Simooya O O, Sijumbil G, Lennard M S, Tucker G T
University of Sheffield Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK.
Br J Clin Pharmacol. 1998 Mar;45(3):315-7. doi: 10.1046/j.1365-2125.1998.00671.x.
To determine the effect of therapeutic loading doses of halofantrine and chloroquine on CYP2D6 activity in healthy black Zambians.
Twenty healthy black male Zambians were phenotyped for CYP2D6 activity by measuring the debrisoquine/4-hydroxydebrisoquine ratio in a 0-8 h urine sample after a 10 mg oral dose of debrisoquine hemi-sulphate. The subjects (all 'extensive metabolizer' phenotype with respect to CYP2D6) were randomized into two groups of 10, and 24 h later one group received 1500 mg halofantrine hydrochloride and the other group 1500 mg chloroquine phosphate both orally in divided doses. All subjects were given further 10 mg doses of debrisoquine at 2 h, 1 week and 2 weeks after the last dose of the antimalarial drug, and phenotyped as described above.
The median debrisoquine/4-hydroxydebrisoquine 0-8 h urinary ratio was increased by halofantrine (1.39 to 6.05; P<0.01; 95% confidence intervals 4.00-11.7) and chloroquine (1.96 to 3.91; P<0.01; 95% confidence intervals 1.34-2.66) when debrisoquine was given 2 h after treatment. The decrease in CYP2D6 activity remained statistically significant for 1 week after both drugs. Halofantrine was a significantly more potent inhibitor of CYP2D6 than chloroquine (P=0.037). Phenocopying occurred in two subjects taking halofantrine and one taking chloroquine (i.e. the debrisoquine/4-hydroxydebrisoquine ratios became consistent with the poor metabolizer phenotype).
Given in therapeutic loading doses, both halofantrine and chloroquine caused significant inhibition of CYP2D6 activity in healthy black Zambians. With respect to halofantrine, this finding reinforces the recommendation that its combination with other drugs known to prolong the QT interval should be avoided, especially those that are metabolized significantly by CYP2D6.
确定治疗负荷剂量的卤泛群和氯喹对健康赞比亚黑人CYP2D6活性的影响。
通过测量口服10mg半硫酸异喹胍后0 - 8小时尿液样本中异喹胍/4 - 羟基异喹胍的比值，对20名健康赞比亚黑人男性进行CYP2D6活性表型分析。受试者（所有CYP2D6均为“广泛代谢者”表型）被随机分为两组，每组10人，24小时后，一组口服1500mg盐酸卤泛群，另一组口服1500mg磷酸氯喹，均为分次给药。在服用抗疟药物的最后一剂后2小时、1周和2周，所有受试者再次口服10mg异喹胍，并按上述方法进行表型分析。
治疗后2小时给予异喹胍时，卤泛群（从1.39增至6.05；P<0.01；95%置信区间4.00 - 11.7）和氯喹（从1.96增至3.91；P<0.01；95%置信区间1.34 - 2.66）使0 - 8小时尿液中异喹胍/4 - 羟基异喹胍的中位数比值升高。两种药物给药后1周内，CYP2D6活性的降低在统计学上仍具有显著性。卤泛群对CYP2D6的抑制作用比氯喹显著更强（P = 0.037）。两名服用卤泛群和一名服用氯喹的受试者出现了表型模拟（即异喹胍/4 - 羟基异喹胍比值与代谢不良者表型一致）。
给予治疗负荷剂量时，卤泛群和氯喹均能显著抑制健康赞比亚黑人的CYP2D6活性。关于卤泛群，这一发现强化了以下建议，即应避免其与已知会延长QT间期的其他药物联用，尤其是那些主要经CYP2D6代谢的药物。
