Tacrolimus oral bioavailability doubles with coadministration of ketoconazole
Tacrolimus oral bioavailability doubles with coadministration of ketoconazole
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DOI：
10.1016/s0009-9236(97)90150-8
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发表时间：
1997-07-01
影响因子：
6.7
通讯作者：
Hebert, MF
中科院分区：
文献类型：
--
作者：
Floren, LC;Bekersky, I;Hebert, MF
目的：定量酮康唑（一种唑类抗真菌剂和CYP 3A 4和P-糖蛋白的强效抑制剂）对他克莫司（CYP 3A系统和P-糖蛋白的底物）生物利用度的影响。本文研究了他克莫司在6名健康志愿者体内的药代动力学（2名女性和4名男性）在一项四剂量研究中，（口服0.1 mg/kg和静脉注射0.025 mg/kg）和联合给药酮康唑（睡前口服200 mg，持续12天）。在酮康唑治疗阶段减少他克莫司的剂量（口服0.04 mg/kg;静脉注射0.01 mg/kg）。酮康唑和他克莫司给药间隔约10小时，全血他克莫司浓度通过酶联免疫吸附测定法测定。全血中估计的药代动力学参数使用非房室模型技术计算酮康唑治疗前和治疗后的平均值（平均值+/- SD）。与酮康唑同时给药不会持续影响他克莫司的清除率（55.6 +/- 16.7 ml/hr/kg vs 42.5 +/- 7.6 ml/hr/kg），稳态分布容积不变（0.99 +/- 0.26 L/kg vs 0.93 +/- 0.25 L/kg）。然而，与酮康唑联合给药时，他克莫司的生物利用度显著增加（14% +/- 5% vs 30% +/- 8%; P < 0.01）。肝脏生物利用度未因酮康唑的存在而改变（96% +/- 1%对97% +/- 1%）。因为酮康唑没有改变肝脏的生物利用度，而且因为药物的给药时间间隔为10小时，他克莫司生物利用度的显著增加似乎可以解释为酮康唑对他克莫司肠道代谢或肠道P-糖蛋白活性
Objective: To quantitate the effect of ketoconazole, an azole antifungal agent and potent inhibitor of CYP3A4 and P-glycoprotein, on the bioavailability of tacrolimus, a substrate of the CYP3A system and of P-glycoprotein.Subjects and Methods, The pharmacokinetics of tacrolimus were studied in six healthy volunteers (two women and four men) in a four-dose study after each received single doses of tacrolimus alone (0.1 mg/kg orally and 0.025 mg/kg intravenously) and with coadministered ketoconazole (200 mg orally at bedtime for 12 days). The dose of tacrolimus was reduced during the ketoconazole phase (0.04 mg/kg orally; 0.01 mg/kg intravenously). Ketoconazole and tacrolimus doses were separated by approximately 10 hours, Whole blood tacrolimus concentrations were determined by enzyme-linked immunosorbent assay. Estimated pharmacokinetic parameters in whole blood (mean +/- SD) before and with ketoconazole were calculated with noncompartmental techniques.Results: Coadministration of ketoconazole did not consistently affect tacrolimus clearance (55.6 +/- 16.7 ml/hr/kg versus 42.5 +/- 7.6 ml/hr/kg), and steady-state volume of distribution was unchanged (0.99 +/- 0.26 L/kg versus 0.93 +/- 0.25 L/kg). However, a significant increase in tacrolimus bioavailability (14% +/- 5% versus 30% +/- 8%; P < 0.01) was observed with coadministered ketoconazole. Hepatic bioavailability was unchanged by the presence of ketoconazole (96% +/- 1% versus 97% +/- 1%).Conclusions: Because ketoconazole did not alter hepatic bioavailability and because 10 hours separated administration times of the drugs, it appears that the marked increase in tacrolimus bioavailability can be explained by ketoconazole having a local inhibitory effect on tacrolimus gut metabolism or on intestinal P-glycoprotein activity.