Oxidation of carbovir, a carbocyclic nucleoside, by rat liver cytosolic enzymes. Enantioselectivity and enantiomeric inhibition.
Previous metabolism studies of (-)-cis-carbovir (1'R-cis-2-amino-1,9-dihydro-9-[4'S-hydroxymethyl-2-cyclopenten-1- yl]-6H- purin-6-one), an antiviral agent, have shown that the major route of metabolism of carbovir in the rat is oxidation of the methylene hydroxyl group of the cyclopentadiene ring to form the corresponding 4'-carboxylic acid metabolite. We have determined that rat hepatic alcohol dehydrogenase and aldehyde dehydrogenase are responsible for this biotransformation through sequential oxidation of the alcohol through the aldehyde to the carboxylic acid. The results of incubations of racemic (+/-)-cis-carbovir with rat liver cytosol showed that this oxidation occurs enantioselectively favoring the (+)-enantiomer by a factor of 6- to 7-fold. We have proven that alcohol dehydrogenase contributes to the enantioselectivity of the overall oxidation process, but were unable to determine whether or not any contribution is made by aldehyde dehydrogenase. Parallel incubations conducted with the separate enantiomers revealed that the concentration required to achieve a half-maximal rate for the oxidation of the (+)-enantiomer (0.27 mM) was one-fifth that required for the (-)-enantiomer (1.36 mM). Results from enantiomeric inhibition studies showed that (+)-carbovir inhibited the oxidation of (-)-carbovir. In contrast, (-)-carbovir did not inhibit the oxidation of (+)-carbovir.
Patanella
J E
JE
Department of Drug Metabolism, Glaxo, Inc., Research Triangle Park, NC 27709.
Walsh
J S
JS
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D003600:Cytosol / Q000201:enzymology*; D015224:Dideoxynucleosides / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology*; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D000998:Antiviral Agents; D015224:Dideoxynucleosides; C057503:carbovir