CLINICAL PHARMACOKINETICS AND METABOLISM OF CHLOROQUINE - FOCUS ON RECENT ADVANCEMENTS

This paper presents the current state of knowledge on chloroquine disp osition, with special emphasis an stereoselectivity and microsomal met abolism. In addition, the impact of the patient's physiopathological s tatus and ethnic origin on chloroquine pharmacokinetics is discussed. In humans, chloroquine concentrations decline multiexponentially. The drug is extensively distributed, with a volume of distribution of 200 to 800 L/kg when calculated from plasma concentrations and 200 L/kg wh en estimated from whole blood data (concentrations being 5 to 10 times higher). Chloroquine is 60% bound to plasma proteins and equally clea red by the kidney and liver. Following administration chloroquine is r apidly dealkylated via cytochrome P450 enzymes (CYP) into the pharmaco logically active desethylchloroquine and bisdesethylchloroquine. Deset hylchloroquine and bisdesethylchloroquine concentrations reach 40 and 10% of chloroquine concentrations, respectively; both chloroquine and desethylchloroquine concentrations decline slowly, with elimination ha lf-lives of 20 to 60 days. Both parent drug and metabolite can be dete cted in urine months after a single dose. In vitro and in vivo, chloro quine and desethylchloroquine competitively inhibit CYP2D 1/6-mediated reactions. Limited in vitro studies and preliminary data from clinica l experiments and observations point to CYP3A and CYP2D6 as the 2 majo r isoforms affected by or involved in chloroquine metabolism. In vitro efficacy studies did not detect any difference in potency between chl oroquine enantiomers but, in vivo in rats, S(+)-chloroquine had a lowe r dose that elicited 50% of the maximal effect (ED9(50)) than that of R(-)-chloroquine. Stereoselectivity in chloroquine body disposition co uld be responsible for this discrepancy. Chloroquine binding to plasma proteins is stereoselective, favouring S(+)-chloroquine (67% vs 35% f or the R-enantiomer). Hence, unbound plasma concentrations are higher for R(-)-chloroquine. Following separate administration of the individ ual enantiomers, R(-)-chloroquine reached higher and more sustained bl ood concentrations. The shorter half-life of S(+)-chloroquine appears secondary to its faster clearance. Blood concentrations of the S(+)-fo rms of desethylchloroquine always exceeded those of the R(-)-forms, po inting to a preferential metabolism of S(+)-chloroquine.