Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: Noninvasive assessment by use of pupillary miosis
Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: Noninvasive assessment by use of pupillary miosis
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DOI：
10.1016/j.clpt.2004.07.006
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发表时间：
2004-11-01
影响因子：
6.7
通讯作者：
Sheffels, P
中科院分区：
文献类型：
--
作者：
Kharasch, ED;Walker, A;Sheffels, P
简介：静脉（IV）阿芬太尼（ALF）的全身清除率是肝细胞色素P450（CYP）3A活性的体内探针，瞳孔缩小是血浆ALF浓度的替代物，IV ALF瞳孔缩小是肝CYP 3A的无创探针。本研究表征了口服ALF的生物利用度和首过代谢，并检验了以下假设：（1）首过ALF清除率反映首过CYP 3A活性，（2）口服ALF后瞳孔缩小将反映肠道和肝脏CYP 3A活性，和（3）瞳孔缩小可以近似IV和口服ALF的基于血浆浓度的药代动力学测量，作为肝脏和第一-通过CYP 3A活性和药物相互作用。结果与咪达唑仑（MDZ），一种替代CYP 3A探针。在给予利福平（INN，利福平）（肝和肠CYP 3A诱导）、三乙酰竹桃霉素（TAO）（肝和肠CYP 3A抑制）、葡萄柚汁（选择性肠CYP 3A抑制）或不给药（对照）后，采用随机、9向、交叉设计对10名志愿者进行了研究。对于每种情况，他们接受1 mg IV MDZ，然后15 μ g/kg IV ALF，以及3 mg口服MDZ，然后在另一天口服ALF（23或60 μ g/kg）。通过液相色谱-质谱法测定血浆浓度。暗适应瞳孔直径与血液采样同时测量。ALF效应的分析与浓度相似，以产生“清除”效应。（剂量/瞳孔直径变化对时间曲线下的面积）。生物利用度（F-口服）、肝提取物（E-H）和肠利用度（F-G）分别为0.26 +/- 0.08、0.52 +/- 0.09和0.56 +/- 0.20，MDZ和ALF分别为0.42 +/- 0.15、0.28 +/- 0.09和0.56 +/- 0.18。口服清除率（CL/F）分别为34.7 +/- 12.8和10.9 +/- 3.5 mL（.）kg（-1.）min（-1）。利福平、TAO和葡萄柚汁后，ALF F-口服为0.04 +/- 0.02（P < .05，与对照组相比），0.99 +/- 0.18（P <0.05，与对照组相比）和0.62 +/- 0.18（P <0.05，与对照组相比）; E-H为0.69 +/- 0.14（P < .05，与对照组相比），0.04 +/- 0.01（P <0.05，与对照组相比）和0.26 ± 0.08; F-G为0.16 +/- 0.10（P < .05，与对照组相比），1.0 +/- 0.2（P < .05，与对照组相比），以及0.85 +/- 0.30（P <0.05，与对照组相比）; CL/F为339 ± 233（P <0.05，与对照组相比），0.62 +/- 0.26（P <0.05，与对照组相比）和6.7 +/- 2.5（与对照组相比，P < .05），效应清除率为2.1 +/- 1.1 0.087 +/- 0.056（P <0.05，相对于对照）和0.54 +/- 0.30（0.73 +/- 0.43 mg（.）mm（-1.）h（-1）。ALF与MDZ的全身清除率（r（2）= 0.92）、E-H（r（2）= 0.93）和CL/F（r（2）= 0.97）以及口服ALF效应（缩瞳）清除率与口服清除率（r（2）= 0.59）之间存在显著相关性。ALF和MDZ具有相似的肠提取，但分别具有低和中等的肝提取。ALF的全身和口服清除率是肝脏和首过CYP 3A活性和药物相互作用的极好体内探针。瞳孔缩小是血浆ALF的可接受替代物。ALF缩瞳可能是一个合适的非侵入性体内探针肝和首过CYP 3A。
Introduction: Systemic clearance of intravenous (IV) alfentanil (ALF) is an in vivo probe for hepatic cytochrome P450 (CYP) 3A activity, miosis is a surrogate for plasma ALF concentrations, and IV ALF miosis is a noninvasive probe for hepatic CYP3A. This investigation characterized the bioavailability and first-pass metabolism of oral ALF and tested the hypotheses that (1) first-pass ALF clearance reflects first-pass CYP3A activity, (2) miosis after oral ALF will reflect intestinal and hepatic CYP3A activity, and (3) miosis can approximate plasma concentration-based pharmacokinetic measures for IV and oral ALF as a noninvasive in vivo probe for hepatic and first-pass CYP3A activity and drug interactions. Results were compared with