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Halofantrine and chloroquine inhibit CYP2D6 activity in healthy Zambians
Author(s) -
Simooya O. O.,
Sijumbil G.,
Lennard M. S.,
Tucker G. T.
Publication year - 1998
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1998.00671.x
Subject(s) - debrisoquine , halofantrine , cyp2d6 , chloroquine , pharmacology , pharmacokinetics , medicine , urine , cytochrome p450 , immunology , metabolism , mefloquine , malaria
Aims To determine the effect of therapeutic loading doses of halofantrine and chloroquine on CYP2D6 activity in healthy black Zambians.Methods Twenty healthy black male Zambians were phenotyped for CYP2D6 activity by measuring the debrisoquine/4‐hydroxydebrisoquine ratio in a 0–8 h urine sample after a 10 mg oral dose of debrisoquine hemi‐sulphate. The subjects (all ‘extensive metabolizer’ phenotype with respect to CYP2D6) were randomized into two groups of 10, and 24 h later one group received 1500 mg halofantrine hydrochloride and the other group 1500 mg chloroquine phosphate both orally in divided doses. All subjects were given further 10 mg doses of debrisoquine at 2 h, 1 week and 2 weeks after the last dose of the antimalarial drug, and phenotyped as described above.Results The median debrisoquine/4‐hydroxydebrisoquine 0–8 h urinary ratio was increased by halofantrine (1.39 to 6.05; P <0.01; 95% confidence intervals 4.00–11.7) and chloroquine (1.96 to 3.91; P <0.01; 95% confidence intervals 1.34–2.66) when debrisoquine was given 2 h after treatment. The decrease in CYP2D6 activity remained statistically significant for 1 week after both drugs. Halofantrine was a significantly more potent inhibitor of CYP2D6 than chloroquine ( P =0.037). Phenocopying occurred in two subjects taking halofantrine and one taking chloroquine (i.e. the debrisoquine/4‐hydroxydebrisoquine ratios became consistent with the poor metabolizer phenotype).Conclusions Given in therapeutic loading doses, both halofantrine and chloroquine caused significant inhibition of CYP2D6 activity in healthy black Zambians. With respect to halofantrine, this finding reinforces the recommendation that its combination with other drugs known to prolong the QT interval should be avoided, especially those that are metabolized significantly by CYP2D6.