Fihlman Mari, Hemmilä Tuija, Hagelberg Nora M, Backman Janne T, Laitila Jouko, Laine Kari, Neuvonen Pertti J, Olkkola Klaus T, Saari Teijo I
Department of Anaesthesiology and Intensive Care, University of Turku, P.O. Box 52, Kiinamyllynkatu 4-8, FI-20520, Turku, Finland.
Division of Perioperative Services, Intensive Care and Pain Medicine, Turku University Hospital, Turku, Finland.
Eur J Clin Pharmacol. 2018 Dec;74(12):1615-1622. doi: 10.1007/s00228-018-2548-8. Epub 2018 Aug 30.
Buprenorphine has low oral bioavailability. Regardless of sublingual administration, a notable part of buprenorphine is exposed to extensive first-pass metabolism by the cytochrome P450 (CYP) 3A4. As drug interaction studies with buprenorphine are limited, we wanted to investigate the effect of voriconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics and pharmacodynamics of oral buprenorphine.
Twelve healthy volunteers were given either placebo or voriconazole (orally, 400 mg twice on day 1 and 200 mg twice on days 2-5) for 5 days in a randomized, cross-over study. On day 5, they ingested 0.2 mg (3.6 mg during placebo phase) oral buprenorphine. We measured plasma and urine concentrations of buprenorphine and norbuprenorphine and monitored their pharmacological effects. Pharmacokinetic parameters were normalized for a buprenorphine dose of 1.0 mg.
Voriconazole greatly increased the mean area under the plasma concentration-time curve (AUC) of buprenorphine (4.3-fold, P < 0.001), its peak concentration (C) (3.9-fold), half-life (P < 0.05), and excretion into urine (A; P < 0.001). Voriconazole also markedly enhanced the C (P < 0.001), AUC (P < 0.001), and A (P < 0.05) of unconjugated norbuprenorphine but decreased its renal clearance (P < 0.001). Mild dizziness and nausea occurred during both study phases.
Voriconazole greatly increases exposure to oral buprenorphine, mainly by inhibiting intestinal and liver CYP3A4. Effect on some transporters may explain elevated norbuprenorphine concentrations. Although oral buprenorphine is not commonly used, this interaction may become relevant in patients receiving sublingual buprenorphine together with voriconazole or other CYP3A4 or transporter inhibitors.
丁丙诺啡口服生物利用度低。无论舌下给药与否，丁丙诺啡的很大一部分都会受到细胞色素P450（CYP）3A4广泛的首过代谢作用。由于与丁丙诺啡的药物相互作用研究有限，我们想研究强效CYP3A4抑制剂伏立康唑对口服丁丙诺啡药代动力学和药效学的影响。
在一项随机交叉研究中，12名健康志愿者接受安慰剂或伏立康唑（第1天口服400mg，每日2次；第2-5天口服200mg，每日2次），持续5天。在第5天，他们服用0.2mg（安慰剂阶段服用3.6mg）口服丁丙诺啡。我们测量了丁丙诺啡和去甲丁丙诺啡的血浆和尿液浓度，并监测了它们的药理作用。药代动力学参数针对1.0mg的丁丙诺啡剂量进行了标准化。
伏立康唑显著增加了丁丙诺啡的血浆浓度-时间曲线下平均面积（AUC）（4.3倍，P<0.001）、其峰值浓度（C）（3.9倍）、半衰期（P<0.05）以及尿液排泄量（A；P<0.001）。伏立康唑还显著提高了游离去甲丁丙诺啡的C（P<0.001）、AUC（P<0.001）和A（P<0.05），但降低了其肾脏清除率（P<0.001）。两个研究阶段均出现轻度头晕和恶心。
伏立康唑主要通过抑制肠道和肝脏的CYP3A4，大大增加了口服丁丙诺啡的暴露量。对某些转运体的影响可能解释了去甲丁丙诺啡浓度的升高。虽然口服丁丙诺啡并不常用，但这种相互作用在同时接受舌下丁丙诺啡和伏立康唑或其他CYP3A4或转运体抑制剂的患者中可能具有相关性。
