hydroxylansoprazole compared with those of the corresponding (R)-enantiomers. Clarithromycin significantly increased Cmax and the AUC0-infinity of (S)-lansoprazole in the homEMs by 110% and 115%, respectively, and in the hetEMs by 105% and 103%, respectively, compared with placebo. Furthermore, clarithromycin slightly prolonged the elimination half-life of (R)-lansoprazole in the homEMs and hetEMs but did not alter that of (S)-lansoprazole. In the of PMs CYP2C19, clarithromycin significantly increased Cmax and the AUC0-infinity and significantly prolonged the elimination half-lives of (R)- and (S)-lansoprazole by 51% and 49%, respectively. The present study suggests that there are significant drug interactions between (R)- or (S)-lansoprazole and clarithromycin in EMs by inhibiting the CYP3A4-catalyzed sulfoxidation primarily during the first pass, whereas in PMs, the overall metabolism of lansoprazole is inhibited.
本研究的目的是在健康日本受试者的三个不同CYP2C19基因型组中，考察CYP3A4抑制剂克拉霉素对兰索拉唑对映体选择性处置的影响。这些受试者包括6名纯合子广泛代谢者（homEMs）、6名杂合子广泛代谢者（hetEMs）和6名慢代谢者（PMs）。在CYP2C19的广泛代谢者中，与相应的（R）-对映体相比，克拉霉素显著增加了（S）-兰索拉唑和（S）-羟基兰索拉唑的Cmax和AUC0至无穷大。与安慰剂相比，克拉霉素使纯合子广泛代谢者中（S）-兰索拉唑的Cmax和AUC0至无穷大分别显著增加110%和115%，使杂合子广泛代谢者中（S）-兰索拉唑的Cmax和AUC0至无穷大分别显著增加105%和103%。此外，克拉霉素使纯合子广泛代谢者和杂合子广泛代谢者中（R）-兰索拉唑的消除半衰期略有延长，但未改变（S）-兰索拉唑的消除半衰期。在CYP2C19的慢代谢者中，克拉霉素显著增加了Cmax和AUC0至无穷大，并使（R）-和（S）-兰索拉唑的消除半衰期分别显著延长51%和49%。本研究表明，在广泛代谢者中，（R）-或（S）-兰索拉唑与克拉霉素之间存在显著的药物相互作用，主要是在首过效应期间抑制CYP3A4催化的硫氧化作用，而在慢代谢者中，兰索拉唑的整体代谢受到抑制。
