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IN VITRO METABOLISM OF CHLOROQUINE: IDENTIFICATION OF CYP2C8, CYP3A4, AND CYP2D6 AS THE MAIN ISOFORMS CATALYZING N-DESETHYLCHLOROQUINE FORMATION

Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada (D.P., J.D.), Département d'Anesthésiologie, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada (J.D.); AstraZeneca R & D Montréal, Ville St-Laurent, Québec, Canada (D.P., J.D.), Faculté de Pharmacie, Université de Paris XI, Chatenay-Malabry, France (B.B., R.F.), I.N.S.E.R.M U490, Faculté de Médecine, Université de Paris V, Paris, France (J.-P.F., P.B.); and Hôpital Universitaire Bicêtre, assistance Publique/Hôpitaux de Paris, Paris, France (A.-M.T.)

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 K_m and V_max 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 6ß-hydroxylation (r = 0.80; p < 0.001), a CYP3A-mediated reaction, and CYP2C8-mediated paclitaxel -hydroxylation (r = 0.82; p < 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.

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