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目的研究克拉霉素对兰索拉唑及其代谢产物5-羟基兰索拉唑和兰索拉唑砜药动学特征的影响。方法 24只大鼠随机分为4组,分别十二指肠给予兰索拉唑(8 mg·kg~(-1))+生理盐水、兰索拉唑(8 mg·kg~(-1))+酮康唑(5 mg·kg~(-1))、兰索拉唑(8 mg·kg~(-1))+反苯环丙胺(5 mg·kg~(-1))、兰索拉唑(8 mg·kg~(-1))+克拉霉素(8 mg·kg~(-1))。于给药后不同时间点采集血样,用LC-MS/MS法测定药物浓度。通过对兰索拉唑及5-羟基兰索拉唑和兰索拉唑砜血药浓度的测定,计算大鼠体内药动学参数。以5-羟基兰索拉唑、兰索拉唑砜与兰索拉唑AUC_(0→4h)的比值分别作为原药经CYP2C19和CYP3A4代谢程度的指标,研究克拉霉素对兰索拉唑代谢的影响。结果克拉霉素显著增加兰索拉唑的AUC_(0→4h)、MRT和t_(1/2),显著降低其CLz。克拉霉素显著降低兰索拉唑砜与兰索拉唑AUC_(0→4h)的比值,从0.63±0.17降至0.15±0.09(P<0.05),兰索拉唑砜的ρ_(max)显著降低,MRT和t_(1/2)显著延长。克拉霉素对5-羟基兰索拉唑的药动学参数无明显影响。结论克拉霉素在大鼠体内对兰索拉唑CYP3A4主导的磺化代谢抑制作用明显,可明显增加兰索拉唑的生物利用度,对临床治疗消化性溃疡有积极意义。
Objective To investigate the effect of clarithromycin on the pharmacokinetics of lansoprazole and its metabolites 5-hydroxy-lansoprazole and lansoprazole-sulfone. Methods Twenty - four rats were randomly divided into 4 groups: lansoprazole (8 mg · kg -1) + normal saline, lansoprazole (8 mg · kg -1) ) And ketoconazole (5 mg · kg -1), lansoprazole (8 mg · kg -1) and tranylcypromine (5 mg · kg -1) Sorazole (8 mg · kg -1) + clarithromycin (8 mg · kg -1). Blood samples were collected at different time points after administration, and the drug concentration was determined by LC-MS / MS. Pharmacokinetic parameters in rats were calculated by measuring the plasma concentrations of lansoprazole, 5-hydroxylan lansoprazole and lansoprazole sulfone. The ratio of 5-hydroxy-lansoprazole, lansoprazole-sulfone and lansoprazole AUC_ (0 → 4h) was used as an indicator of the metabolism of CYP2C19 and CYP3A4 in clarithromycin to study the effects of clarithromycin on the metabolism of lansoprazole Impact. Results Clarithromycin significantly increased the AUC_ (0 → 4h), MRT and t_ (1/2) of lansoprazole, and significantly decreased its CLz. Clarithromycin significantly decreased the ratio of lansoprazole sulfone to lansoprazole AUC_ (0 → 4h) from 0.63 ± 0.17 to 0.15 ± 0.09 (P <0.05), and the ρ max of lansoprazole sulfone was significant Decreased, MRT and t_ (1/2) significantly prolonged. The clarithromycin had no significant effect on the pharmacokinetic parameters of 5-hydroxy-lansoprazole. Conclusion Clarithromycin inhibits the sulfonation metabolism of lansoprazole CYP3A4 significantly in rats, which can significantly increase the bioavailability of lansoprazole and has a positive effect on the treatment of peptic ulcer.