Chloroquine Elimination in Humans: Effect of Low‐Dose Cimetidine

Abstract

A controlled study was carried out in ten healthy, male volunteers (randomly distributed into control and test groups of five subjects each) to determine the effect of low-dose cimetidine on chloroquine elimination. The control group subjects received two tablets of chloroquine sulfate (300-mg base) only, while the test group subjects took 400-mg cimetidine at bedtime for four days prior to chloroquine (two tablets of chloroquine sulfate) administration and throughout the duration of the study. Blood samples, 5 mL, were collected periodically after chloroquine administration. The samples were assayed for chloroquine and monodesethylchloroquine using a combination of thin-layer chromatography and spectrophotometry. Wilcoxon's test for unpaired data at P less than .05 was used to determine if there was any significant difference in the elimination of chloroquine in the test group when compared with the control group. The apparent oral clearance rate of chloroquine was reduced from 0.49 +/- 0.04 L/d/kg in the control group to 0.23 +/- 0.02 L/d/kg in the test group, and the elimination half-life was prolonged from 3.11 days in the control group to 4.62 days in the test group. There was a 47.04% reduction in the AUC0-7d of monodesethylchloroquine, the major metabolite of chloroquine, in the test group when compared with the control group. The apparent volume of distribution at steady state was increased from 0.46 +/- 0.07 L/kg in the control group to 0.72 +/- 0.10 L/kg in the test group. All these changes were statistically significant. The conclusion is that cimetidine impairs the elimination of chloroquine in healthy subjects.

Molecular Mechanism of Renal Tubular Secretion of the Antimalarial Drug Chloroquine

“…The lower IC 50 in double-transfected cells can be explained by higher intracellular cimetidine concentrations due to OCT2-mediated cimetidine uptake (40). In vivo, chloroquine elimination is inhibited by concomitantly administered cimetidine (11). So far, this has been attributed to the inhibition of hepatic metabolism of chloroquine by cimetidine, but our results indicate that inhibition of renal secretion might also contribute to this interaction.…”

Chronic use of chloroquine disrupts the urine concentration mechanism by lowering cAMP levels in the inner medulla

“…Although relatively well tolerated, chloroquine has a narrow therapeutic index that predisposes patients to nephrotoxicity (17). Anywhere from 40 to 70% of chloroquine is eliminated from the kidney (17).…”

Pharmacology of Chloroquine and Hydroxychloroquine

“…For example, ketoconazole, an inhibitor of CYP3A4, inhibited the formation of desethylchloroquine by 33 % and 1 × 10 −5 M/L, respectively [ 93 ]. Cimetidine, another CYP3A4 inhibitor, increased the half-life of an oral dose of chloroquine by 48 % [ 95 ]. The elimination half-lives of chloroquine, desethylchloroquine, and bisdesethylchloroquine are all from 20 to 60 days.…”