Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
Clin Pharmacol Ther. 2010 Feb;87(2):191-6. doi: 10.1038/clpt.2009.206. Epub 2009 Nov 18.
We aimed to assess the effect of coadministration and withdrawal of a potent cytochrome P450 3A (CYP3A) inhibitor (ritonavir) and a potent CYP3A inducer (St John's wort) on CYP3A enzyme activity in an open, fixed-sequence study design. We investigated the pharmacokinetics of midazolam: (i) at baseline, (ii) after a single dose of either St John's wort or ritonavir (each n = 6), (iii) after 14 days of coadministration of ritonavir (300 mg b.i.d.) and St John's wort (300 mg t.i.d.), and (iv) at 2 days after cessation of both St John's wort and ritonavir. Combined administration of inducer and inhibitor resulted in a predominance of enzyme inhibition: coadministration of St John's wort and ritonavir with intravenous administration of midazolam resulted in an increase in the area under the plasma concentration-time curve (AUC)(0-8 h) of midazolam to 180% of baseline value, whereas with orally administered midazolam, the AUC(0-6 h) increased to 412% of baseline value (P < 0.05 for each). After cessation of the coadministered drugs, the AUC(0-6 h) of orally administered midazolam decreased to 6% of the level observed during combined administration, and the AUC(0-8 h) of intravenously administered midazolam decreased to 33% of the values observed during combined administration (P < 0.001 for each). Induction may be unmasked after the withdrawal of a combination of a potent CYP3A inhibitor and a potent CYP3A inducer, leading to substantial drops in drug exposure of CYP3A substrates. This may require substantial dose adjustments, particularly of orally administered drugs.
我们旨在评估强细胞色素 P450 3A（CYP3A）抑制剂（利托那韦）和强 CYP3A 诱导剂（圣约翰草）联合给药和停药对 CYP3A 酶活性的影响，采用开放、固定序列设计方案。我们研究了咪达唑仑的药代动力学：（i）在基线时，（ii）单次给予圣约翰草或利托那韦时（每组 n = 6），（iii）联合给予利托那韦（300 mg 每日两次）和圣约翰草（300 mg 每日三次） 14 天后，以及（iv）同时停用圣约翰草和利托那韦 2 天后。诱导剂和抑制剂联合给药导致酶抑制为主：联合给予圣约翰草和利托那韦与咪达唑仑静脉给药导致咪达唑仑的血药浓度-时间曲线下面积（AUC）（0-8 h）增加到基线值的 180%，而口服咪达唑仑时，AUC（0-6 h）增加到基线值的 412%（每个 P < 0.05）。停止联合用药后，口服咪达唑仑的 AUC（0-6 h）降至联合用药时观察到的水平的 6%，静脉注射咪达唑仑的 AUC（0-8 h）降至联合用药时观察到的水平的 33%（每个 P < 0.001）。在停用强 CYP3A 抑制剂和强 CYP3A 诱导剂的联合用药后，可能会揭示诱导作用，导致 CYP3A 底物的药物暴露大幅下降。这可能需要进行大量剂量调整，特别是口服药物。
