Mirghani R A, Hellgren U, Westerberg P A, Ericsson O, Bertilsson L, Gustafsson L L
Department of Medical Laboratory Sciences and Technology, Karolinska Institutet at Huddinge University Hospital, Sweden.
Clin Pharmacol Ther. 1999 Nov;66(5):454-60. doi: 10.1016/S0009-9236(99)70008-1.
To investigate the roles of CYP3A4 and CYP1A2 in the 3-hydroxylation of quinine in vivo.
In a randomized, three-way crossover study, nine healthy Swedish volunteers received single oral doses of quinine hydrochloride (500 mg), quinine hydrochloride (500 mg) plus ketoconazole (100 mg twice daily for 3 days), and quinine hydrochloride (500 mg) plus fluvoxamine (25 mg twice daily for 2 days) on three different occasions. Blood and urine samples were collected before quinine intake and up to 96 hours thereafter. Plasma and urine samples were analyzed for both quinine and its main metabolite 3-hydroxyquinine with HPLC methods.
Coadministration with ketoconazole (which inhibits CYP3A4) decreased the mean apparent oral clearance of quinine significantly (P < .001) by 31% (from 8.7 to 6.0 L/h), whereas coadministration with fluvoxamine (which inhibits CYP1A2 and to some extent CYP2C19) had no significant effect (P > .05) on the mean apparent oral clearance of quinine. Coadministration with ketoconazole also decreased the mean area under the plasma concentration versus time curve (AUC) of 3-hydroxyquinine (from 28.4 to 19.7 micromol x h x L(-1); P < .001), whereas coadministration with fluvoxamine increased 3-hydroxyquinine AUC significantly (from 28.4 to 30.2 micromol x h x L(-1); P < .05).
Cytochrome P450 3A4 is important for the 3-hydroxylation of quinine in vivo. On the other hand, CYP1A2 had no significant effect on this metabolic pathway.
研究细胞色素P450 3A4（CYP3A4）和细胞色素P450 1A2（CYP1A2）在体内奎宁3 - 羟基化过程中的作用。
在一项随机、三交叉试验研究中，9名健康瑞典志愿者在三个不同时间分别单次口服盐酸奎宁（500 mg）、盐酸奎宁（500 mg）加酮康唑（100 mg，每日两次，共3天）以及盐酸奎宁（500 mg）加氟伏沙明（25 mg，每日两次，共2天）。在服用奎宁前及之后长达96小时采集血液和尿液样本。采用高效液相色谱法分析血浆和尿液样本中的奎宁及其主要代谢产物3 - 羟基奎宁。
与酮康唑（抑制CYP3A4）合用时，奎宁的平均表观口服清除率显著降低（P <.001），降低了31%（从8.7降至6.0 L/h），而与氟伏沙明（抑制CYP1A2并在一定程度上抑制CYP2C19）合用时，对奎宁的平均表观口服清除率无显著影响（P >.05）。与酮康唑合用时，3 - 羟基奎宁的血浆浓度 - 时间曲线下平均面积（AUC）也降低（从28.4降至19.7 μmol·h·L⁻¹；P <.001），而与氟伏沙明合用时，3 - 羟基奎宁的AUC显著增加（从28.4增至30.2 μmol·h·L⁻¹；P <.05）。
细胞色素P450 3A4在体内奎宁的3 - 羟基化过程中起重要作用。另一方面，CYP1A2对该代谢途径无显著影响。
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