Muralidharan G, Cooper J K, Hawes E M, Korchinski E D, Midha K K
College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Canada.
Eur J Clin Pharmacol. 1996;50(1-2):121-8. doi: 10.1007/s002280050079.
Quindine is a potent inhibitor of CYP2D6 (debrisoquine 4-hydroxylase). Its effect on the disposition of chlorpromazine was investigated in ten healthy volunteers using a randomised crossover design with two phases. A single oral dose of chlorpromazine hydrochloride (100 mg) was given with and without prior administration of quinidine bisulphate (250 mg). Chlorpromazine and seven of its metabolites were quantified in the 0- to 12-h urine while plasma concentrations of chlorpromazine and 7-hydroxychlorpromazine were measured over 48 h. All volunteers were phenotyped as extensive metabolisers with respect to CYP2D6 using the methoxyphenamine/O-desmethyl-methoxyphenamine metabolic ratio. Quinidine significantly decreased the urinary excretion of 7-hydroxylchlorpromazine 2.2-fold. Moreover the urinary excretion of this metabolite correlated inversely (rs = -0.80) with the metabolic ratio. The urinary recoveries of chlorpromazine, chlorpromazine N-oxide, 7-hydroxy-N-desmethylchlorpromazine, N-desmethyl-chlorpromazine sulphoxide and the total of all eight analytes were unaltered by quinidine. However, quinidine administration caused significant increases in the urinary excretions of chlorpromazine sulphoxide, N-desmethylchlorpromazine and N, N-didesmethylchlorpromazine sulphoxide, which indicated that compensatory increase in these metabolic routes of chlorpromazine might have been responsible for the lack of change observed in the urinary recovery of the parent drug. Quinidine administration produced modest decreases (1.2- to 1.3-fold) in the mean peak plasma concentrations and mean areas under the plasma concentration-time curves of 7-hydroxychlorpromazine and increases (1.3- to 1.4-fold) in these parameters for the parent drug chlorpromazine, but none of these changes reached statistical significance. Based on ANOVA the sample sizes required to detect these differences as significant (alpha = 0.5) with a probability of 0.8 were determined to vary between 15 and 42. These data suggest that CYP2D6 is involved in the metabolism of chlorpromazine to 7-hydroxychlorpromazine. However, genetic polymorphism in this metabolic process did not play a dominant role in accounting for the extremely large interindividual variations in plasma concentrations encountered with this drug.
奎尼丁是细胞色素P450 2D6（异喹胍4-羟化酶）的强效抑制剂。在10名健康志愿者中采用两阶段随机交叉设计研究了其对氯丙嗪处置的影响。在服用和未服用硫酸奎尼丁（250mg）的情况下分别给予单次口服剂量的盐酸氯丙嗪（100mg）。在0至12小时尿液中对氯丙嗪及其7种代谢产物进行定量，同时在48小时内测定氯丙嗪和7-羟基氯丙嗪的血浆浓度。使用甲氧苯丙胺/O-去甲基-甲氧苯丙胺代谢比将所有志愿者表型鉴定为细胞色素P450 2D6的广泛代谢者。奎尼丁使7-羟基氯丙嗪的尿排泄量显著降低2.2倍。此外，该代谢产物的尿排泄与代谢比呈负相关（rs = -0.80）。氯丙嗪、氯丙嗪N-氧化物、7-羟基-N-去甲基氯丙嗪、N-去甲基氯丙嗪亚砜以及所有8种分析物的总尿回收率不受奎尼丁影响。然而，服用奎尼丁导致氯丙嗪亚砜、N-去甲基氯丙嗪和N，N-二去甲基氯丙嗪亚砜的尿排泄量显著增加，这表明氯丙嗪这些代谢途径的代偿性增加可能是母体药物尿回收率未观察到变化的原因。服用奎尼丁使7-羟基氯丙嗪的平均血浆峰浓度和血浆浓度-时间曲线下平均面积适度降低（1.2至1.3倍），而母体药物氯丙嗪的这些参数增加（1.3至1.4倍），但这些变化均未达到统计学显著性。基于方差分析，确定在概率为0.8时将这些差异检测为显著差异（α = 0.5）所需的样本量在15至42之间变化。这些数据表明细胞色素P450 2D6参与氯丙嗪代谢生成7-羟基氯丙嗪。然而，该代谢过程中的基因多态性在解释该药物血浆浓度中遇到的个体间极大差异方面并未起主导作用。
