Clinical Pharmacokinetics and Metabolism of Chloroquine

Abstract

This paper presents the current state of knowledge on chloroquine disposition, with special emphasis on stereoselectivity and microsomal metabolism. In addition, the impact of the patient's physiopathological status 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 when estimated from whole blood data (concentrations being 5 to 10 times higher). Chloroquine is 60% bound to plasma proteins and equally cleared by the kidney and liver. Following administration chloroquine is rapidly dealkylated via cytochrome P450 enzymes (CYP) into the pharmacologically active desethylchloroquine and bisdesethylchloroquine. Desethylchloroquine and bisdesethylchloroquine concentrations reach 40 and 10% of chloroquine concentrations, respectively; both chloroquine and desethylchloroquine concentrations decline slowly, with elimination half-lives of 20 to 60 days. Both parent drug and metabolite can be detected in urine months after a single dose. In vitro and in vivo, chloroquine and desethylchloroquine competitively inhibit CYP2D1/6-mediated reactions. Limited in vitro studies and preliminary data from clinical experiments and observations point to CYP3A and CYP2D6 as the 2 major isoforms affected by or involved in chloroquine metabolism. In vitro efficacy studies did not detect any difference in potency between chloroquine enantiomers but, in vivo in rats, S(+)-chloroquine had a lower dose that elicited 50% of the maximal effect (ED950) than that of R(-)-chloroquine. Stereoselectivity in chloroquine body disposition could be responsible for this discrepancy. Chloroquine binding to plasma proteins is stereoselective, favouring S(+)-chloroquine (67% vs 35% for the R-enantiomer). Hence, unbound plasma concentrations are higher for R(-)-chloroquine. Following separate administration of the individual enantiomers, R(-)-chloroquine reached higher and more sustained blood concentrations. The shorter half-life of S(+)-chloroquine appears secondary to its faster clearance. Blood concentrations of the S(+)-forms of desethylchloroquine always exceeded those of the R(-)-forms, pointing to a preferential metabolism of S(+)-chloroquine.

Two complementary fluorimetric assays for the determination of aminoquinoline binding and uptake by human erythrocytes in vitro

“…Preliminary pharmacokinetic data indicate that more than 60% of compounds are bound to the corpuscular blood fraction. This is consistent with what has been described previously for CQ [4].…”

“…Preliminary pharmacokinetic data indicate that more than 60% of compounds are bound to the corpuscular blood fraction. This is consistent with what has been described previously for CQ [4].Since the early 1970s, the capacity of red blood cells (RBC) uninfected or infected by different strains of Pf to bind CQ or other aminoquinoline antimalarial drugs has been evaluated using 3 H-or 14 C-labeled compounds. The uptake of the drug by RBC was quantified by counting the radioactivity that is associated with the cell pellet or that disappeared from the incubation medium after centrifugation [5][6][7].…”

Chloroquine-induced lipidosis mimicking Fabry disease

“…The extensive distribution of chloroquine has been attributed to its amphiphilic nature, which allows for lysosomal trapping. 11 The mechanism by which chloroquine induces lipidosis in tissues remains unknown. In vitro studies in Madin Darby canine kidney cells have shown chloroquine to be a potent inhibitor of lysosomal phospholipase A and C, suggesting a block in intralysosomal phospholipid catabolism as a possible explanation for the resulting lipidosis.…”

A review of clinical pharmacokinetics of chloroquine and primaquine and their application in malaria treatment in Thai population

“…Slow, rate-controlled intravenous infusion, is an acceptable mode of CQ administration in seriously illpatients or where oral therapy is not possible (Looareesuwan et al, 1986;Edwards et al,1987). CQ is generally well tolerated (Ducharme et al, 1996). The main adverse effects reported after therapeutic or prophylactic regimens include nausea, vomiting, abdominal discomfort, diarrhea, headache, blurred vision, lightheadedness, and fatigue.…”