Gender difference in ifosfamide metabolism by human liver microsomes

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Abstract
Pharmacokinetic gender-dependent differences in cytochrome P450-mediated drug metabolism, especially CYP3A4, and their clinical implications are increasingly apparent. CYP3A4 seems to be the most important CYP isoform in both bioactivation and N-dechloroethylation of the alkylating prodrug ifosfamide, but informations about possible gender-related differences are lacking. Therefore we compared in 10 male and 10 female liver microsomal preparations the contents and activities of specific isoenzymes, involved in both metabolic pathways, especially CYP3A4, further CYP2A6, CYP2C9 and CYP2B6 and measured the in vitro activities of these microsomes in the ifosfamide 4-hydroxylation and N-dechloroethylation using high-sensitive HPLC/MS and--UV detection methods. Statistically significant differences between male and female livers were found in the mean CYP3A4 contents and activities. These differences had no consequences on the ifosfamide 4-hydroxylation activities of liver microsomes in vitro. In contrast, in the ifosfamide N-dechloroethylation reaction we found a statistically significant difference between the liver microsomes of male and female patients (0.13 ± 0.05 nmol/min · nmolP450 vs. 0.28 ± 0.13 nmol/min · nmolP450, respectively). In conclusion, we firstly demonstrated such gender-related difference in the ifosfamide N-dechloroethylation, which could result in a higher risk of partly severe neurotoxic side effects in female patients.