Inversion of optical configuration of alpha-methylfluorene-2-acetic acid (cicloprofen) in rats and monkeys.
A simple and sensitive radiometric method to determine the individual enantiomers of cicloprofen has been developed. 14C-Cicloprofen was converted to its L-leucine diastereoisomers, which were separated by thin-layer chromatography and quantified by measuring the radioactivity in the area corresponding to each individual diastereoisomer. This technique has also been used to measure the enantiomers of unlabeled cicloprofen by condensing with 14C-labeled L-leucine. By using the radiometric method, a unique biotransformation process, the inversion of the (-)-enantiomer of alpha-methylfluorene-2-acetic acid to its (+)-enantiomer, has been demonstrated in the rat and monkey. The rate of (-)- to (+)-inversion was found to be faster in the rat than in the monkey. After single or repeated oral adminstration of the racemic modification or the (-)-enantiomer of cicloprofen to both species, the ratio of (+)- to (-)-enantiomers of cicloprofen in plasma, urine, or bile increased with time. At 5, 22, and 48 hr after oral administration of a single 50-mg/kg dose of the (-)-enantiomer, 14C-cicloprofen in rat plasma contained 20, 50, and 79%, respectively, of the (+)-enantiomer. After receiving the same dose of (-)-enantiomer, monkey plasma contained 16.5% and 32% of (+)-enantiomer at 8 and 24 hr, respectively. After oral administration of a single 50-mg/kg dose of the (+)-enantiomer of 14C-cicloprofen to rats and monkeys, the percentage of (-)-enantiomer in plasma varied from 2 to 15%. Since the administered (+)-enantiomer contained 4% of (-)-enantiomer and the (+)-enantiomer was excreted at a faster rate than its (-)-antipode by rats or monkeys, it is not known whether an occasional small percentage increase of (-)-enantiomer in plasma resulted from the (+)-to-(-) inversion, or from faster elimination of the (+)-enantiomer. Nevertheless, if (+)-to-(-) inversion does occur in these two species, the rate is much slower than for the (-)-to-(+) inversion.
D000818:Animals; D002855:Chromatography, Thin Layer; D005243:Feces / Q000032:analysis; D005449:Fluorenes / Q000097:blood / Q000378:metabolism* / Q000652:urine; D000882:Haplorhini; D008253:Macaca mulatta; D013058:Mass Spectrometry; D008968:Molecular Conformation; D009904:Optical Rotation; D051381:Rats; D013045:Species Specificity; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism
D005449:Fluorenes