Effects of cytochrome P450 3A modulators ketoconazole and carbamazepine on quetiapine pharmacokinetics
Effects of cytochrome P450 3A modulators ketoconazole and carbamazepine on quetiapine pharmacokinetics
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DOI：
10.1111/j.1365-2125.2005.02507.x
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发表时间：
2006-01-01
影响因子：
3.4
通讯作者：
Reele, SB
中科院分区：
文献类型：
--
作者：
Grimm, SW;Richtand, NM;Reele, SB
Aims To explore potential for drug interactions on quetiPK using in vitro and in vivo assessments.Methods负责queti代谢产物形成的代谢酶使用重组表达CYP和CYP选择性抑制剂进行评估。在表达人MDR 1基因的MDCK细胞中检测P-糖蛋白（Pgp）转运。在12名健康志愿者中进行了临床评估，这些志愿者在每日200 mg酮康唑治疗4天之前和之后接受了25 mg奎硫平，对CYP 3A 4抑制作用进行了临床评估。为了评估CYP 3A 4在体内的诱导，18例精神疾病患者滴定到稳态奎替利水平（300毫克，每天两次），然后滴定到600毫克，每天卡马西平2 weeks.Results CYP 3A 4被发现负责形成奎替利亚砜和N-和O-脱烷基奎替利，而不是Pgp底物。在临床研究中，酮康唑使喹替鲁酮的平均血浆C-max增加了3.35倍，从45 ng ml（-1）增加到150 ng ml（-1）（平均C-max比90% CI 2.51，4.47），清除率（Cl/F）降低了84%，从138 l h（-1）减少到22 l h（-1）（平均比值90% CI 0.13，0.20）。卡马西平使奎替尼血浆C-max降低80%，从1042 ng/ml降至205 ng/ml（平均C-max比90% CI 0.14，0.28），清除率增加7.5倍，从65小时增加至483小时（-1）结论细胞色素P450 3A 4是代谢清除喹替利嗪的主要酶。喹替鲁的药代动力学受酮康唑和卡马西平联合给药的影响，因此，预计强烈调节CYP 3A 4活性或表达的其他药物和摄入的天然产物会改变喹替鲁的暴露量。
Aims To explore the potential for drug interactions on quetiapine pharmacokinetics using in vitro and in vivo assessments.Methods The CYP enzymes responsible for quetiapine metabolite formation were assessed using recombinant expressed CYPs and CYP-selective inhibitors. P-glycoprotein (Pgp) transport was tested in MDCK cells expressing the human MDR1 gene. The effects of CYP3A4 inhibition were evaluated clinically in 12 healthy volunteers that received 25 mg quetiapine before and after 4 days of treatment with ketoconazole 200 mg daily. To assess CYP3A4 induction in vivo, 18 patients with psychiatric disorders were titrated to steady-state quetiapine levels (300 mg twice daily), then titrated to 600 mg daily carbamazepine for 2 weeks.Results CYP3A4 was found to be responsible for formation of quetiapine sulfoxide and N- and O-desalkylquetiapine and not a Pgp substrate. In the clinical studies, ketoconazole increased mean quetiapine plasma C-max by 3.35-fold, from 45 to 150 ng ml(-1) (mean C-max ratio 90% CI 2.51, 4.47) and decreased its clearance (Cl/F) by 84%, from 138 to 22 l h(-1) (mean ratio 90% CI 0.13, 0.20). Carbamazepine decreased quetiapine plasma C-max by 80%, from 1042 to 205 ng ml(-1) (mean C-max ratio 90% CI 0.14, 0.28) and increased its clearance 7.5-fold, from 65 to 483 l h(-1) (mean ratio 90% CI 6.04, 9.28).Conclusions Cytochrome P450 3A4 is a primary enzyme responsible for the metabolic clearance of quetiapine. Quetiapine pharmacokinetics were affected by concomitant administration of ketoconazole and carbamazepine, and therefore other drugs and ingested natural products that strongly modulate the activity or expression of CYP3A4 would be predicted to change exposure to quetiapine.