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 3h incubation of pentamidine (100 microM) 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.
Atsriku
C
C
Department of Pharmaceutical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow, G4 0NR, UK.
Watson
D G
DG
Grant
M H
MH
Skellern
G G
GG
D000818:Animals; D002853:Chromatography, Liquid; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D004133:Diminazene / Q000031:analogs & derivatives* / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D009570:Nitriles; D010419:Pentamidine / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011722:Pyrethrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D014344:Trypanocidal Agents / Q000378:metabolism*
D009570:Nitriles; D011722:Pyrethrins; D014344:Trypanocidal Agents; C017180:decamethrin; D008748:Methylcholanthrene; D010419:Pentamidine; D003577:Cytochrome P-450 Enzyme System; C003915:diminazene aceturate; D004133:Diminazene; D010634:Phenobarbital