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Mefloquine resistance reversal action of ketoconazole – a cytochrome P450 inhibitor, against mefloquine-resistant malaria

  • R. TRIPATHI (a1), A. AWASTHI (a2) and G. P. DUTTA (a3)


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×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×10 days) failed to suppress infection effectively. When ketoconazole at a low dose (25 mg/kg/day×10 days) treatment was combined with mefloquine (20 mg/kg/day×4), 1 of the 2 infected monkeys was cured, while the combination of a higher dose of ketoconazole (75 mg/kg/day×10 days) with mefloquine (20 mg/kg/day×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.


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Division of Parasitology, P.O. Box No. 173, Central Drug Research Institute, Chattar Manzil Palace, Lucknow-226001, India. Tel: +91 522 2212411 18, Extn. 4461. Fax: +01 522 223405/223938. E-mail:


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AWASTHI, A., DUTTA, G. P., BHAKUNI, V. & TRIPATHI, R. ( 2004). Resistance reversal action of Retoconazole against mefloquine resistance of Plasmodium yoelii nigeriensis. Experimental Parasitology 107, 115119.
AWASTHI, A., MEHROTRA, S., BHAKUNI, V., DUTTA, G. P., LEVY, H. B. & MAHESHWARI, R. K. ( 1997). Poly ICLC enhances the antimalarial activity of chloroquine against multidrug resistant Plasmodium yoelii nigeriensis. Journal of Interferon Cytokines 17, 419423.
BANGCHANG, K. N., KARBWANG, J. & BACK, D. J. ( 1992). Mefloquine metabolism by human liver microsomes. Effect of other antimalarial drugs. Biochemical Pharmacology 43, 19571961.
BOUDREAU, E. F., WELISTER, H. K., PAVANNAD, K. & TSOSINGHA, I. ( 1982). Type II mefloquine resistance in Thailand. Lancet ii, 1335.
CIACH, M., ZONG, K., KAIN, K. C. & CRANDALL, I. ( 2003). Reversal of mefloquine and quinine resistance in Plasmodium falciparum with NP30. Antimicrobial Agents and Chemotherapy 47, 23932396.
DHAWAN, S., AWASTHI, A., TRIPATHI, R., PURI, S. K. & DUTTA, G. P. ( 2000). Reversal of chloroquine/mefloquine resistance of Plasmodium yoelii nigeriensis (MDR) by IFN-gamma and chloroquine resistance by Poly ICLC. Journal of Parasitic Diseases 24, 195201.
EKINS, S., STRESSER, D. M. & WILLIAMS, J. A. ( 2003). In vitro and pharmacophore insights into CPY3A enzymes. Trends in Pharmacological Sciences 24, 161166.
FONTAINE, F., DE SOUSA, G., VURCHAM, P. C., DUCHENE, P. & RAHMANI, R. ( 2000). Role of cytochrome P450 3A in the metabolism of mefloquine in human and animal hepatocytes. Life Sciences 66L, 21932212.
FREDERICH, M., HAYETTE, M. P., TITS, M., MOL, P. D. & ANGENOT, L. ( 2001). Reversal of chloroquine and mefloquine resistance in Plasmodium falciparum by the two monoindole alkaloids, Icajine and Isoretuline. Planta Medicine 67, 523527.
KROGSTAD, D. J., GLUZMAN, I. Y. & KYLE, D. E. ( 1987). Efflux of chloroquine from Plasmodium falciparum: mechanism of chloroquine resistance. Science 238, 12831285.
KYLE, D. E., MILHOUS, W. K. & ODULA, M. M. J. ( 1988). Reversal of mefloquine resistance in Plasmodium falciparum in vitro. The 37th Annual Meeting of the American Society of Tropical medicine and Hygiene, Washington, D.C. 4–8 December, 1988, p. 218.
