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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
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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

Information

Type
Research Article
Information
Parasitology , Volume 130 , Issue 5 , May 2005 , pp. 475 - 479
Copyright
© 2005 Cambridge University Press

INTRODUCTION

The emergence of mefloquine-resistant Plasmodium falciparum has been documented during the last two decades (Boudreau et al. 1982; WHO, 1984). Nearly 50% of the mefloquine resistance in P. falciparum has been recorded in Thailand (Nosten et al. 1991). During the last decade the use of mefloquine therapy alone for treating multidrug-resistant (MDR) P. falciparum has been replaced by the combinations of mefloquine with artemisinin derivatives e.g. artemether/artesunate, which have proved very effective in the treatment of mefloquine resistant/MDR P. falciparum infections. Clinical trial data show that artemether+mefloquine or artesunate+mefloquine combinations are preferred over artemether or artesunate monotherapy in South East Asia, because of very high cure rates with these drug combinations (Shwe et al. 1988; Price et al. 1995, 1998; Looareesuwan et al. 1997).

Studies to reverse mefloquine resistance of P. falciparum have been very limited. Mefloquine resistance of P. falciparum can be partly reversed in vitro by penfluridol (WR 256473) (Kyle et al. 1988). Further studies showed that resistance to mefloquine in NS/110 line of P. yoelii could be reversed by administering penfluridol along with mefloquine to infected mice (Peters & Robinson, 1991). A combination of IFN-gamma and mefloquine (8 mg/kg) could partially reverse mefloquine resistance of MDR P. yoelii nigeriensis giving 62% protection of mice, while this dose of mefloquine administered alone gave 25% protection of mice (Dhawan et al. 2000). More recently, a preliminary study has shown the reversal of mefloquine resistance of P. falciparum in vitro by two monoindole alkaloids, namely icajine and isoretuline isolated from the plant Strychnos myrptoides (Frederich et al. 2001). In another in vitro study, NP30 (an uncharged polyethoxylated nonphenol surfactant) had a reversal effect against mefloquine resistance P. falciparum (Ciach et al. 2003). The present communication deals with the effect of ketoconazole in reversing mefloquine resistance in P. knowlesi.

MATERIALS AND METHODS

Plasmodium knowlesi (W1 strain) – a non-gametocyte producing strain was received in 1980 from the UK through the courtesy of late Professor P. C. C. Garnham, and was used in this study. P. knowlesi produces a virulent, fatal infection in rhesus monkey (Macaca mulatta) following intravenous inoculation of 1×104 – 1×106 parasitized RBC. Rhesus monkeys used in the study were maintained at the primate malaria facility at the Central Drug Research Institute, Lucknow under standard conditions, and fed on pellet diet, fresh fruits and seasonal vegetable diet, and water ad libitum, under 12 h photo-periodicity. The animals were quarantined for 45 days, chest X-rayed and tuberculin tested. Blood smears of healthy animals were examined weekly for 4 weeks to ensure that they were free of any haemoprotozoan infections.

In order to establish the mefloquine-resistant character of P. knowlesi (W1), a batch of 5 infected monkeys was treated orally with 160 mg/kg mefloquine (80 mg/kg+40 mg+40 mg/kg on 3 successive days) at an initial parasitaemia ranging between 2·0 and 8·0%. Another batch of 4 monkeys was treated orally with 80 mg/kg mefloquine (40 mg+20 mg+20 mg/kg on 3 successive days) at an initial parasitaemia of 3·7–6·8%. Another batch of 2 monkeys at an initial parasitaemia of 0·2–0·4% were treated orally with 80 mg/kg mefloquine (20 mg/kg×4 days) and the treated monkeys were followed-up for 60 days, by examining the blood smears of treated monkeys stained with Giemsa stain. Data on day of recrudescence of parasitaemia in treated monkeys together with mortality/survival data were recorded.

In order to assess the effect of ketoconazole on P. knowlesi infection 3 monkeys were treated with ketoconazole orally either at a dose of 25 mg/kg×10 days (1 monkey) or 75 mg/kg×10 days (2 monkeys). Day of recrudescence or mortality was recorded.

