The stereoselectivity of 1,2-phenylethanediol and mandelic acid metabolism and disposition in the rat

Abstract

1. The steps involved in determining the chirality of the mandelic acid excreted by rats after administration of ethylbenzene and styrene were investigated by studying the fate of racemic, (R)- and (s)1,2-phenylethanediol, a precursor of mandelic acid. These investigations indicate the occurrence of two alternative routes of metabolism for 1,2-phenylethanediol, one involving retention of configuration and the other resulting in the loss of the chiral centre. 2. The stereoselectivity of the disposition of mandelic acid was investigated; rats were dosed with mandelic acid either as the racemate or as the individual enantiomers, G.1.c.-mass spectrometry and h.p.l.c. were used to determine the enantiomers of mandelic acid. 3. There were at least two routes by which mandelic acid could be metabolized and/or excreted; there is a stereoselective pathway in rat for (s)-mandelic acid, which gives rise to phenylglyoxylic acid. 4. The chiral inversion of (s)-mandelic acid to (R)-mandelic acid is reported; although this has been observed in bacteria it has not previously been observed in mammals. 5. The extent to which mandelic acid is metabolized to phenylglyoxylic acid is dependent on the enantiomeric composition of the mandelic acid administered. There is no evidence to indicate significant ketone-alcohol conversion, that is phenylglyoxylic acid is not significantly reduced to mandelic acid in vivo.

Simultaneous determination of phenylglyoxylic acid, mandelic acid, styrene glycol and hippuric acid in primary culture of rat hepatocytes incubate by high‐performance liquid chromatography

“…Almost all the MA was metabolized after 24 h incubation. The stereoselective metabolism of MA enantiomers observed in this study was in agreement with an in vivo study using Wistar rats (Drummond et al, 1990). MA was not found in the culture medium of the SG-treated cell group.…”

Renal d-Amino Acid Oxidase Mediates Chiral Inversion ofNG-Nitro-d-arginine

“…Such drugs include 2-arylpropionic acid analogs (Drummond et al, 1990), the new quinoxaline toposomerase poison 2-[4-(7-chloro-2-quinoxaliny)oxy] phenoxy propionic acid (Zheng et al, 2002), and thalidomide (Eriksson et al, 1998). The metabolic chiral inversion of 2-arylpropionic acids such as ibuprofen and ketoprofen (nonsteroidal anti-inflammatory agents) has been well characterized.…”

Enantioconvergent production of (R)‐1‐phenyl‐1,2‐ethanediol from styrene oxide by combining the Solanum tuberosum and an evolved Agrobacterium radiobacter AD1 epoxide hydrolases

“…For example, the pharmaceutical intermediate, enantio-pure (R)-or (S)-mandelic acid, is used in the synthesis of b-lactam antibiotics and analytical reagents (Groger, 2001), and (R)-mandelic acid may be made from (R)-1-phenyl-1,2-ethanediol (Drummond et al, 1990;Lindstad et al, 1998).…”