The effect of inducing agents on the metabolism of trypanocidal diamidines by isolated rat hepatocytes

This study has investigated the effect of phenobarbitone (PB), 3-methylcholanthrene (3-MC), and deltamethrin (DM) on the metabolism of two trypanocidal diamidines; pentamidine isethionate and diminazene aceturate in freshly isolated Sprague-Dawley rat hepatocytes. There were significant increases in the total cytochrome P450 content of hepatocytes obtained from rats pre-treated with PB and 3-MC, whereas pre-treatment with DM did not produce any significant induction of cytochrome P450. However, pre-treatment of rats with each of the three agents led to inhibition of pentamidine metabolism following a 3 h incubation of pentamidine (100 μM) with freshly isolated rat hepatocytes (5×106 cells ml−1). Pre-treatment with 3-MC caused the highest inhibitory effect on pentamidine metabolism (8-fold inhibition), compared with PB (4.8-fold) and DM (2.2-fold). Six previously reported phase I metabolites of pentamidine were identified in cells from all the pre-treated animals as well as controls. When compared to the control group, there were significant differences between the profiles of the three major metabolites of pentamidine, 1,5-di(4′-amidinophenoxy)-2-pentanol, 1,5-di(4′-amidinophenoxy)-3-pentanol and 5-(4′-amidinophenoxy) pentanoic acid, in hepatocytes from the DM and 3-MC pre-treated rats, whereas no significant differences were observed in the cells from the PB pre-treated group. In contrast, diminazene was not metabolised with the same experimental conditions. Differences in the metabolic profiles of pentamidine and its metabolites as a result of concomitant exposure to environmental xenobiotics could have important toxicological and pharmacological implications for patients that receive the drug.