Pharmacokinetics of naproxen, its metabolite O‐desmethylnaproxen, and their acyl glucuronides in humans

Abstract

The aim of this investigation was to assess the pharmacokinetics of naproxen in 10 human subjects after an oral dose of 500 mg using a direct HPLC analysis of the acyl glucuronide conjugates of naproxen and its metabolite O-desmethylnaproxen. The mean t1/2 of naproxen in 9 subjects 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 case (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 cent, and its isoglucuronide for 5.5 +/- 1.3 per cent (n = 10; 100 h collection period). Naproxen and O-desmethylnaproxen are excreted in negligible 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 glucuronides, isomerization takes place in blood when the acyl glucuronide is released from the liver for excretion by the kidney. Binding to plasma proteins was measured as 98 per cent and 100 per cent, respectively for the unconjugated compounds naproxen and O-desmethylnaproxen. Binding of the acyl glucuronides was less, being 92 per cent; for naproxen acyl glucuronide, 66 per cent for naproxen isoglucuronide, 72 per cent for O-desmethylnaproxen acyl glucuronide and 42 per cent for O-desmethylnaproxen isoglucuronide.

An LC–MS/MS procedure for the quantification of naproxen in human plasma: Development, validation, comparison with other methods, and application to a pharmacokinetic study

“…Many of the methods reported in Table 3 have been applied in pharmacokinetic studies [26,[60][61][62][63][64][65][66][67][68]. However, besides interferences by co-eluting drugs, especially other NSAIDs, inter-day, intra-day CV's, and recovery data, no additional validation experiments are provided by most of the methods listed in Table 3.…”

“…Until today, no liquid chromatography of naproxen has been reported with a run time of less than 5 min. More than 50% of the liquid chromatography based methods outlined in Table 3 report run times above 10 min (14 reports [21][22][23][24]27,28,31,32,35,36,38,40,44,56]). Due to UV and fluorescence detection, of which especially the former lacks additional analyte discrimination, extended run times are needed to achieve good chromatographic resolution and to avoid potential interferences from endogenous components, naproxen metabolites or co-administered drugs.…”

Recent developments in analytical determination of furosemide

“…Human plasma and urine [72] Using a Bondapak C18 reversed-phase column (15 cm × 3.9 mm ID, 10 m particle size) for plasma and a resolve spherical C18 column (15 cm × 3.9 mm ID, 5 m particle size) for urine; mobile phase containing 0.01 M potassium dihydrogen (62:38, v/v) adjusted to pH 3.0 with phosphoric acid (1:3, v/v); mixture filtered through a 0.22 m membrane filter under vacuum; flow-rate 1.5 mL min −1 ; at excitation and emission wavelengths 225 and 389 nm, respectively…”

Determination of furosemide in plasma and urine using monolithic silica rod liquid chromatography

“…drugs which use the same renal secretory pathways) and in bioequivalence studies. Several HPLC, HPLC/MS and CE methods have been developed for the determination of furosemide in biological fluids [12][13][14][15][16][17][18][19]. However, employing classical HPLC columns can be rather time consuming, especially in larger pharmacokinetic studies.…”