Metabolism of sameridine to monocarboxylated products by hepatocytes isolated from the male rat. 2000

A K Sohlenius-Sternbeck, and H V Chelpin, and A Orzechowski, and M M Halldin
Department of Preclinical Development, AstraZeneca R&D Södertälje, Södertälje, Sweden. Anna-Karin.Sternbeck@astrazeneca.com

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.

UI MeSH Term Description Entries
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D008297 Male Males
D010880 Piperidines A family of hexahydropyridines.
D011335 Proadifen An inhibitor of drug metabolism and CYTOCHROME P-450 ENZYME SYSTEM activity. Propyladiphenin,Diethylaminoethyldiphenylpropyl Acetate,Proadifen Hydrochloride,SK&F-525-A,SK-525A,SKF-525-A,SKF-525A,Acetate, Diethylaminoethyldiphenylpropyl,Hydrochloride, Proadifen,SK 525A,SK&F 525 A,SK&F525A,SK525A,SKF 525 A,SKF525A
D011720 Pyrazoles Azoles of two nitrogens at the 1,2 positions, next to each other, in contrast with IMIDAZOLES in which they are at the 1,3 positions.
D002994 Clofibrate A fibric acid derivative used in the treatment of HYPERLIPOPROTEINEMIA TYPE III and severe HYPERTRIGLYCERIDEMIA. (From Martindale, The Extra Pharmacopoeia, 30th ed, p986) Athromidin,Atromid,Atromid S,Clofibric Acid, Ethyl Ester,Ethyl Chlorophenoxyisobutyrate,Miscleron,Miskleron,Chlorophenoxyisobutyrate, Ethyl
D003577 Cytochrome P-450 Enzyme System A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism. Cytochrome P-450,Cytochrome P-450 Enzyme,Cytochrome P-450-Dependent Monooxygenase,P-450 Enzyme,P450 Enzyme,CYP450 Family,CYP450 Superfamily,Cytochrome P-450 Enzymes,Cytochrome P-450 Families,Cytochrome P-450 Monooxygenase,Cytochrome P-450 Oxygenase,Cytochrome P-450 Superfamily,Cytochrome P450,Cytochrome P450 Superfamily,Cytochrome p450 Families,P-450 Enzymes,P450 Enzymes,Cytochrome P 450,Cytochrome P 450 Dependent Monooxygenase,Cytochrome P 450 Enzyme,Cytochrome P 450 Enzyme System,Cytochrome P 450 Enzymes,Cytochrome P 450 Families,Cytochrome P 450 Monooxygenase,Cytochrome P 450 Oxygenase,Cytochrome P 450 Superfamily,Enzyme, Cytochrome P-450,Enzyme, P-450,Enzyme, P450,Enzymes, Cytochrome P-450,Enzymes, P-450,Enzymes, P450,Monooxygenase, Cytochrome P-450,Monooxygenase, Cytochrome P-450-Dependent,P 450 Enzyme,P 450 Enzymes,P-450 Enzyme, Cytochrome,P-450 Enzymes, Cytochrome,Superfamily, CYP450,Superfamily, Cytochrome P-450,Superfamily, Cytochrome P450
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D000077604 Fomepizole A pyrazole and competitive inhibitor of ALCOHOL DEHYDROGENASE that is used for the treatment of poisoning by ETHYLENE GLYCOL or METHANOL. 4-Methylpyrazole,4-Methylpyrazole Monohydrochloride,Antizol,4 Methylpyrazole,4 Methylpyrazole Monohydrochloride
D000779 Anesthetics, Local Drugs that block nerve conduction when applied locally to nerve tissue in appropriate concentrations. They act on any part of the nervous system and on every type of nerve fiber. In contact with a nerve trunk, these anesthetics can cause both sensory and motor paralysis in the innervated area. Their action is completely reversible. (From Gilman AG, et. al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed) Nearly all local anesthetics act by reducing the tendency of voltage-dependent sodium channels to activate. Anesthetics, Conduction-Blocking,Conduction-Blocking Anesthetics,Local Anesthetic,Anesthetics, Topical,Anesthetic, Local,Anesthetics, Conduction Blocking,Conduction Blocking Anesthetics,Local Anesthetics,Topical Anesthetics

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