THE PHARMACOKINETICS OF NAPROXEN, ITS METABOLITE O-DESMETHYLNAPROXEN,AND THEIR ACYL GLUCURONIDES IN HUMANS - EFFECT OF CIMETIDINE

1 The pharmacokinetics of 500 mg naproxen given orally were described in 10 subjects using a direct h.p.l.c. analysis of the acyl glucuronid e conjugates of naproxen and its metabolite O-desmethylnaproxen. 2 The mean elimination half-life of naproxen was 24.7 +/- 6.4 h (range 7 to 36 h). 3 Naproxen acyl glucuronide accounted for 50.8 +/- 7.3% of the dose recovered in the urine, its isomerised conjugate isoglucuronide for 6.5 +/- 2.0%, O-desmethylnaproxen acyl glucuronide for 14.3 +/- 3. 4%, and its isoglucuronide for 5.5 +/- 1.3%. Naproxen and O-desmethyln aproxen were excreted in negligible amounts (< 1%). 4 Even though the urine pH of the subjects was kept acid in order to stabilize the acyl glucuronides, isomerisation took place in blood. 5 The extents of plas ma binding of the unconjugated compounds were 98% (naproxen) and 100% (O-desmethylnaproxen), while naproxen acyl glucuronide binding was 92% ; that of its isomer isoglucuronide 66%. O-desmethylnaproxen acyl gluc uronide was 72% bound and its isoglucuronide was 42% bound. 6 Cimetidi ne (400 mg twice daily) decreased the t1/2 of naproxen by 39-60% (mean 47.3 +/- 11.5%; P = 0.0014) from 24.7 +/- 6.4 h to 13.2 +/- 1.0 h. It increased (10%) the urinary recovery of naproxen acyl glucuronide (P = 0.0492). The urinary recoveries of naproxen isoglucuronide and O-des methylnaproxen acyl glucuronide remained unchanged.