TY - JOUR T1 - IN VITRO METABOLISM OF CHLOROQUINE: IDENTIFICATION OF CYP2C8, CYP3A4, AND CYP2D6 AS THE MAIN ISOFORMS CATALYZING <em>N</em>-DESETHYLCHLOROQUINE FORMATION JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 748 LP - 754 DO - 10.1124/dmd.31.6.748 VL - 31 IS - 6 AU - Denis Projean AU - Bruno Baune AU - Robert Farinotti AU - Jean-Pierre Flinois AU - Philippe Beaune AU - Anne-Marie Taburet AU - Julie Ducharme Y1 - 2003/06/01 UR - http://dmd.aspetjournals.org/content/31/6/748.abstract N2 - In humans, the antimalarial drug chloroquine (CQ) is metabolized into one major metabolite, N-desethylchloroquine (DCQ). Using human liver microsomes (HLM) and recombinant human cytochrome P450 (P450), we performed studies to identify the P450 isoform(s) involved in the N-desethylation of CQ. In HLM incubated with CQ, only DCQ could be detected. Apparent Km and Vmax values (mean ± S.D.) for metabolite formation were 444 ± 121 μM and 617 ± 128 pmol/min/mg protein, respectively. In microsomes from a panel of 16 human livers phenotyped for 10 different P450 isoforms, DCQ formation was highly correlated with testosterone 6β-hydroxylation (r = 0.80; p &lt; 0.001), a CYP3A-mediated reaction, and CYP2C8-mediated paclitaxel α-hydroxylation (r = 0.82; p &lt; 0.001). CQ N-desethylation was diminished when coincubated with quercetin (20–40% inhibition), ketoconazole, or troleandomycin (20–30% inhibition) and was strongly inhibited (80% inhibition) by a combination of ketoconazole and quercetin, which further corroborates the contribution of CYP2C8 and CYP3As. Of 10 cDNA-expressed human P450s examined, only CYP1A1, CYP2D6, CYP3A4, and CYP2C8 produced DCQ. CYP2C8 and CYP3A4 constituted low-affinity/high-capacity systems, whereas CYP2D6 was associated with higher affinity but a significantly lower capacity. This property may explain the ability of CQ to inhibit CYP2D6-mediated metabolism in vitro and in vivo. At therapeutically relevant concentrations (∼100 μM CQ in the liver), CYP2C8, CYP3A4, and, to a much lesser extent, CYP2D6 are expected to account for most of the CQ N-desethylation. The American Society for Pharmacology and Experimental Therapeutics ER -