Effect of chronic administration of ritonavir on function of cytochrome P450 3A and P-glycoprotein in rats
Effect of chronic administration of ritonavir on function of cytochrome P450 3A and P-glycoprotein in rats
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DOI：
10.1248/bpb.28.130
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发表时间：
2005-01-01
影响因子：
2
通讯作者：
Takada, K
中科院分区：
文献类型：
--
作者：
Kageyama, M;Namiki, H;Takada, K
众所周知，利托那韦(ritonavir，RTV)是许多药物的抑制剂，这些药物由细胞色素P450(CYP)3A代谢或通过P-糖蛋白(Pgp)代谢，但也有报道称RTV是它们的有效诱导剂。为了阐明这些矛盾现象，本研究观察了大鼠慢性服用RTV过程中细胞色素P3A和前列腺素P蛋白的功能变化。在RTV预处理指定的天数后(第3天~第14天)，用大鼠进行实验。大鼠口服RTV(20 mg/kg)后，血药浓度-时间曲线下面积(AUC(0-无穷))随RTV治疗时间的延长而减少，第14天RTV的平均AUC(0-无穷大)较对照组显著降低57%。静脉注射后的AUC(0-无穷大)与对照组相比，给药第3天和第5天的大鼠分别增加了28%和22%，而第7天和第14天的AUC(0-无穷大)没有显著变化。至于静脉注射。给RTV组大鼠注射红霉素(EM)或咪达唑仑(MDZ)后，第3天和第5天的AUC(0-无穷大)较对照组显著增加，而第7天和利福平处理组的EM(0-无穷大)的AUC分别比对照组降低82%和42%。对于MDZ，第7天或第14天大鼠的AUC(0-无穷大)没有显著变化。静脉注射后。给予罗丹明123(Rho123)后，第14天大鼠从血液循环到肠腔的排泄清除量和胆道排泄清除量分别比对照组显著增加2.2倍和2.6倍。现已证实，RTV不仅是细胞色素P3A的有效抑制因子，也是细胞色素P3A的有效诱导剂，是肠道PGP的有效诱导剂。RTV的这一特性负责调节由CYP3A和PGP介导的药物的口服生物利用度。
Ritonavir (RTV) is well known as an inhibitor of many drugs that are metabolized by cytochrome P450 (CYP) 3A or fluxed via P-glycoprotein (Pgp), although it is also reported that RTV is a potent inducer for them. In this study, to elucidate these contradictory phenomena, functional changes of CYP3A or Pgp during chronic administration of RTV were examined in rats. After pretreatment with RTV for indicated days (day 3-day 14), rats were used in the experiments. The area under the plasma drug concentration vs. time curve (AUC(0-infinity)) after oral administration of RTV (20 mg/kg) to these rats showed an RTV-treatment period-dependent decrease, and the mean AUC(0-infinity) of RTV in Day 14 rats decreased significantly by 57% as compared to the control. The AUC(0-infinity) after intravenous (i.v.) administration of RTV to Day 3 and Day 5 rats increased significantly by 28% and 22%, respectively, while there were no significant changes in the AUC(0-infinity) in Day 7 and Day 14 rats as compared to the control. As for i.v. administration of erythromycin (EM) or midazolam (MDZ) to RTV-treated rats, the AUC(0-infinity) in Day 3 and Day 5 rats increased significantly as compared to the control, while in Day 7 rats and rifampicin-treated rats, the AUC(0-infinity) of EM decreased significantly by 82% and 42%, respectively, as compared to the control. For MDZ, there were no significant changes in the AUC(0-infinity) in Day 7 or Day 14 rats. After i.v. administration of rhodamine123 (Rho123), the excretion clearances from blood circulation to the intestinal lumen and the biliary excretion clearances in Day 14 rats increased markedly by 2.2-fold and 2.6-fold as compared to the control. It has been confirmed that RTV is not only a potent inhibitor but also a potent inducer of CYP3A, and that RTV is a potent inducer of intestinal Pgp. This property of RTV is responsible for regulating the oral bioavailability of drugs that are mediated by CYP3A and Pgp.