those for midazolam (MDZ), an alternative CYP3A probe.Methods. Ten volunteers were studied by use of a randomized, 9-way, crossover design after administration of rifampin (INN, rifampicin) (hepatic and intestinal CYP3A induction), troleandomycin (TAO) (hepatic and intestinal CYP3A inhibition), grapefruit juice (selective intestine CYP3A inhibition), or nothing (control). For each condition, they received 1 mg IV MDZ and then 15 mug/kg IV ALF, as well as 3 mg oral MDZ and then oral ALF (23 or 60 mug/kg) on another day. Plasma concentrations were determined by liquid chromatography-mass spectrometry. Dark-adapted pupil diameters were measured coincident with blood sampling. ALF effect was analyzed similarly to concentration to yield an effect "clearance" (Dose/Area under the pupil diameter change versus time curve).Results: Bioavailability (F-oral), hepatic extraction (E-H), and intestinal availability (F-G) were 0.26 +/- 0.08, 0.52 +/- 0.09, and 0.56 +/- 0.20, respectively, for MDZ and 0.42 +/- 0.15, 0.28 +/- 0.09, and 0.56 +/- 0.18, respectively, for ALF. Oral clearance (CL/F) was 34.7 +/- 12.8 and 10.9 +/- 3.5 mL(.)kg(-1.)min(-1), respectively, for MDZ and ALF. After rifampin, TAO, and grapefruit juice, ALF F-oral was 0.04 +/- 0.02 (P < .05, versus control), 0.99 +/- 0.18 (P < .05, versus control), and 0.62 +/- 0.18 (P < .05, versus control), respectively; E-H was 0.69 +/- 0.14 (P < .05, versus control), 0.04 +/- 0.01 (P < .05, versus control), and 0.26 +/- 0.08, respectively; F-G was 0.16 +/- 0.10 (P < .05, versus control), 1.0 +/- 0.2 (P < .05, versus control), and 0.85 +/- 0.30 (P < .05, versus control), respectively; CL/F was 339 +/- 233 (P < .05, versus control), 0.62 +/- 0.26 (P < .05, versus control), and 6.7 +/- 2.5 (P < .05, versus control), respectively, and effect clearance was 2.1 +/- 1.1 (P < .05, versus control), 0.087 +/- 0.056 (P < .05, versus control), and 0.54 +/- 0.30 (0.73 +/- 0.43 mg(.)mm(-1.)h(-1) in controls), respectively. There were significant correlations between ALF and MDZ systemic clearances (r(2) = 0.92), E-H (r(2) = 0.93), and CL/F (r(2) = 0.97), as well as between oral ALF effect (miosis) clearance and oral clearance (r(2) = 0.59).Conclusions. ALF and MDZ have similar intestinal extraction but low and intermediate hepatic extraction, respectively. Systemic and oral clearances of ALF are excellent in vivo probes for hepatic and first-pass CYP3A activities and drug interactions. Miosis was an acceptable surrogate for plasma ALF. ALF miosis may be a suitable noninvasive in vivo probe for both hepatic and first-pass CYP3A.