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Abstract
1. The stereoselective metabolism and pharmacokinetics of the enantiomers of flurbiprofen were investigated following the oral administration of the racemic drug (100 mg) to four young and four elderly healthy volunteers (two males and two females per group).
2. The stereochemical composition of the drug and the 4′-hydroxy- metabolite in serum and the drug, 4′-hydroxy- and 3′-hydroxy-4′-methoxy- metabolites, both free and conjugated, in urine were determined by a direct chromatographic method of enantiomeric analysis.
3. Modest enantioselectivity in clearance (CL S/R: young, 0.86; elderly, 0.88) was largely responsible for the apparent elimination half-life of (S)-flurbiprofen being significantly greater ( p<0.01) than that of the R-enantiomer in both age groups (young, S: 5.2 ± 0.7 versus R: 4.5 ± 0.6 h; elderly, S: 9.6 ± 1.2 versus R: 7.1 ± 1.0 h). The serum concentrations of 4′-hydroxyflurbiprofen were five- to 20-fold lower than those of the corresponding drug enantiomers, stereoselective disposition being evident in the significantly greater ( p<0.05) apparent half-lives of the S- compared with the R-enantiomer in both groups (young, S: 10.6 ± 2.4 versus R: 6.7 ± 1.1 h; elderly, S: 13.7 ± 1.7 versus R: 10.2 ± 1.2 h).
4. Some 60 and 72% of the dose was excreted in 24-h urine in elderly and young volunteers, respectively, a significantly greater ( p<0.05) proportion of which was of the R-configuration in both age groups (S/R: young, 0.87; elderly, 0.81). The major urinary excretion products were flurbiprofen and 4′-hydroxyflurbiprofen, and their acyl-conjugates in both groups.
5. Age-associated differences in the pharmacokinetics of flurbiprofen occurred in a non-stereoselective manner and were primarily as a consequence of a significant ∼ 40% decrease ( p<0.01) in clearance of both enantiomers in the elderly due to reduced metabolic activity. Consequently, the elderly had greater exposure to both enantiomers, as reflected by the AUCs0–inf being significantly higher ( p<0.05), by 60%, in this age group compared with the young.
6. The findings suggest that age-related alterations in the disposition of flurbiprofen could have significant implications for the use of the drug in the elderly.