PHARMACOKINETICS OF NAPROXEN, ITS METABOLITE O-DESMETHYLNAPROXEN, ANDTHEIR ACYL GLUCURONIDES IN HUMANS

The aim of this investigation was to assess the pharmacokinetics of na proxen in 10 human subjects after an oral dose of 500 mg using a direc t HPLC analysis of the acyl glucuronide conjugates of naproxen and its metabolite O-desmethylnaproxen. The mean t1/2, of naproxen in 9 subje cts was 24.7+/-6.4 h (range 16 to 36 h). The t1/2, of 7.4 as found in subject number 10 must, therefore, be regarded as an extraordinary cas e (p < 0.0153). Naproxen acyl glucuronide accounts for 50.8+/-7.32 per cent of the dose, its isomerized conjugate isoglucuronide for 6.5+/-2 .0 per cent, O-desmethylnaproxen acyl glucuronide for 14.3+/-3.4 per c ent, and its isoglucuronide for 5.5+/-1.3 per cent (n = 10; 100 h coll ection period). Naproxen and O-desmethylnaproxen are excreted in negli gible amounts (< 1 per cent). Even though urine pH of the subjects was kept acid (range pH 5.0-5.5) in order to stabilize the acyl glucuroni des, isomerization takes place in blood when the acyl glucuronide is r eleased from the liver for excretion by the kidney. Binding to plasma proteins was measured as 98 per cent and 100 per cent, respectively fo r the unconjugated compounds naproxen and O-desmethylnaproxen. Binding of the acyl glucuronides was less, being 92 per cent; for naproxen ac yl glucuronide, 66 per cent for naproxen isoglucuronide, 72 per cent f or O-desmethylnaproxen acyl glucuronide and 42 per cent for O-desmethy lnaproxen isoglucuronide.