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

Atsriku, C. and Skellern, G.G. and Watson, D.G. and Grant, M.H. (2002) The effects of inducing agents on the metabolism of trypanocidal diamidines by isolated rat hepatocytes. In: RSC-DMG 2002: New technologies in Drug Discovery, 2002-12-12 - 2002-12-13, Edinburgh.

Abstract

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 muM) with freshly isolated rat hepatocytes (5 x 10(6) 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.

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