Metabolism of alfentanil by isolated hepatocytes of rat and dog |
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Abstract: | 1. The biotransformation of 3H-alfentanil was studied using suspension cultures of isolated hepatocytes of male and female rats and of dogs.2. In hepatocytes of the male rat, alfentanil was readily metabolized, following linear Michaelis-Menten kinetics over the concentration range 5—400μM. The metabolism was strongly inhibited by the cytochrome P-450 inhibitors metyrapone, α-naphthoflavone and piperonyl butoxide.3. The major metabolites of alfentanil, which were formed in suspension cultures of male rat hepatocytes, were identified by h.p.l.c. co-chromatography and by mass spec-trometry and included N-4-(hydroxymethyl)-4-piperidinyl]-N-phenylpropanamide. N-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide or noralfentanil and N-1-2-(4-ethyl-4,5-dihydro-5-oxo-1-H-tetrazol-1-yl)ethyl]-4-(hydroxymethyl)-4-piperidinyl]-N-phenylpropanamide or desmethylalfentanil.4. The major in-vitro metabolic pathways of alfentanil in hepatocytes of the three sources were oxidative N-dealkylation at the piperidine nitrogen and oxidative O-demethylation at the methoxymethyl moiety. |
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