Hostname: page-component-cd9895bd7-8ctnn Total loading time: 0 Render date: 2024-12-18T11:17:39.430Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  06 January 2005

R. TRIPATHI ,
A. AWASTHI  and
G. P. DUTTA
R. TRIPATHI
Affiliation:
Division of Parasitology, Central Drug Research Institute, Lucknow-226001, India
A. AWASTHI
Affiliation:
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada T6G2P6
G. P. DUTTA
Affiliation:
CSIR, India
Get access Rights & Permissions [Opens in a new window]

Abstract

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.

Keywords

multidrug-resistant malariaPlasmodium knowlesiketoconazolemefloquine resistance reversal
Type
Research Article
Information
Parasitology , Volume 130 , Issue 5 , May 2005 , pp. 475 - 479
Copyright
© 2005 Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

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, 115–119.CrossRefGoogle Scholar
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, 419–423.CrossRefGoogle Scholar
BANGCHANG, K. N., KARBWANG, J. & BACK, D. J. ( 1992). Mefloquine metabolism by human liver microsomes. Effect of other antimalarial drugs. Biochemical Pharmacology 43, 1957–1961.CrossRefGoogle Scholar
BOUDREAU, E. F., WELISTER, H. K., PAVANNAD, K. & TSOSINGHA, I. ( 1982). Type II mefloquine resistance in Thailand. Lancet ii, 1335.CrossRefGoogle Scholar
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, 2393–2396.CrossRefGoogle Scholar
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, 195–201.Google Scholar
EKINS, S., STRESSER, D. M. & WILLIAMS, J. A. ( 2003). In vitro and pharmacophore insights into CPY3A enzymes. Trends in Pharmacological Sciences 24, 161–166.CrossRefGoogle Scholar
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, 2193–2212.CrossRefGoogle Scholar
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, 523–527.CrossRefGoogle Scholar
KROGSTAD, D. J., GLUZMAN, I. Y. & KYLE, D. E. ( 1987). Efflux of chloroquine from Plasmodium falciparum: mechanism of chloroquine resistance. Science 238, 1283–1285.CrossRefGoogle Scholar
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, 613–617.CrossRefGoogle Scholar
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, 899–899.Google Scholar
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, 1140–1143.Google Scholar
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, 5–10.Google Scholar
PFALLER, M. A. & KROGSTAD, D. J. ( 1981). Activity of ketoconazole against chloroquine resistant Plasmodium falciparum in vitro. Clinical Research 29, 1534A.Google Scholar
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, 207–211.CrossRefGoogle Scholar
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, 523–527.CrossRefGoogle Scholar
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, 387–389.Google Scholar
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, 343–348.CrossRefGoogle Scholar
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, 381–386.Google Scholar
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, 665–666.CrossRefGoogle Scholar
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.), 23–28.Google Scholar
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.