Department of Anesthesiology, Duke University School of Medicine, 905 S. LaSalle St, GSRB1 Room 2031, Box 3094, Durham, NC, 27710, USA.
Bermaride LLC, Durham, NC, 27712, USA.
Clin Pharmacokinet. 2024 Aug;63(8):1121-1135. doi: 10.1007/s40262-024-01406-y. Epub 2024 Jul 29.
Clearances and the area under the plasma concentration-time curve extrapolated to infinity (AUC) of intravenous (IV) and oral midazolam and alfentanil are probes for hepatic and first-pass cytochrome P450 3A (CYP3A) activity, drug interactions, and phenotyping. Single-time plasma concentrations are also used as a proxy for clearance and AUC. Pupil diameter change is a noninvasive surrogate for plasma alfentanil. An ideal probe should have minimal intrasubject (interday) variability. Despite their widespread use, the intrasubject variability of CYP3A probes is not well characterized. This investigation determined the intrasubject (interday) variability of midazolam and alfentanil metrics of hepatic and first-pass CYP3A.
Twelve volunteers were studied in a four-period protocol, with each period identical and separated by approximately 2 weeks. In each period, participants received 1 mg IV midazolam then 15 μg/kg IV alfentanil 1 h later. The next day, they received 3 mg oral midazolam then 60 μg/kg oral alfentanil. Plasma drug concentrations were determined by liquid chromatography-mass spectrometry (LCMS). Dark-adapted pupil diameters were measured coincident with blood sampling. Plasma concentrations and pupil effects (miosis) were analyzed using noncompartmental methods. The results were the coefficient of variation (%CV, mean ± SD) across four sessions in 12 participants.
For IV midazolam: AUC, clearance, and 5 h concentration, the %CVs were 12 ± 3, 12 ± 3, and 18 ± 8. For IV alfentanil AUC, clearance, 2 h concentration, and area under the effect curve from time zero to infinity (AUEC), the %CVs were 16 ± 5, 15 ± 4, 22 ± 7, and 50 ± 28. For oral midazolam AUC, clearance, and 5 h concentration, %CVs were 19 ± 5, 18 ± 4, and 28 ± 11. For oral alfentanil: AUC, clearance, 4 h concentration, and AUEC, %CVs were 20 ± 4, 21 ± 4, 42 ± 26, and 37 ± 14.
Midazolam and alfentanil had comparable intrasubject variabilities of clearance and AUC. Single-time point metrics had greater intrasubject variability than AUC and clearance. Miosis was a surrogate for alfentanil concentrations and provided real-time results, but intrasubject variability was greater than that of clearances and AUC.
静脉（IV）和口服咪达唑仑和阿芬太尼的清除率和血浆浓度-时间曲线下面积外推至无穷大（AUC）以及 AUC 是肝和首次通过细胞色素 P450 3A（CYP3A）活性、药物相互作用和表型的探针。单次血浆浓度也可用作清除率和 AUC 的替代物。瞳孔直径变化是阿芬太尼血浆的非侵入性替代物。理想的探针应该具有最小的个体内（日内）变异性。尽管它们被广泛使用，但 CYP3A 探针的个体内变异性尚未得到很好的描述。本研究旨在确定肝和首次通过 CYP3A 的咪达唑仑和阿芬太尼指标的个体内（日内）变异性。
12 名志愿者按照四期方案进行研究，每个时期相同，间隔约 2 周。在每个时期，参与者先接受 1 毫克 IV 咪达唑仑，然后 1 小时后接受 15 微克/公斤 IV 阿芬太尼。第二天，他们接受 3 毫克口服咪达唑仑，然后接受 60 微克/公斤口服阿芬太尼。通过液相色谱-质谱法（LCMS）测定血浆药物浓度。在采血的同时测量暗适应瞳孔直径。使用非房室分析方法分析血浆浓度和瞳孔效应（缩瞳）。结果是 12 名参与者在 4 个疗程中的变异系数（%CV，平均值±标准差）。
对于 IV 咪达唑仑：AUC、清除率和 5 小时浓度的%CV 分别为 12±3、12±3 和 18±8。对于 IV 阿芬太尼 AUC、清除率、2 小时浓度和从零时到无穷大的效应曲线下面积（AUEC），%CV 分别为 16±5、15±4、22±7 和 50±28。对于口服咪达唑仑 AUC、清除率和 5 小时浓度，%CV 分别为 19±5、18±4 和 28±11。对于口服阿芬太尼：AUC、清除率、4 小时浓度和 AUEC 的%CV 分别为 20±4、21±4、42±26 和 37±14。
咪达唑仑和阿芬太尼的清除率和 AUC 的个体内变异性相当。单点指标的个体内变异性大于 AUC 和清除率。瞳孔缩小是阿芬太尼浓度的替代物，并提供实时结果，但个体内变异性大于清除率和 AUC。
