Korean J Parasitol.  2013 Apr;51(2):165-175. 10.3347/kjp.2013.51.2.165.

Effect of Ketoconazole, a Cytochrome P450 Inhibitor, on the Efficacy of Quinine and Halofantrine against Schistosoma mansoni in Mice

• Seif el-Din SH
• Sabra AN
• Hammam OA
• El-Lakkany NM

• KMID: 1499694
• DOI: http://doi.org/10.3347/kjp.2013.51.2.165

Abstract

The fear that schistosomes will become resistant to praziquantel (PZQ) motivates the search for alternatives to treat schistosomiasis. The antimalarials quinine (QN) and halofantrine (HF) possess moderate antischistosomal properties. The major metabolic pathway of QN and HF is through cytochrome P450 (CYP) 3A4. Accordingly, this study investigates the effects of CYP3A4 inhibitor, ketoconazole (KTZ), on the antischistosomal potential of these quinolines against Schistosoma mansoni infection by evaluating parasitological, histopathological, and biochemical parameters. Mice were classified into 7 groups: uninfected untreated (I), infected untreated (II), infected treated orally with PZQ (1,000 mg/kg) (III), QN (400 mg/kg) (IV), KTZ (10 mg/kg)+QN as group IV (V), HF (400 mg/kg) (VI), and KTZ (as group V)+HF (as group VI) (VII). KTZ plus QN or HF produced more inhibition (P<0.05) in hepatic CYP450 (85.7% and 83.8%) and CYT b5 (75.5% and 73.5%) activities, respectively, than in groups treated with QN or HF alone. This was accompanied with more reduction in female (89.0% and 79.3%), total worms (81.4% and 70.3%), and eggs burden (hepatic; 83.8%, 66.0% and intestinal; 68%, 64.5%), respectively, and encountering the granulomatous reaction to parasite eggs trapped in the liver. QN and HF significantly (P<0.05) elevated malondialdehyde levels when used alone or with KTZ. Meanwhile, KTZ plus QN or HF restored serum levels of ALT, albumin, and reduced hepatic glutathione (KTZ+HF) to their control values. KTZ enhanced the therapeutic antischistosomal potential of QN and HF over each drug alone. Moreover, the effect of KTZ+QN was more evident than KTZ+HF.

Keyword

Schistosoma mansoni; quinine; halofantrine; ketoconazole; CYP3A4; glutathione; malondialdehyde

MeSH Terms

Animals
Anthelmintics/*administration & dosage
Disease Models, Animal
Drug Synergism
Female
Humans
Intestines/parasitology
Ketoconazole/*administration & dosage
Liver/parasitology/pathology
Male
Mice
Parasite Load
Phenanthrenes/*administration & dosage
Quinine/*administration & dosage
Schistosoma mansoni/isolation & purification
Schistosomiasis mansoni/*drug therapy/pathology
Treatment Outcome
Anthelmintics
Phenanthrenes
Quinine
Ketoconazole