Vree T B, van den Biggelaar-Martea M, Verwey-van Wissen C P, Vree J B, Guelen P J
Department of Clinical Pharmacy, Academic Hospital Sint Radboud, Nijmegen, The Netherlands.
Biopharm Drug Dispos. 1993 Aug;14(6):491-502. doi: 10.1002/bdd.2510140605.
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.
本研究的目的是通过对萘普生及其代谢物O-去甲基萘普生的酰基葡糖醛酸共轭物进行直接高效液相色谱分析，评估10名人类受试者口服500 mg剂量萘普生后的药代动力学。9名受试者中萘普生的平均t1/2为24.7±6.4小时（范围为16至36小时）。因此，在第10名受试者中发现的7.4小时的t1/2必须被视为一个特殊情况（p<0.0153）。萘普生酰基葡糖醛酸占给药剂量的50.8±7.32%，其异构化共轭物异葡糖醛酸占6.5±2.0%，O-去甲基萘普生酰基葡糖醛酸占14.3±3.4%，其异葡糖醛酸占5.5±1.3%（n = 10；收集期100小时）。萘普生和O-去甲基萘普生的排泄量可忽略不计（<1%）。尽管为了稳定酰基葡糖醛酸而将受试者的尿液pH保持在酸性（pH范围5.0 - 5.5），但当酰基葡糖醛酸从肝脏释放以通过肾脏排泄时，它会在血液中发生异构化。未结合的化合物萘普生和O-去甲基萘普生与血浆蛋白的结合率分别测定为98%和100%。酰基葡糖醛酸的结合率较低，萘普生酰基葡糖醛酸为92%；萘普生异葡糖醛酸为66%，O-去甲基萘普生酰基葡糖醛酸为72%，O-去甲基萘普生异葡糖醛酸为42%。
