Kharasch Evan D, Whittington Dale, Hoffer Christine
Department of Anesthesiology, University of Washington, Seattle, Washington 98195, USA.
Anesthesiology. 2004 Sep;101(3):729-37. doi: 10.1097/00000542-200409000-00022.
Oral transmucosal fentanyl citrate (OTF) was developed to provide rapid analgesia and is specifically approved for treating breakthrough cancer pain. Fentanyl in OTF is absorbed across the oral mucosa, but a considerable portion is swallowed and absorbed enterally. Fentanyl metabolism is catalyzed by cytochrome P4503A4 (CYP3A). The role of intestinal or hepatic first-pass metabolism and CYP3A activity in OTF disposition is unknown. This investigation examined the influence of hepatic and intestinal CYP3A activity on the disposition and clinical effects of OTF.
Healthy volunteers (n = 12) were studied in an Institutional Review Board-approved, randomized, balanced, four-way crossover. They received OTF (10 microg/kg) after hepatic/intestinal CYP3A induction by rifampin, hepatic/intestinal CYP3A inhibition by troleandomycin, selective intestinal CYP3A inhibition by grapefruit juice, or nothing (control). Plasma fentanyl and norfentanyl concentrations were determined by mass spectrometry. Fentanyl effects were measured by dark-adapted pupil diameter and subjective self-assessments using visual analog scales.
: Peak plasma fentanyl concentrations, time to peak, and maximum pupil diameter change from baseline were unchanged after rifampin, troleandomycin, and grapefruit juice. Fentanyl elimination, however, was significantly affected by CYP3A alterations. After control, rifampin, troleandomycin and grapefruit juice, respectively, area under the curve of plasma fentanyl versus time was 5.9 +/- 3.7, 2.2 +/- 0.8,* 10.4 +/- 8.9,* and 5.8 +/- 3.3 h x ng/ml; norfentanyl/fentanyl plasma area under the curve ratios were 0.92 +/- 0.63, 3.2 +/- 1.8,* 0.08 +/- 0.14,* and 0.67 +/- 0.33 (*P < 0.05 versus control).
Peak fentanyl concentrations and clinical effects after OTF were minimally affected by altering both intestinal and hepatic CYP3A activity, whereas fentanyl metabolism, elimination, and duration of effects were significantly affected; selective intestinal CYP3A inhibition had minimal effects. This suggests that first-pass metabolism minimally influences OTF bioavailability. When treating breakthrough pain, with careful attention to maximal mucosal absorption and minimal swallowing, CYP3A variability and drug interactions are unlikely to affect the onset or magnitude of OTF analgesia; however, duration may be affected.
口腔黏膜芬太尼枸橼酸盐（OTF）被研发用于提供快速镇痛，且专门获批用于治疗癌症突破性疼痛。OTF中的芬太尼通过口腔黏膜吸收，但相当一部分会被吞咽并经肠道吸收。芬太尼的代谢由细胞色素P4503A4（CYP3A）催化。肠道或肝脏首过代谢以及CYP3A活性在OTF处置中的作用尚不清楚。本研究考察了肝脏和肠道CYP3A活性对OTF处置及临床效果的影响。
在机构审查委员会批准的一项随机、平衡、四交叉试验中对12名健康志愿者进行了研究。他们在接受利福平诱导肝脏/肠道CYP3A、醋竹桃霉素抑制肝脏/肠道CYP3A、葡萄柚汁选择性抑制肠道CYP3A或不进行任何处理（对照）后，接受OTF（10微克/千克）。通过质谱法测定血浆芬太尼和去甲芬太尼浓度。芬太尼效应通过暗适应瞳孔直径和使用视觉模拟量表的主观自我评估来测量。
利福平、醋竹桃霉素和葡萄柚汁处理后，血浆芬太尼浓度峰值、达峰时间以及瞳孔直径相对于基线的最大变化均未改变。然而，芬太尼的消除受到CYP3A改变的显著影响。对照、利福平、醋竹桃霉素和葡萄柚汁处理后，血浆芬太尼浓度 - 时间曲线下面积分别为5.9±3.7、2.2±0.8*、10.4±8.9和5.8±3.3小时×纳克/毫升；去甲芬太尼/芬太尼血浆曲线下面积比值分别为0.92±0.63、3.2±1.8。0.08±0.14*和0.67±0.33（*与对照相比，P<0.05）。
改变肠道和肝脏CYP3A活性对OTF给药后的芬太尼浓度峰值和临床效果影响极小，而芬太尼的代谢、消除及效应持续时间受到显著影响；选择性肠道CYP3A抑制的影响极小。这表明首过代谢对OTF生物利用度的影响极小。在治疗突破性疼痛时，在密切关注最大程度的黏膜吸收和最小程度的吞咽的情况下，CYP3A的变异性和药物相互作用不太可能影响OTF镇痛的起效或程度；然而，持续时间可能会受到影响。
