洛匹那韦/利托那韦可诱导细胞色素P450酶CYP2C9、CYP2C19和CYP1A2的肝脏活性，但在健康志愿者中，通过表型药物鸡尾酒检测发现，它会抑制CYP3A的肝脏和肠道活性。
Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers.
作者信息
Yeh Rosa F, Gaver Vincent E, Patterson Kristine B, Rezk Naser L, Baxter-Meheux Faustina, Blake Michael J, Eron Joseph J, Klein Cheri E, Rublein John C, Kashuba Angela D M
机构信息
School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA.
出版信息
J Acquir Immune Defic Syndr. 2006 May;42(1):52-60. doi: 10.1097/01.qai.0000219774.20174.64.
OBJECTIVE
The effect of lopinavir/ritonavir (LPV/r) administration on cytochrome P450 (CYP) enzyme activity was quantified using a phenotyping biomarker cocktail. Changes in CYP2C9, CYP2C19, CYP3A, CYP1A2, N-acetyltransferase-2 (NAT-2), and xanthine oxidase (XO) activities were evaluated using warfarin (WARF) + vitamin K, omeprazole (OMP), intravenous (IV) and oral (PO) midazolam (MDZ), and caffeine (CAF).
DESIGN
: Open-label, multiple-dose, pharmacokinetic study in healthy volunteers.
METHODS
Subjects (n = 14) simultaneously received PO WARF 10 mg, vitamin K 10 mg, OMP 40 mg, CAF 2 mg/kg, and IV MDZ 0.025 mg/kg on days (D) 1 and 14, and PO MDZ 5 mg on D2 and D15. LPV/r (400/100 mg twice daily) was administered on D4-17. CYP2C9 and CYP2C19 activities were quantified by S-WARF AUC0-inf and OMP/5-hydroxy OMP ratio, respectively. CYP1A2, NAT-2, and XO activities were quantified by urinary CAF metabolite ratios. Hepatic and intestinal + hepatic CYP3A activities were quantified by IV (CL) and PO (CL/F) MDZ clearance, respectively.
RESULTS
After LPV/r therapy, CYP2C9, CYP2C19, and CYP1A2 activity increased by 29%, 100%, and 43% (P = 0.001, 0.046, and 0.001), respectively. No changes were seen in NAT-2 or XO activity. Hepatic and intestinal + hepatic CYP3A activity decreased by 77% (P < 0.001) and 92% (P = 0.001), respectively.
CONCLUSION
LPV/r therapy results in modest induction of CYP1A2 and CYP2C9 and potent induction of CYP2C19 activity. Increasing doses of concomitant medications metabolized by these enzymes may be necessary. LPV/r inhibited intestinal CYP3A to a greater extent than hepatic CYP3A activity. Doses of concomitant CYP3A substrates should be reduced when combined with LPV/r, although intravenously administered compounds may require less of a relative dose reduction than orally administered compounds.
目的
使用表型生物标志物混合物定量测定洛匹那韦/利托那韦（LPV/r）给药对细胞色素P450（CYP）酶活性的影响。使用华法林（WARF）+维生素K、奥美拉唑（OMP）、静脉注射（IV）和口服（PO）咪达唑仑（MDZ）以及咖啡因（CAF）评估CYP2C9、CYP2C19、CYP3A、CYP1A2、N-乙酰转移酶-2（NAT-2）和黄嘌呤氧化酶（XO）活性的变化。
设计
在健康志愿者中进行的开放标签、多剂量药代动力学研究。
方法
受试者（n = 14）在第1天和第14天同时接受口服WARF 10 mg、维生素K 10 mg、OMP 40 mg、CAF 2 mg/kg以及静脉注射MDZ 0.025 mg/kg，并在第2天和第15天接受口服MDZ 5 mg。在第4至17天给予LPV/r（400/100 mg，每日两次）。CYP2C9和CYP2C19活性分别通过S-WARF AUC0-inf和OMP/5-羟基OMP比值进行定量。CYP1A2、NAT-2和XO活性通过尿CAF代谢物比值进行定量。肝脏和肠道+肝脏CYP3A活性分别通过静脉注射（CL）和口服（CL/F）MDZ清除率进行定量。
结果
LPV/r治疗后，CYP2C9、CYP2C19和CYP1A2活性分别增加了29%、100%和43%（P = 0.001、0.046和0.001）。NAT-2或XO活性未见变化。肝脏和肠道+肝脏CYP3A活性分别降低了77%（P < 0.001）和92%（P = 0.001）。
结论
LPV/r治疗导致CYP1A2和CYP2C9适度诱导以及CYP2C19活性强力诱导。可能需要增加由这些酶代谢的伴随药物剂量。LPV/r对肠道CYP3A的抑制作用比对肝脏CYP3A活性的抑制作用更大。与LPV/r联合使用时，CYP3A底物的剂量应降低，尽管静脉注射化合物可能比口服化合物需要相对较少的剂量降低。
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