Metabolism of sameridine to monocarboxylated products by hepatocytes isolated from the male rat

The metabolism of sameridine (LPB) (an amide-type local anesthetic-analgesi c agent with a hexyl side chain) to carboxylic acid derivatives by isolated male rat hepatocytes was studied using gradient reversed-phase HPLC and ma ss spectrometry. Incubation of sameridine with hepatocytes resulted in the formation of numerous different metabolites. Two carboxylic acids, i.e., th e C-6 and C-4 carboxylated derivatives of sameridine (LPB-6'-oic acid and L PB-4'-oic acid), were found to be produced from the intermediate omega-hydr oxy metabolite (6'-hydroxy-LPB). Shortening of the alkyl chain in LPB-6'-oi c acid by two carbon atoms resulted in LPB-4'-oic acid. However, incubation of rat hepatocytes with 5'-hydroxy-LPB [the (omega-1)-hydroxy derivative o f sameridine] did not give rise to any carboxylated derivative. Addition of SKF525A inhibited the metabolism of sameridine by rat hepatocytes, indicat ing that the initial step is catalyzed by cytochrome P450. Furthermore, the metabolism of sameridine to LPB-4'-oic acid was enhanced in hepatocytes is olated from rats treated with clofibrate, an up-regulator of peroxisomal fa tty acid beta-oxidation and of microsomal cytochrome P450 4A. L-Carnitine ( which increases the rate of mitochondrial fatty acid beta-oxidation) had no effect on the level of LPB-4'-oic acid produced by isolated rat hepatocyte s. The metabolism of 6'-hydroxy-LPB to LPB-6'-oic acid was inhibited almost completely by 4-methylpyrazole, an inhibitor of alcohol dehydrogenase. Con sidered together, our findings suggest that cytochrome P450 4A, cytosolic d ehydrogenases, and the enzymes involved in peroxisomal fatty acid beta-oxid ation catalyze the metabolism of sameridine to LPB-4'-oic acid.