Stereoselective disposition of flurbiprofen in uraemic patients.

Abstract

1 Both single and multiple oral doses of 50 mg racemic flurbiprofen were given to eight patients with mild to moderate renal impairment. The plasma and urine concentrations of the R-and S-enantiomers of flurbiprofen and its major metabolites were measured by a stereoselective h.p.l.c. assay. 2 For R-flurbiprofen the oral clearance (mean ± s.d.: 38.3 ± 12.8 vs 30.8 ± 11.5 ml min-1) and volume of distribution (V.; 17.6 ± 3.9 vs 14.6 ± 2.5 1) were significantly greater (P < 0.05) than for the S-enantiomer. A significantly greater (P < 0.05) percent of the dose was excreted in the urine in the R-configuration (16.4 ± 6.0 vs 10.9 ± 4.2%). 3 Plasma protein binding of the enantiomers of flurbiprofen was determined by ultrafiltration. The unbound clearance and unbound V, were not different between enantiomers consistent with the (not significantly) greater percent unbound of Rflurbiprofen (0.079 ± 0.014%) vs S-flurbiprofen (0.064 ± 0.015%). 4 Relative to normal volunteers, the uraemic subjects exhibited a significantly greater (P < 0.05) oral clearance, V, and percent unbound for both enantiomers; unbound clearance and unbound V, did not differ from healthy controls.5 The disposition of flurbiprofen enantiomers was not changed upon multiple dosing and no evidence of futile cycling was found. Adjustment of flurbiprofen dosing rate in uraemic subjects is not indicated on the basis of pharmacokinetics.

Flurbiprofen concentration in soft tissues is higher after topical application than after oral administration

“…In the present study, the mean plasma concentration was 3331 ng ml -1 in the patients receiving orally administered flurbiprofen. This result is comparable with the previous data [9,[11][12][13][14]. Concerning topical application with the same two tapes as used in the present study, it was reported that the Cmax in the plasma was 870 ng ml -1 at the tmax of 11.6 h [8].These data are also comparable with the present result (1369 ng ml -1 ) on the plasma concentration in the patients receiving topically applied flurbiprofen.…”

“…After oral administration of a tablet containing 40 mg flurbiprofen, the Cmax in the plasma was 5600 ng ml -1 and the tmax was 1.4 h [9]. After oral administration of a tablet containing 50 mg flurbiprofen, several studies reported that the Cmax ranged from 4200 to 8200 ng ml -1 and that the tmax ranged from 1.3 to 2.8 h [11][12][13][14]. In the present study, the mean plasma concentration was 3331 ng ml -1 in the patients receiving orally administered flurbiprofen.…”

The influence of renal function on the enantioselective pharmacokinetics and pharmacodynamics of ketoprofen in patients with rheumatoid arthritis.

“…Furthermore, in the presence of the 'futile cycle', renal dysfunction should cause greater elevations in AUCu for those drugs (such as ketoprofen) cleared predominantly by acyl-glucuronidation relative to drugs subject to significant phase I (non-conjugative) metabolism. This might explain why Knadler and associates [24] were unable to demonstrate 'futile cycling' based upon measurement of unbound flurbiprofen enantiomers in uraemic patients, since elimination of this drug proceeds by substantial oxidative metabolic pathways in addition to glucuronide conjugation.…”

“…Recent studies with flurbiprofen [24,32] have shown a decrease in plasma protein binding of both enantiomers in uraemic patients, compared with normal subjects, which was attributed to a significantly lower plasma albumin concentration in the former. Some of our patients (none of whom was clinically uraemic) had serum albumin concentration values below the normal range.…”

“…Few studies have examined the influence of renal function on the disposition of 2-arylpropanoic acid NSAIDs, and still fewer have addressed this issue with regard to unbound drug concentrations [11,23,24]. No studies have described the disposition of ketoprofen enantiomers in terms of unbound drug.…”