The primary goal of this proposal is the establishment of an animal model in inbred mice C57BL/6N (B6) and DBA/2N (D2) which mimics the human debrisoquine--type oxidation phenotype. Since praziquantel is hydroxylated extensively in liver, this human phenotype may significantly effect praziquantel metabolism, particularly in endemic areas where the incidence of the phenotype is high. Laboratory studies in mice will characterize differences in host oxidation status and its effect on praziquantel metabolism and/or clinical toxicity at the intestinal, brain and hepatic level. In particular, the pharmacokinetics of 4- hydroxypraziquantel, the major human metabolite of praziquantel, will be defined in these inbred strains as well as the urinary praziquantel/4-hydroxypraziquantel ratio. This ratio may serve as a useful marker for characterizing differences in host oxidation status in humans. Additional studies will investigate the effects of S. mansoni disease on praziquantel metabolism and therapeutic response in these same inbred strains. The methodologies to be employed include high pressure liquid chromatography and gas liquid chromatography. Using these methodologies, serum, urine and tissue concentrations of praziquantel, debrisoquine and their respective 4-hydroxylated metabolites will be measured. In addition histopathological assessment and in vitro assay of microsomal enzyme activity will also be undertaken in order to better define the effect of the debrisoquine-type oxidation phenotype on praziquantel metabolism, efficacy and toxicity. These laboratory studies are intended as a model to characterize host genetic and disease factors which affect praziquantel therapy. Based on the results of these laboratory investigations future clinical studies in humans in endemic countries will be planned.
| Xiao, S H; Catto, B A (1989) Comparative in vitro and in vivo activity of racemic praziquantel and its levorotated isomer on Schistosoma mansoni. J Infect Dis 159:589-92 |
