Disposition of flurbiprofen in man: influence of stereochemistry and age

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 approximately 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 AUCs(0-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.

Predominant Contribution of UDP-Glucuronosyltransferase 2B7 in the Glucuronidation of Racemic Flurbiprofen in the Human Liver

“…This is because the amount of UGT in each recombinant UGT system and the relative abundance of UGT isozymes in the liver remain to be determined. In addition, this study represents the predominant glucuronidation of (R)-flurbiprofen, which is consistent with the results in humans given racemic flurbiprofen (Patel et al, 2003). Although the ratio of (R)-glucuronide to (S)-glucuronide varied among the UGT isozymes investigated, UGT1A1, 1A3, 1A9, 2B4, and 2B7 showed glucuronidation activity for both (R)-and (S)-flurbiprofen.…”

“…The plasma levels of (R)-flurbiprofen were lower than those of (S)-flurbiprofen in humans given racemic flurbiprofen with the plasma area under the curve ratio of (R)-flurbiprofen to (S)-flurbiprofen ranging from 0.79 to 0.88 (Davies, 1995). In addition, the plasma levels of (R)-flurbiprofen glucuronide were higher than those of (S)-flurbiprofen glucuronide, with a S/R ratio of 0.74 (Patel et al, 2003). This ratio is somewhat higher than that in vitro [in HLMs (0.48)], but the in vivo plasma levels of (R)-and (S)-flurbiprofen glucuronide are influenced by other processes such as plasma protein binding and excretion clearance.…”

“…Approximately 60 to 70% of the administered dose is eliminated as acyl glucuronides (Davies, 1995). After oral administration of racemic flurbiprofen (100 mg/kg), 8.4 and 7.3% of the dose was excreted into the urine as the acyl glucuronide of (R)-and (S)-flurbiprofen, respectively (Patel et al, 2003). However, the flurbiprofen glucuronidation fraction is difficult to determine and may be higher because of the instability of acyl glucuronides in vivo.…”

Inhibition of Methotrexate Uptake <i>via</i> Organic Anion Transporters OAT1 and OAT3 by Glucuronides of Nonsteroidal Anti-inflammatory Drugs

“…Although unbound plasma concentrations of NSAIDs-Glu have not been previously reported, total plasma concentrations of glucuronide conjugates of diclofenac (1.8±0.5 µM), 24) ibuprofen (3.6±2.0 µM), 23) naproxen (undetectable) 35) and flurbiprofen (undetectable) 36) have been determined after administration of clinical doses. Therefore, considering plasma concentration and inhibitory potencies, it is unlikely that NSAIDs-Glu other than diclofenac glucuronide inhibit OAT3-mediated MTX uptake at clinical doses.…”

Stereoselective Inhibition of Methotrexate Excretion by Glucuronides of Nonsteroidal Anti-inflammatory Drugs via Multidrug Resistance Proteins 2 and 4

“…Physiologic characteristics such as metabolic profile (Knihinicki et al, 1990;Rudy et al, 1991), protein binding in serum (Lagrange et al, 2000;Nagao et al, 2003), plasma concentrations (Foster and Jamali, 1988;Geisslinger et al, 1993Geisslinger et al, , 1994Patel et al, 2003), as well as pharmacologic effects (Muller et al, 1990), differ among enantiomers. Accordingly, the effect of NSAIDs and NSAIDs-Glu on the renal excretion of MTX probably differs among enantiomers or diastereomers.…”