The Disposition and Metabolism of Flurbiprofen in Several Species Including Man

Abstract

Flurbiprofen was rapidly absorbed in all species studied. 2. Half-lives of elimination measured 0 to 12 h after a single dose were: mouse 3.4 h, rat 2.5 h, dog 10.1 h, baboon 3.1 h and man 3.9 h. A second phase of elimination was seen in the dog. Flurbiprofen accumulated in the circulation of the dog on repeated dosing. 3. After dosing with [14C]flurbiprofen, tissue levels of radioactivity in dog and baboon were similar to that in plasma. In the rat, levels were slightly elevated in liver, kidney, large intestine and thyroid after repeated dosing. 4. The dog excreted equal amounts of radioactivity in urine and faeces. In other species renal excretion was the more important route. 5. Six metabolites have been detected, the most important being: 2-(2-fluoro-4'-hydroxy-4-biphenylyl)propionic acid (metabolite 1), 2-(i-fluoro-3',4'-dihydroxy-4-biphenylyl)propionic acid (metabolite 2) and 2-(2-fluoro-3'-hydroxy-4'-methoxy-4-biphenylyl)propionic acid (metabolite 3). The proportions of the metabolites and the extents of their conjugation varied among the species. 6. Metabolites were detected in the circulation of rat, mouse and baboon but not in dog and man. 7. Flurbiprofen did not affect the hepatic drug-metabolizing enzyme system of rat. 8. Flurbiprofen was extensively bound to serum protein of rat, dog, baboon and man.

Stereoselective disposition of flurbiprofen in uraemic patients.

“…Flurbiprofen, and most of the 2-arylpropionic acid nonsteroidal anti-inflammatory drugs are characterized by a low systemic clearance and a small volume of distribution, and therefore their disposition is sensitive to changes in plasma protein binding which is usually extensive (Lin et al, 1987;Risdall et al, 1978). The uraemic patients of this study exhibited a modest but significant degree of enantioselectivity in both oral clearance and volume of distribution which disappeared when unbound drug concentrations were considered (Tables 2 and 4).…”

“…Like other arylpropionic acids, the major mode of elimination is metabolism to either glucuronide conjugates or to oxidized forms which also undergo glucuronidation (Drew & Knights, 1985;Risdall et al, 1978). Traditionally, elimination of such drugs was considered to be insensitive to changes in renal function (Fabre & Balant, 1976) but more recently a number of exceptions to this expectation have been documented.…”

“…The protein binding of both R-and S-flurbiprofen was determined by ultrafiltration as described previously of oral 50 mg doses were excreted in urine (Risdall et al, 1978) and the bioavailability of 100, 200, or 300 mg tablets relative to a solution was 94% (Spzunar et al, 1987). The accumulation factor after multiple dose administration was calculated as the ratio AUC last dose/AUC first dose as proposed by Wagner (1988).…”

Stereoselective disposition of flurbiprofen in normal volunteers.

“…Flurbiprofen does not appear to undergo enantiomeric inversion in humans and is eliminated predominantly through the formation of oxidation products and acyl glucuronides Risdall et al, 1978;Szpunar et al, 1987) as indicated in Figure 1. In common with most arylpropionic acids, flurbiprofen is characterized by a relatively low clearance and volume of distribution; plasma protein binding and intrinsic clearance may therefore be expected to be primary determinants of its disposition (Lin et al, 1987;Szpunar et al, 1987).…”

“…This study examines the disposition of the enantiomers of flurbiprofen in terms of total and unbound drug concentrations and the formation of known metabolites. Figure 1 Proposed metabolic fate of flurbiprofen in humans (adapted from Risdall et al, 1978). The percent dose recovered as flurbiprofen, 4'-hydroxyflurbiprofen (4'-OHF), 3',4'-dihdroxyflurbiprofen (3',4'-DOHF) and 3'-hydroxy, 4'-methoxy flurbiprofen (3'-OH,4'-CH30F) is indicated and represents the sum of unconjugated and conjugated species.…”