For assessing the mefloquine resistance reversal effect of ketoconazole, 2 monkeys infected with P. knowlesi were orally treated with a combination of both ketoconazole 25 mg/kg×10 days+mefloquine 20 mg/kg×4 days, and another batch of 7 monkeys was treated orally with ketoconazole 75 mg/kg×10 days+mefloquine 20 mg/kg×4 days. Ketoconazole was always given in 2 divided doses daily while the mefloquine was given once per day. Follow-up of treated monkeys was continued for 60 days by examining the blood smears stained with Giemsa.

RESULTS

Mefloquine resistance of P. knowlesi

P. knowlesi (W1) infection in rhesus monkeys has revealed a high level of innate resistance to mefloquine as shown by recrudescence of infection following treatment with 80–160 mg/kg of mefloquine. Two P. knowlesi-infected monkeys treated with 20 mg/kg×4 doses of mefloquine recrudesced on day 18 and 21 (Table 1). Another 4 monkeys treated with mefloquine at 40+20+20 mg/kg doses (over 3 days) also showed recrudescence in 3 out of 4 monkeys, including the death of 1 monkey on day 22 post-treatment. The remaining 2 monkeys showed recrudescence on days 22 and 40 respectively. Treatment of 5 monkeys with a high dose of mefloquine (80+40+40 mg/kg on 3 consecutive days) showed recrudescence in 1 monkey on day 22. The present study shows that P. knowlesi exhibits an exceptionally high level of mefloquine resistance to 80–160 mg/kg doses of the drug and could be a useful strain to study the mefloquine resistance reversal effect of various chemotherapeutic agents in vivo.

Antimalarial action of ketoconazole on P. knowlesi infection

No antimalarial effect of ketoconazole on blood-induced P. knowlesi infection was observed in 1 rhesus monkey treated with the low dose of ketoconazole (25 mg/kg/day×10 days), and the treated monkey died on day 11 post-infection. However, treatment of 2 infected monkeys with a higher ketoconazole dose i.e. 75 mg/kg/day×10 days, showed curative/suppressive antimalarial action against mefloquine resistant strain of P. knowlesi as evidenced by complete cure in 1 of the 2 monkeys, while the second monkey showed a delayed recrudescence on day 30 (Table 1).

Antimalarial action of ketoconazole and mefloquine combination against P. knowlesi

The antimalarial potential of a combination of orally administered ketoconazole (75 mg/kg/day×10 days) and mefloquine (20 mg/kg/day×4 days) against P. knowlesi infection in rhesus monkey, was assessed in 2 batches of rhesus monkeys comprising a total of 7 monkeys. The results presented in Table 1 show that this combination of high dose ketoconazole and mefloquine was fully curative in 7/7 rhesus monkeys, giving 100% cure rate against mefloquine-resistant P. knowlesi infection, and there was no break-through parasitaemia or recrudescence.

The non-curative lower doses of both ketoconazole (25 mg/kg/day×10 days) and mefloquine (20 mg/kg×4 days) when administered in combination produced partial curative effect in 1 out of 2 monkeys, whereas the second treated monkey showed recrudescence on day 19. The study shows that ketoconazole potentiates the antimalarial action of mefloquine against mefloquine resistant P. knowlesi (W1). The study also shows that a combination of ketoconazole and mefloquine can overcome the mefloquine resistance of P. knowlesi in vivo. The present study further shows that mefloquine alone at a dose of 80 mg/kg (administered over 3–4 days) cured only 1 out of 6 monkeys, but when mefloquine (20 mg/kg×4 days) was combined with ketoconazole (75 mg/kg/day×10 days), the combination produced 100% curative action against mefloquine-resistant P. knowlesi. Further, lower non-curative dose of ketoconazole (25 mg/kg/day×10 days) when administered together with mefloquine (20 mg/kg/day×4 days) was able to overcome mefloquine resistance only partially, resulting in a curative action in 1 out of 2 monkeys (Table 1).

DISCUSSION

In the present investigation, ketoconazole, an antifungal drug, was evaluated for its antimalarial action against P. knowlesi, a virulent, lethal strain in rhesus monkey. The study has established its partial antimalarial effect and even P. knowlesi-infected monkeys can be protected with ketoconazole. In an earlier report on ketoconazole, its in vitro antimalarial action against P. falciparum (both chloroquine sensitive and resistant isolates) was documented (Pfaller & Krogstad, 1981).

