Foisy Michelle M, Yakiwchuk Erin M, Hughes Christine A
Northern Alberta HIV Program & Regional Pharmacy Services, Capital Health Authority, Edmonton, Alberta, Canada.
Ann Pharmacother. 2008 Jul;42(7):1048-59. doi: 10.1345/aph.1K615. Epub 2008 Jun 24.
To review the literature on the induction effects of ritonavir on the cytochrome P450 enzyme system and glucuronyl transferase and identify resultant established and potential drug interactions.
Primary literature was identified from MEDLINE (1950-April 2008), EMBASE (1988-April 2008) and International Pharmaceutical Abstracts (1970-April 2008) using the search terms ritonavir, cytochrome P450 enzyme system, enzyme induction, glucuronyl transferase, and drug interactions. Additionally, relevant conference abstracts and references of relevant articles were reviewed.
All English-language articles and abstracts identified were reviewed.
Ritonavir is a well-known inhibitor of the metabolism of numerous medications that are substrates of the CYP3A and CYP2D6 pathways. It also exhibits a biphasic, time-dependent effect on P-glycoprotein of inhibition followed by induction. Numerous pharmacokinetic studies suggested that ritonavir induces cytochrome P450 enzymes 3A, 1A2, 2B6, 2C9, and 2C19, as well as glucuronyl transferase. Additionally, several case reports described clinically significant subtherapeutic effects of drugs metabolized by these isoenzymes when coadministered with ritonavir. Both therapeutic and boosting doses of ritonavir appear to induce these enzymes; however, most of the studies of low-dose ritonavir involved a second protease inhibitor such as lopinavir, darunavir, or tipranavir. It is, therefore, difficult to distinguish the relative effects of additional medications unless well-designed, 3-way studies are conducted.
At both therapeutic and boosting doses, ritonavir exhibits a clinically relevant induction effect on numerous drug-metabolizing enzymes. A decrease or loss of therapeutic effect may be observed when ritonavir is coadministered with medications that are substrates for these enzymes. It is important for clinicians to be aware of drugs potentially impacted by ritonavir therapy to identify and manage these interactions.
回顾关于利托那韦对细胞色素P450酶系统和葡糖醛酸转移酶的诱导作用的文献，并确定由此产生的已明确的和潜在的药物相互作用。
使用搜索词“利托那韦”“细胞色素P450酶系统”“酶诱导”“葡糖醛酸转移酶”和“药物相互作用”，从MEDLINE（1950年 - 2008年4月）、EMBASE（1988年 - 2008年4月）和《国际药学文摘》（1970年 - 2008年4月）中检索原始文献。此外，还查阅了相关会议摘要和相关文章的参考文献。
对所有检索到的英文文章和摘要进行了回顾。
利托那韦是众多作为CYP3A和CYP2D6途径底物的药物代谢的知名抑制剂。它对P - 糖蛋白也表现出双相、时间依赖性的作用，先是抑制，随后是诱导。众多药代动力学研究表明，利托那韦可诱导细胞色素P450酶3A、1A2、2B6、2C9和2C19，以及葡糖醛酸转移酶。此外，一些病例报告描述了与利托那韦合用时，由这些同工酶代谢的药物出现临床上显著的治疗效果不足的情况。利托那韦的治疗剂量和增效剂量似乎都能诱导这些酶；然而，大多数关于低剂量利托那韦的研究都涉及第二种蛋白酶抑制剂，如洛匹那韦、达芦那韦或替拉那韦。因此，除非进行精心设计的三方研究，否则很难区分其他药物的相对作用。
在治疗剂量和增效剂量下，利托那韦对多种药物代谢酶均表现出临床相关的诱导作用。当利托那韦与这些酶的底物药物合用时，可能会观察到治疗效果降低或丧失。临床医生了解利托那韦治疗可能影响的药物，以识别和处理这些相互作用非常重要。
