Metabolism of sameridine to monocarboxylated products by hepatocytes isolated from the male rat.
The metabolism of sameridine (LPB) (an amide-type local anesthetic-analgesic agent with a hexyl side chain) to carboxylic acid derivatives by isolated male rat hepatocytes was studied using gradient reversed-phase HPLC and mass spectrometry. Incubation of sameridine with hepatocytes resulted in the formation of numerous different metabolites. Two carboxylic acids, i.e., the C(6) and C(4) carboxylated derivatives of sameridine (LPB-6'-oic acid and LPB-4'-oic acid), were found to be produced from the intermediate omega-hydroxy metabolite (6'-hydroxy-LPB). Shortening of the alkyl chain in LPB-6'-oic 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 of sameridine] did not give rise to any carboxylated derivative. Addition of SKF525A inhibited the metabolism of sameridine by rat hepatocytes, indicating that the initial step is catalyzed by cytochrome P450. Furthermore, the metabolism of sameridine to LPB-4'-oic acid was enhanced in hepatocytes isolated from rats treated with clofibrate, an up-regulator of peroxisomal fatty 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 hepatocytes. The metabolism of 6'-hydroxy-LPB to LPB-6'-oic acid was inhibited almost completely by 4-methylpyrazole, an inhibitor of alcohol dehydrogenase. Considered together, our findings suggest that cytochrome P450 4A, cytosolic dehydrogenases, and the enzymes involved in peroxisomal fatty acid beta-oxidation catalyze the metabolism of sameridine to LPB-4'-oic acid.
Sohlenius-Sternbeck
A K
AK
Department of Preclinical Development, AstraZeneca R&D Södertälje, Södertälje, Sweden. Anna-Karin.Sternbeck@astrazeneca.com
Chelpin
H V
HV
Orzechowski
A
A
Halldin
M M
MM
D000779:Anesthetics, Local / Q000378:metabolism*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D002994:Clofibrate / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000077604:Fomepizole; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D020675:Peroxisomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism*; D011335:Proadifen / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000779:Anesthetics, Local; D000924:Anticholesteremic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D010880:Piperidines; D011720:Pyrazoles; D000077604:Fomepizole; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D002994:Clofibrate; C113809:sameridine