Reference

The metabolic chiral inversion of 2-phenylpropionic acid in rat, mouse and rabbit

The metabolic chiral inversion of 2-phenylpropionic acid in rat, mouse and rabbit. Fournel, Sylvie; Caldwell, John (Med. Sch., St. Mary's Hosp., London W2 1PG, UK). Biochem. Pharmacol., 35(23), 4153-9 (English) 1986. CODEN: BCPCA6. ISSN: 0006-2952. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) The metabolic chiral inversion of the 2-arylpropionic acids, which are an important class of anti-inflammatory drugs, was investigated in lab. animals, with the use of the simplest congener RS-2-phenylpropionic acid [2328-24-7] as a model compd. Chiral inversion was found to occur after administration of the racemate to the rat and rabbit, but not in the mouse. The formation of the ester glucuronide was enantioselective for the R-(-)-isomer [7782-26-5] in the rat and rabbit, but was preferential for the S-(+)-form [7782-24-3] in the mouse. In the rat, the extent of inversion from R-(-) to S-(+) was greater at a dose of 30 mg/kg than at 150 or 300 mg/kg. The enantiomeric compn. of the acid in urine was the same when the racemate was given orally or by i.p. injection. When the R-(-)isomer was given to rats, some 30% of the excreted acid was in the S-(+)-form, but when the S-(+)-isomer was given, the inversion was much less evident. In this case, the S/R ratio of the excreted phenylproprionic acid was approx. 9:1. Following the administration of the racemate to rats, the plasma elimination half-life of the R-(-)-form was shorter (3.0 vs 4.8 h for the S-(-)-isomer); this was due to its considerably greater plasma clearance (65.9 vs 43.6 mg/mL h), since the vols. of distribution of the enantiomers were the same. The S/R ratio of 2-phenylpropionic acid in plasma rose progressively with time, from 1:1 in the dose soln. to 2.1:1 at 8 h.

Loading-washout studies of the stereoselective sinusoidal uptake of (R)- and (S)-2-phenylpropionyl acyl glucuronide

All Rights Reserved. Loading-washout studies of the stereoselective sinusoidal uptake of (R)- and (S)-2-phenylpropionyl acyl glucuronide. Shackleford, David M.; Evans, Allan M.; Milne, Robert W.; Nation, Roger L. (Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5000, Australia). Current Drug Metabolism, 7(7), 817-826 (English) 2006 Bentham Science Publishers Ltd. CODEN: CDMUBU.Several reagents with their cas registry numbers 7782-24-3 and 106623-54-5 are used here. ISSN: 1389-2002. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) The vectorial movement of glucuronide conjugates from blood into bile can be an important elimination route for many drug metabolites, however the intrinsic hydrophilicity of those conjugates may conceptually act to reduce the overall efficiency of that process by limiting the flux of such conjugates across the sinusoidal membrane domain of hepatocytes. In this investigation, the hepatic disposition of the diastereomeric glucuronides of (R)- and (S)-2-phenylpropionic acid (a model "profen" compd.) have been studied using the isolated perfused rat liver to establish whether a permeability barrier at the sinusoidal membrane domain (demonstrated previously for those conjugates) is of a sufficient magnitude to impact on the overall biliary excretion of these conjugates. Livers were perfused (30 mL/min) with perfusate contg. either (R)-PPA, (S)-PPA, (R)-PPA-Glucuronide or (S)-PPA-Glucuronide to det. the dispositional profile of each glucuronide administered to the liver as both a preformed and an hepatically-generated metabolite. Once an apparent steady-state condition had been reached, infusion of test compd. was ceased to establish the kinetics of the hepatic washout. The extent of biliary excretion of each glucuronide was dependent upon whether the glucuronide was presented to the liver as a preformed or hepatically-generated metabolite, and those differences, when analyzed using a physiol.-based pharmacokinetic model, were consistent with the sinusoidal membrane acting as a barrier to the cellular entry of the glucuronides. Furthermore, that barrier was more pronounced for (R)-PPAG than it was for (S)-PPAG, suggesting that the hepatocellular uptake of the two diastereomers is stereoselective. .