The anti-Pneumocystis carinii drug pentamidine has generally been considered to be inert to metabolic transformation in mammals, with all therapeutic and toxic properties attributable to the unchanged molecule. Pentamidine, however, has now been shown to be extensively metabolized by the hepatic cytochrome P450 system of rats, with at least seven primary metabolites and additional secondary metabolites formed. Preliminary data suggests pentamidine is also metabolized by humans. One goal of the proposed research is to isolate, identify and quantify, using high performance liquid chromatography, capillary zone electrophoresis, tandem mass spectrometry, 13C nuclear magnetic resonance spectrometry and unequivocal chemical synthesis, the primary and secondary metabolites in body fluids of humans treated therapeutically and prophylactically with pentamidine. Metabolism of pentamidine appears to be mediated by the UTH isoenzyme in rats. The analogous isoenzyme in humans, P450IID6, is polymorphic in most populations studied. A second objective of the proposed research is to use safe, non-toxic probe drugs to examine in HIV infected populations the distribution of the cytochrome P450 isoenzyme responsible for metabolizing pentamidine. The ultimate goal is to determine if any relation exists between extent of metabolism and either therapeutic success or toxic manifestations of pentamidine administration. The use of specific and more general probes should also permit evaluation of the impact of HIV infection upon the overall drug metabolizing system of humans. The current clinical assays for pentamidine are inadequate for the analysis of most pentamidine metabolites. The final objective of the proposed research is to develop relatively simple, yet sensitive and specific new clinical assays for pentamidine and selected metabolites. Such assays, based upon high performance liquid chromatography and capillary electrophoresis methods developed in objective 1, could be used to accurately and comprehensively evaluate patient therapeutic and prophylactic regimes and to monitor patient compliance. The assays could be used to reassess pentamidine pharmacokinetics in humans, based upon the full pattern of metabolites observed. The proposed research should greatly alter current concepts of pentamidine pharmacokinetics and therapeutic and toxic activities in humans. The research is also important to our continuing efforts to develop safer, more effective pentamidine analogs for treatment of P. carinii pneumonia.
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