Christensen Magnus, Tybring Gunnel, Mihara Kazuo, Yasui-Furokori Norio, Carrillo Juan Antonio, Ramos Sara I, Andersson Katarina, Dahl Marja-Liisa, Bertilsson Leif
Department of Medical Laboratory Sciences and Technology, Division of Clinical Pharmacology at Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
Clin Pharmacol Ther. 2002 Mar;71(3):141-52. doi: 10.1067/mcp.2002.121788.
Fluvoxamine is metabolized by the polymorphic cytochrome P450 (CYP) 2D6 and the smoking-inducible CYP1A2. Therapeutic doses of fluvoxamine inhibit both CYP1A2 and CYP2C19. In this study we used extensive metabolizers (EMs) and poor metabolizers (PMs) of debrisoquin (INN, debrisoquine) (CYP2D6) and two probes, caffeine (CYP1A2) and omeprazole (CYP2C19), to investigate whether nontherapeutic doses of fluvoxamine inhibit CYP1A2 but possibly not CYP2C19.
Single oral doses of 100 mg caffeine and 20 mg omeprazole were given separately to 5 EMs and 5 PMs of debrisoquin to assess the activity of CYP1A2 and CYP2C19, respectively. Initially, a single oral dose of fluvoxamine (25 mg to PMs and 50 mg to EMs) was given, followed by 1 week of daily administration of 25 mg x 2 to EMs and 25 mg x 1 to PMs. Caffeine (day 6) and omeprazole (day 7) were again administered at the steady state of fluvoxamine. Later the study protocol was repeated with a lower dose of fluvoxamine, 10 mg x 2 to EMs and 10 mg x 1 to PMs for 1 week. Concentrations of fluvoxamine, caffeine, omeprazole, and their metabolites were analyzed by HPLC methods in plasma and urine.
The kinetics of fluvoxamine were not significantly different in EMs and PMs after a single oral dose of the drug. At the higher but not the lower steady-state dose of fluvoxamine, a significantly lower clearance in PMs compared with EMs was observed (geometric mean, 0.86 versus 1.4 L/h per kilogram; P <.05). At steady state, the 25 mg x 1 or x 2 fluvoxamine dose caused a pronounced inhibition of about 75% to 80% for both CYP1A2 and CYP2C19, whereas the inhibition after the lower 10 mg x 1 or x 2 dose was about 40% to 50%. The area under the plasma concentration-versus-time curve from 0 to 24 hours [AUC(0-24)] of caffeine increased 5-fold (P <.001) after the higher dose of fluvoxamine and 2-fold (P <.05) after the lower dose. The area under the plasma concentration-time curve from time zero to 8 hours [AUC(0-8)] ratio of 5-hydroxyomeprazole/omeprazole decreased 3.4-fold (P <.001) and 2.4-fold (P <.001), respectively. One EM subject had a very low oral clearance of fluvoxamine after both single and multiple dosing of the drug. This subject might have a deficient transporter protein in the gut, leading to an increased absorption of fluvoxamine.
No convincing evidence was found that CYP2D6 is an important enzyme for the disposition of fluvoxamine. Other factors seem to be more important. A nontherapeutic oral daily dose of fluvoxamine is sufficient to provide a marked inhibition of both caffeine (CYP1A2) and omeprazole (CYP2C19) metabolism. It was not possible to separate the inhibitory effects of fluvoxamine on these enzymes, even after such a low daily dose such as 10 mg x 1 or x 2 of fluvoxamine.
氟伏沙明由多态性细胞色素P450（CYP）2D6和吸烟诱导型CYP1A2代谢。治疗剂量的氟伏沙明可抑制CYP1A2和CYP2C19。在本研究中，我们使用异喹胍（国际非专利药品名称，去甲异喹胍）（CYP2D6）的广泛代谢者（EMs）和代谢不良者（PMs）以及两种探针，咖啡因（CYP1A2）和奥美拉唑（CYP2C19），来研究非治疗剂量的氟伏沙明是否抑制CYP1A2但可能不抑制CYP2C19。
分别给5名异喹胍EMs和5名PMs单次口服100 mg咖啡因和20 mg奥美拉唑，以分别评估CYP1A2和CYP2C19的活性。最初，给PMs单次口服25 mg氟伏沙明，给EMs单次口服50 mg氟伏沙明，随后EMs每日服用25 mg×2，PMs每日服用25 mg×1，持续1周。在氟伏沙明达到稳态时，再次给予咖啡因（第6天）和奥美拉唑（第7天）。之后，研究方案重复进行，给EMs服用较低剂量的氟伏沙明，即10 mg×2，给PMs服用10 mg×1，持续1周。采用高效液相色谱法分析血浆和尿液中氟伏沙明、咖啡因、奥美拉唑及其代谢产物的浓度。
单次口服氟伏沙明后，EMs和PMs中氟伏沙明的动力学无显著差异。在氟伏沙明较高但非较低的稳态剂量下，观察到PMs中的清除率显著低于EMs（几何平均值，每千克0.86对1.4 L/h；P<.05）。在稳态时，25 mg×1或×2的氟伏沙明剂量对CYP1A2和CYP2C19均产生约75%至80%的显著抑制，而较低的10 mg×1或×2剂量后的抑制率约为40%至50%。较高剂量的氟伏沙明后，咖啡因0至24小时血浆浓度-时间曲线下面积[AUC(0 - 24)]增加5倍（P<.001），较低剂量后增加2倍（P<.05）。5-羟基奥美拉唑/奥美拉唑的血浆浓度-时间曲线下从0至8小时的面积[AUC(0 - 8)]比值分别降低3.4倍（P<.00
