Mefloquine resistance reversal action of ketoconazole - a cytochrome P450 inhibitor, against mefloquine-resistant malaria.
Plasmodium knowlesi (W1) shows a high level of innate resistance to mefloquine as shown by recrudescence of blood-induced infection in rhesus monkeys, following oral mefloquine treatment with up to 80-160 mg/kg total dose over 3-4 days. Ketoconazole, at a dose of 75 mg/kg/day x 10 days given orally to P. knowlesi-infected rhesus monkeys, exerted a suppressive antimalarial effect in 1 of the 2 monkeys as evidenced by a delayed recrudescence (on day 30) and curative action in case of the other monkey, whereas a lower dose of ketoconazole (25 mg/kg/day x 10 days) failed to suppress infection effectively. When ketoconazole at a low dose (25 mg/kg/day x 10 days) treatment was combined with mefloquine (20 mg/kg/ day x 4), 1 of the 2 infected monkeys was cured, while the combination of a higher dose of ketoconazole (75 mg/kg/day x 10 days) with mefloquine (20 mg/kg/day x 4), had a complete curative effect on P. knowlesi infection in all the treated monkeys (7/7). Besides exerting direct antimalarial action against a mefloquine-resistant P. knowlesi, ketoconazole also acts as an inhibitor of hepatic microsomal CYP4503A, which regulates and slows down mefloquine biotransformation to carboxymefloquine, resulting in a possible elevation of the effective plasma drug level, which seems to be responsible for elimination of the resistant P. knowlesi. The study shows a resistance reversal effect of a ketoconazole - mefloquine combination that could be exploited for the control of mefloquine-resistant malaria infection. The study shows that ketoconazole can reverse mefloquine resistance of P. knowlesi. These findings can also be applied to reverse mefloquine resistance of P.falciparum in areas where mefloquine resistance is already established. The precise role of parasite CYP450 in mefloquine resistance and its possible role, if any, in expelling the intracellular mefloquine from the resistant plasmodia still remains to be elucidated.
Tripathi
R
R
Division of Parasitology, Central Drug Research Institute, Lucknow-226001, India. renn1113@rediffmail.com
Awasthi
A
A
Dutta
G P
GP
D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000627:therapeutic use*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000187:drug effects; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D007654:Ketoconazole / Q000008:administration & dosage / Q000627:therapeutic use*; D008253:Macaca mulatta; D008288:Malaria / Q000188:drug therapy*; D015767:Mefloquine / Q000008:administration & dosage / Q000627:therapeutic use*; D016790:Plasmodium knowlesi
D000962:Antimalarials; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007654:Ketoconazole; D015767:Mefloquine