The enantiomers of 2-n-propyl-4-pentenoic acid (delta 4-VPA), a known hepatotoxic metabolite of 2-n-propylpentanoic acid (valproix acid, VPA), were synthesized with the aid of the chiral auxiliaries (4S)-4-(2-propyl)-2-oxazolidone and (4R,5S)-4-methyl-5-phenyloxazolidone. Alkylation of the n-valeryl derivatives of these oxazolidones with allyl bromide, followed by reductive cleavage and chromic acid oxidation of the product, afforded the desired acids, (R)- and (S)-delta 4-VPA. Greater than 93% enantiomeric excess was achieved in the preparation of both enantiomers. Preliminary studies on the metabolic fate of (R)- and (S)-delta 4-VPA in freshly isolated rat hepatocytes revealed striking differences in the biotransformation of the two enantiomers. Quantification of two major metabolites of delta 4-VPA, viz., 4,5-diOH-VPA gamma-lactone and 2-n-propyl-2(E),4-pentadienoic acid (delta 2E,4-VPA), indicated that larger amounts of the gamma-lactone were formed in incubations utilizing (R)-delta 4-VPA as substrate, whereas production of the diene was greater in incubations with (S)-delta 4-VPA. On the basis of the premise that delta 4-VPA serves as a mechanism-based irreversible inhibitor of enzymes of the fatty acid beta-oxidation complex, these differences in metabolism suggest that the two enantiomers of delta 4-VPA may differ in their hepatotoxic potential.

Animals↗

PubMedDate not supplied

Enantiotopic differentiation during the biotransformation of valproic acid to the hepatotoxic olefin 2-n-propyl-4-pentenoic acid.

The enantiomers of 2-[( 3-13C]-n-propyl)pentanoic acid [(R)- and (S)-[13C]VPA] were employed as metabolic probes to investigate stereochemical aspects of the biotransformation of valproic acid (VPA) to 2-n-propyl-4-pentenoic acid (delta 4-VPA), a hepatotoxic metabolite of VPA. When incubated with hepatocytes freshly isolated from untreated male rats, each labeled substrate (initial concentration 1.0 mM) underwent metabolism to [13C]-delta 4-VPA, the formation of which was time-dependent and occurred at a rate of ca. 20 ng/(10(6) cells.4-h incubation). Analysis of this unsaturated metabolite by GC-MS techniques revealed that, following incubation of (R)-[13C]VPA, desaturation had taken place preferentially (by a factor of approximately 4) on the labeled propyl group (i.e., on the R side chain). Parallel incubations with (S)-[13C]VPA supported this conclusion, in that metabolism of this isotopic variant of VPA led to a terminal olefin that also was predominantly (83 +/- 2%) of R configuration (in this case oxidized selectively on the unlabeled side chain). Hence, biotransformation of VPA to delta 4-VPA in rat hepatocytes occurs with marked enantiotopic differentiation, favoring production of the R enantiomer of this chiral metabolite. When rats were pretreated with phenobarbital (80 mg kg-1 day-1 ip for 3 days) prior to isolation of hepatocytes, the overall rate of metabolism of VPA to delta 4-VPA over the 4-h incubation period increased approximately 3-fold, while the degree of product enantioselectivity was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

British AIDS.

Explore the source record for details and available documents.

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

Mechanistic studies on the metabolic chiral inversion of R-ibuprofen in the rat.

Deuterium labeling techniques and stereoselective GC/MS methodology have been employed to investigate the mechanism by which R-ibuprofen undergoes metabolic chiral inversion in the rat in vivo. Following oral administration of a mixture of R-ibuprofen (7.5 mg kg-1) and R-[ring-2H4; 2-2H]ibuprofen (R-[2H5]ibuprofen) (7.5 mg kg-1) to male Sprague-Dawley rats, the enantiomeric composition and deuterium excess of the drug were determined in serial plasma samples and in pooled urine collected over 10 hr. The results demonstrate that: (i) R-ibuprofen undergoes extensive inversion of configuration to its S antipode in the rat; (ii) chiral inversion of R-[2H5]ibuprofen yields S-[2H4]ibuprofen in a process that involves quantitative loss of the deuterium atom present originally at C-2; (iii) labeling of R-ibuprofen with deuterium at C-2 does not introduce a measurable kinetic deuterium isotope effect on the chiral inversion reaction; and (iv) metabolism of R-[2H5]ibuprofen leads to the appearance in plasma and urine of molecules of R-ibuprofen labeled with 4 atoms of deuterium. On the basis of these findings, a mechanism is proposed for the chiral inversion reaction that invokes the stereoselective formation of the coenzyme A thioester of R-ibuprofen as a key metabolite; conversion of this species to the corresponding enolate tautomer affords a symmetrical intermediate through which racemization of ibuprofen occurs in vivo.

Animals↗