LOOAREESUWAN, S., WILARIATANA, P., VIRAVAN, C., VANIJANONTA, S., PITISUTITHUM, P. & KYLE, D. E. ( 1997). Open randomized trial of oral artemether alone and a sequential combination with mefloquine for acute uncomplicated falciparum malaria. American Journal of Tropical Medicine and Hygiene 56, 613617.
MARTIN, S. K., ODVOLA, A. M. & MILHOUS, W. K. ( 1987). Reversal of chloroquine resistance in P. falciparum by verapamil. Bulletin of the World Health Organization 235, 899899.
NOSTEN, F., TERKULIE, F., CHONGSUPHAJAISIDDHI, T., WHITE, N. J., KUILE, F. T., LUXEM BURGER, C., WEBSTOR, H. K., EDSTEIN, M., PHAIPAN, L., THEW, K. L. & WHITE, N. J. ( 1991). Mefloquine resistant P. falciparum malaria in Thai Burmese border. Lancet 337, 11401143.
PETERS, W. & ROBINSON, B. L. ( 1991). The chemotherapy of rodent malaria. XLVI Reversal of mefloquine resistance in rodent Plasmodium. American Journal of Tropical Medicine and Parasitology 88, 510.
PFALLER, M. A. & KROGSTAD, D. J. ( 1981). Activity of ketoconazole against chloroquine resistant Plasmodium falciparum in vitro. Clinical Research 29, 1534A.
PRICE, R. N., LUXEMBURGER, C., VAN VUGT, M., NOSTEN, F., KHAM, A. M., SIMPSON, J., LOOAREESUWAN, S., CHONGSUPHAJAISIDDHI, T. & WHITE, N. J. ( 1998). Artesunate and mefloquine in the treatment of uncomplicated multidrug resistant hyperparasitaemia falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 92, 207211.
PRICE, R. N., NOSTEN, F., LUXEMBURGER, C., KHAM, A. M., BROCKMAN, A., CHONGSUPHAJAISIDDHI, T. & WHITEM, N. J. ( 1995). Artesunate versus artemether in combination with mefloquine for the treatment of multidrug resistant falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 89, 523527.
RABINOVICH, S. A., KULIKOVSKAYA, I. M. & MAKSAKOVSKAYA, E. V. ( 1987). Suppression of chloroquine resistance of Plasmodium berghei by treatment of infected mice with a microsomal monoxygenase inhibitor. Bulletin of the World Health Organization 65, 387389.
RENTON, K. W. & MANNERING, G. J. ( 1976). Depression of hepatic cytochrome P450 dependent monooxygenase systems with administered interferon inducing agents. Biochemical and Biophysical Research Communications 73, 343348.
SALYANIK, R. I., PANKOVA, T. G., CHEKHONADSKIKH, T. V. & IGONINA, T. M. ( 1987). Chloroquine resistance of Plasmodium berghei: biochemical basis and countermeasures. Bulletin of the World Health Organization 65, 381386.
SHWE, T., MYINT, P., HTUT, Y., MYINT, W. & SOE, L. ( 1988). The effect of mefloquine – artemether compared with quinine on patients with complicated falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 82, 665666.
SINGH, P. P. & DUTTA, G. P. ( 1981). Antimalarial activity of mefloquine and chloroquine against blood induced Plasmodium knowlesi infection in rhesus monkeys. Indian Journal of Medical Research 73 (Suppl.), 2328.
WORLD HEALTH ORGANIZATION ( 1984). Chemotherapy of malaria. WHO Technical Report Series, No. 711. WHO, Geneva.
WORLD HEALTH ORGANIZATION (1996). WHO Fact Sheet NX94 Revised December 1996. Malaria. WHO, Geneva.


Mefloquine resistance reversal action of ketoconazole – a cytochrome P450 inhibitor, against mefloquine-resistant malaria

  • R. TRIPATHI (a1), A. AWASTHI (a2) and G. P. DUTTA (a3)


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