INVERSION OF OPTICAL CONFIGURATION OF ALPHA-METHYLFLUORENE-2-ACETIC ACID (CICLOPROFEN) IN RATS AND MONKEYS

  • 1 January 1976
    • journal article
    • research article
    • Vol. 4  (4) , 330-339
Abstract
A simple and sensitive radiometric method to determine the individual enantiomers of cicloprofen was developed. 14C-Cicloprofen was converted to its L-leucine diastereoisomers, which were separated by TLC and quantified by measuring the radioactivity in the area corresponding to each individual diastereoisomer. This technique was also 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, was demonstrated in the rat and monkey. The rate of (-)- to (+)-inversion was faster in the rat than in the monkey. After single or repeated oral administration 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 h 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 h, 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 2-15%. 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 2 species, the rate is much slower than for the (-)-to-(+) inversion.