Pharmacokinetic and drug metabolism studies of cyclophosphamide and ifosfamide

Cyclophosphamide (CP) and ifosfamide (IF) are two widely used anticancer drugs. Several important aspects of pharmacokinetics and metabolism of these drugs were investigated in this dissertation research. Preclinical pharmacokinetics of N-2-chloroethylaziridine (CEA), a cytotoxic metabolite of CP, in the rat were studied. Clinical pharmacokinetics of CP was also investigated with the specific reference to CEA formation.; Presystemic metabolism of IF in a rat model was investigated using the in vitro microsomal metabolism and the in vivo pharmacokinetic modeling techniques. Bioavailability of IF in the rat was found to be only 33%, and the liver was the major organ for the observed first-pass effect. In addition, it was found that liver preferentially metabolized IF through the 4-hydroxylation pathway, while the small intestines biotransformed IF in preference to N{dollar}sp3{dollar}-dechloroethylation. The results in this study help to explain the higher CNS toxicity following the oral administration of IF.; Since IF is a chiral drug, stereoselective pharmacokinetics of IF enantiomers in normal and phenobarbital (PB)-treated Sprague-Dawley rats were studied using deuterium labeled pseudoracemate and GC/MS techniques. IF and its metabolites, 4-hydroxylF (HOIF), N{dollar}sp2{dollar}-dechloroethyllF (N2D), N{dollar}sp3{dollar}-dechloroethyllF (N3D), and isophosphoramide mustard (IPM) were analyzed. The intrinsic clearances of IF isomers were estimated by the in vitro studies in rat and human liver microsomes. Cytochrome P450 isozymes responsible for the enantioselective metabolism of IF were identified using specific enzyme inducers, inhibitors, multivariate correlation, and human cDNA-expressed P450 systems. Both the in vitro and in vivo studies in the rat showed that (R)-IF metabolism was in favor of 4-hydroxylation, while (S)-IF preferentially underwent N-dechloroethylation. Following PB-treatment, IF was cleared more rapidly with reversal of stereoselectivity in N{dollar}sp3{dollar}-dechloroethylation and 4-hydroxylation. In PB-treated rats CYP2B1/2 was found to preferentially mediate 4-hydroxylation and N{dollar}sp2{dollar}-dealkylation of (S)-IF and N{dollar}sp3{dollar}-dealkylation of (R)-IF. In human microsomes, CYP3A4 was the major P450 isozyme responsible for IF metabolism for all metabolic pathways with a stereoselectivity opposite to those by CYP2B. The results from these studies suggest that (R)-IF is a better drug than (S)-IF or IF racemate.