The present study shows that the P. knowlesi (W1) strain used is fully resistant to an 80 mg/kg total oral dose of mefloquine and both the treated monkeys showed recrudescence on day 18 and 21 post-infection. Resistance of the P. knowlesi W1 strain to 80 as well as 160 mg/kg mefloquine (over 3 days) had been reported earlier from this Institute (Singh & Dutta, 1981). In spite of a high level of resistance to mefloquine, this parasite (P. knowlesi W1) is fully sensitive to chloroquine (20 mg base/kg) administered orally over 3 days (Singh & Dutta, 1981). In view of the high level of mefloquine resistance, it could be an ideal parasite to study the problems related to mefloquine resistance in vivo.

Evaluation of ketoconazole (75 mg/kg/day×10 days) together with mefloquine (20 mg/kg/day×4 days) showed an improved additive antimalarial effect of the two drugs, which provided 100% cure (7/7) of rhesus monkeys infected with mefloquine-resistant P. knowlesi. The study shows that ketoconazole combined with mefloquine is able to overcome the mefloquine resistance of P. knowlesi, and also shows that ketoconazole, when combined with mefloquine, can reverse mefloquine resistance in P. knowlesi.

Work done on the reversal of chloroquine resistance of plasmodia (Krogstad, Gluzman & Kyle, 1987; Martin, Odvola & Milhous, 1987; Rabinovich, Kulikovskaya & Maksakovskaya, 1987; Salyanik et al. 1987) pointed out that microsomal mono-oxygenases are the enzymes that metabolize xenobiotics (Salyanik et al. 1987). These workers suggested that the parasite cytochrome P450 could be responsible for chloroquine resistance of malaria parasites. Elevated levels of the monooxygenases (namely aryl hydrocarbon hydroxylase and aminopyrine N-dimethylase) could be responsible for inactivation of chloroquine, in chloroquine resistant P. berghei in comparison to the sensitive parasite. They found those inhibitors of micosomal mono-oxygenases e.g. copper-lysine complex such as copper (lysine)2 was the most effective chloroquine-resistant reversal agent. Further, it was reported that copper (lysine)2, in combination with chloroquine, considerably decreased P. berghei chloroquine-resistant parasitaemia in mice and, in comparison, neither chloroquine alone nor copper (lysine)2 complex had any effect on the sensitive P. berghei parasitaemia in mice (Rabinovich et al. 1987). These workers concluded that elevated cytochrome P450 levels in chloroquine-resistant P. berghei was responsible for the high rate of chloroquine inactivation by the parasite which was responsible for chloroquine resistance. Another mechanism of resistance was also proposed (Martin et al. 1987) which showed that the calcium channel blocker, verapamil, exhibited chloroquine (CQ) resistance reversal action against CQ-resistant P. falciparum when the parasite was exposed in vitro to a subinhibitory concentration of verapamil in the presence of CQ. In CQ-resistant parasites, verapamil blocked the drug efflux process, which is responsible for the pumping out of potentially lethal drug concentrations. Increased active efflux of cytotoxic drug prevented chloroquine accumulation in the resistant parasite but not in the sensitive parasite.

Another important study (Krogstad et al. 1987) also reported that labelled chloroquine (3H-CQ) was released at a very high rate from drug-resistant P. falciparum (Indo-China I) strain compared to the sensitive (Haiti 135) parasite (234 vs 10027 f mol/106 parasitized RBC).

Earlier workers had postulated that depression of the hepatic cytochrome P450-dependent mono-oxygenase system may be a general property of interferon (IFN) and interferon-inducing agents, including poly rI-poly rC (Renton & Mannering, 1976). Later it had been reported that when poly-ICLC, an inducer of interferons, was administered (5 mg/kg/day×9 days) in combination with subcurative dose of chloroquine (4 mg/kg×3 days), it exerted a strong suppressive effect on multi-resistant P. yoelii nigeriensis in Swiss mice, resulting in complete parasite clearance in 73% of mice which finally survived, while poly-ICLC or chloroquine alone-treated groups did not survive (Awasthi et al. 1997). The protection afforded by IFN – inducer (Poly-ICLC) and chloroquine could be reversed by phenobarbitone (5 mg/kg×11 days) – an inducer of cytochrome P450. The major conclusion of investigators was that because of the suppressive effect of poly- ICLC on the cytochrome mono-oxygenase system, the rate of detoxification of chloroquine by the mouse liver was slowed down, which led to a raised chloroquine level in blood that could be responsible for improved chloroquine efficacy against MDR parasite.

