Gender difference in ifosfamide metabolism by human liver microsomes

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 nmol P450 vs. 0.28 +/- 0.13 nmol/min x 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.

Sex Differences of Drug-metabolizing Enzyme: Female Predominant Expression of Human and Mouse Cytochrome P450 3A Isoforms

“…1, model 1). 20) A similar tendency observed in in vitro studies using human liver microsomes has been reported by other groups, [21][22][23][24] while studies that failed to detect female dominance have also been reported. [25][26][27][28] Assessment of CYP3A activity in vivo has been carried out by measuring the clearance of various CYP3A substrates.…”

CYP3A4, CYP2C9 and CYP2B6 expression and ifosfamide turnover in breast cancer tissue microsomes

“…Comparatively, the same antibody detected levels of CYP3A in female liver microsomes, which has been demonstrated to be significantly higher than in male samples, amounting to 141 and 69 pmol mg protein À1 (median; P ¼ 0.038, Mann -Whitney rank sum test), respectively ( Figure 6) (Schmidt et al, 2001). The use of a CYP3A5-specific antibody allowed us to exclude the expression of CYP3A5 in the tested tumours, but the involvement of CYP3A7 could not be further clarified because of the absence of a specific anti-CYP3A7 antibody.…”

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

“…Accordingly, certain CYP3A4 drug substrates, including cyclosporine (Kahan et al, 1986), erythromycin (Austin et al, 1980), and nifedipine (Krecic-Shepard et al, 2000), show higher clearance rates in women. CYP3A4-catalyzed hepatic microsomal N-dechloroethylation of the anticancer drug ifosfamide is also more rapid in women, suggesting that women could be more susceptible to the neurotoxic side affects associated with this metabolic pathway (Schmidt et al, 2001). CYP3A4 also metabolizes steroids, such as cortisol, whose conversion to 6␤-hydroxycortisol is more rapid in women than in men and serves as a biomarker for CYP3A4 metabolic activity (Inagaki et al, 2002).…”