Kashuba A D, Nafziger A N, Kearns G L, Leeder J S, Gotschall R, Rocci M L, Kulawy R W, Beck D J, Bertino J S
Department of Medicine, Bassett Healthcare, Cooperstown, NY 13326, USA.
Clin Pharmacol Ther. 1998 Sep;64(3):257-68. doi: 10.1016/S0009-9236(98)90174-6.
To determine the effect of 150 mg/day fluvoxamine on the activities of CYP1A2, CYP2D6, CYP3A, N-acetyltransferase-2 (NAT2), and xanthine oxidase (XO) by phenotyping with caffeine, dextromethorphan, and midazolam.
Oral caffeine (2 mg/kg), oral dextromethorphan (30 mg), and intravenous midazolam (0.025 mg/kg) were administered to 10 white male volunteers every 14 days for 4 months and to 10 white premenopausal female volunteers during the midfollicular and midluteal phases of the menstrual cycle for 4 complete cycles (8 total phenotyping measures). The first 6 phenotyping measures were used to establish baseline activity. Subjects were given 150 mg/day fluvoxamine for the fourth month or cycle of the study. Enzyme activity for CYP1A2, CYP2D6, NAT2, and XO was expressed as urinary metabolite ratios. Midazolam plasma clearance was used to express CYP3A activity.
No difference between baseline and weeks 2 and 4 of fluvoxamine therapy was observed for NAT2 or XO metabolite ratios. For CYP1A2, CYP2D6, and CYP3A phenotypes, significant differences existed between baseline and fluvoxamine therapy. For CYP1A2, the mean urinary metabolite ratio (+/-SD) was 7.53 +/- 7.44 at baseline and 4.30 +/- 2.82 with fluvoxamine ( P = .012). Mean CYP2D6 molar urinary dextromethorphan ratios before and after fluvoxamine therapy were 0.00780 +/- 0.00694 and 0.0153 +/- 0.0127, respectively (P = .011). Midazolam clearance decreased from 0.0081 +/ 0.0024 L/min/kg at baseline to 0.0054 +/- 0.0021 L/min/kg with therapy (P = .0091). For CYP1A2, CYP2D6, and CYP3A, fluvoxamine therapy changed the phenotyping measures by a median of -44.4%, 123.5%, and -34.4%, respectively.
We concluded that fluvoxamine may cause significant inhibition of CYP1A2, CYP2D6, and CYP3A activity. This metabolic inhibition may have serious implications for a variety medications.
通过用咖啡因、右美沙芬和咪达唑仑进行表型分析，确定每天150毫克氟伏沙明对细胞色素P450 1A2（CYP1A2）、细胞色素P450 2D6（CYP2D6）、细胞色素P450 3A（CYP3A）、N - 乙酰转移酶 - 2（NAT2）和黄嘌呤氧化酶（XO）活性的影响。
每14天给10名白人男性志愿者口服咖啡因（2毫克/千克）、口服右美沙芬（30毫克）和静脉注射咪达唑仑（0.025毫克/千克），持续4个月；在月经周期的卵泡期中期和黄体期中期给10名白人绝经前女性志愿者进行同样操作，持续4个完整周期（共8次表型分析测量）。前6次表型分析测量用于建立基线活性。在研究的第四个月或周期，给受试者服用每天150毫克的氟伏沙明。CYP1A2、CYP2D6、NAT2和XO的酶活性以尿代谢物比率表示。咪达唑仑血浆清除率用于表示CYP3A活性。
对于NAT2或XO代谢物比率，在氟伏沙明治疗的第2周和第4周与基线之间未观察到差异。对于CYP1A2、CYP2D6和CYP3A表型，基线与氟伏沙明治疗之间存在显著差异。对于CYP1A2，基线时尿代谢物平均比率（±标准差）为7.53±7.44，氟伏沙明治疗时为4.30±2.82（P = 0.012）。氟伏沙明治疗前后CYP2D6的尿右美沙芬摩尔比率分别为0.00780±0.00694和0.0153±0.0127（P = 0.011）。咪达唑仑清除率从基线时的0.0081±0.0024升/分钟/千克降至治疗时的0.0054±0.0021升/分钟/千克（P = 0.0091）。对于CYP1A2、CYP2D6和CYP3A，氟伏沙明治疗使表型分析测量值分别中位数改变了 - 44.4%、123.5%和 - 34.4%。
我们得出结论认为，氟伏沙明可能会显著抑制CYP1A2、CYP2D6和CYP3A的活性。这种代谢抑制可能对多种药物有严重影响。