In our earlier report (Awasthi et al. 2004) on its antimalarial effect against multidrug-resistant P. yoelii nigeriensis (highly resistant to chloroquine, mefloquine and quinine), a dose of 200 mg/kg×10 days protected 2 out of 8 Swiss mice and a dose of 100 mg/kg×8 days, could not protect any mouse out of 8 treated mice (Awasthi et al., unpublished observations). When both ketoconazole (100 mg/kg) and mefloquine (4 mg/kg×8 days) were administered together, the drug combination protected 5 out of 6 mice. Likewise, a combination of a lower dose i.e. 25 mg/kg ketoconazole, with a 4 mg/kg dose of mefloquine was protective in 4/6 mice only. In conclusion, mefloquine resistance could be overcome by administering ketoconazole together with mefloquine. Ketoconazole was reported to reverse mefloquine resistance of the multi-drug-resistant parasite. Since a low level of P. yoelii nigeriensis parasitaemia persisted for 2 weeks or so, the protective effect of the combination was not interpreted as a synergistic but rather as a resistance reversal action of ketoconazole.

Recent studies show that the cytochrome P4503A enzymes play a major role in the metabolism of drugs in humans, and researchers have further reported that ketoconazole is a strong and effective inhibitor of cytochrome P450 (Ekins, Stresser & Williams, 2003). An enhanced antimalarial effect of the ketoconazole and mefloquine combination could possibly be due to drug--drug interaction involving their metabolism. Mefloquine is known to be metabolized by human liver microsomal cytochrome P450 enzyme that metabolizes mefloquine into carboxymefloquine. It had been observed that ketoconazole, an inhibitor of CYP4503A, caused marked inhibition of mefloquine metabolism to carboxymefloquine formation with an IC50 of 7 μmol (Bangchang, Karbwang & Back, 1992). This inhibition is due to an inhibitory effect of ketoconazole on cytochrome P450 isoenzymes that regulate the conversion of mefloquine into carboxymefloquine. Recently it has also been reported that mefloquine also undergoes conversion into two major metabolites namely carboxymefloquine and hydroxymefloquine in vivo (Fontaine et al. 2000). The involvement of the cytochrome P4503A subfamily in mefloquine biotransformation had been suggested by several lines of evidence, which showed that mefloquine biotransformation in rifampycin-induced human hepatocytes, was also inhibited in a concentration-dependent manner by the cytochrome P4503A inhibitor ketoconazole. The present study has provided a new lead that ketoconazole and other CYP4503A inhibitors, which inhibit the biotransformation of mefloquine, can be used to reverse mefloquine resistance of plasmodia. This finding has an important clinical application in the control of mefloquine-resistant P. falciparum.

Ketoconazole seems to play a dual role during its interaction with mefloquine. It not only exerts a suppressive antimalarial action but, in addition, it acts as a strong inhibitor of cytochrome P4503A, which regulates mefloquine biotransformation to carboxymefloquine in liver microsomes, thereby slowing down the rate of degradation of mefloquine and consequently increasing the effective plasma drug level or bioavailability of mefloquine. The mechanism of antimalarial action of ketoconazole has not been elucidated. Likewise, whether the ketoconazole exerts an inhibitory action on the cytochrome P450 level of plasmodia is also not known. Further work is needed to understand whether ketoconazole alters the level of cytochrome P450 in the plasmodia, although its inhibitory effect on the host liver microsomal system is well established.

The authors would like to thank Dr C. M. Gupta, Director, C.D.R.I. for his continuous support for the present study. Thanks are also due to Dr S. K. Puri, Head of the Parasitology Division for providing excellent research facilities and for his valuable suggestions. One of the authors (A.A.) is thankful to the Walter Reed Army Institute of Research, Washington, D.C., USA for the award of a research fellowship. This is C.D.R.I. communication number 6486.

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Table 1. Reversal of mefloquine resistance of Plasmodium knowlesi (W1) by ketoconazole in rhesus monkey