Osman M, Chandrasekaran A, Chan K, Scatina J, Ermer J, Cevallos W, Sisenwine S F
Wyeth-Ayerst Research, Princeton, New Jersey 08543, USA.
J Clin Pharmacol. 1998 Aug;38(8):744-52. doi: 10.1002/j.1552-4604.1998.tb04815.x.
The metabolic disposition of 14C-bromfenac, an orally active, potent, nonsteroidal, nonnarcotic, analgesic agent was investigated in six healthy male subjects after a single oral 50-mg dose. The absorption of radioactivity was rapid, producing a mean maximum plasma concentration (Cmax) of 4.9 +/- 1.8 microg x equiv/mL, which was reached 1.0 +/- 0.5 hours after administration. Unchanged drug was the major component found in plasma, and no major metabolites were detected in the plasma. Total radioactivity recovered over a 4-day period from four of the six subjects averaged 82.5% and 13.2% of the dose in the urine and feces, respectively. Excretion into urine was rapid; most of the radioactivity was excreted during the first 8 hours. Five radioactive chromatographic peaks, a cyclic amide and four polar metabolites, were detected in 0- to 24-hour urine samples. Similarity of metabolite profiles between humans and cynomolgus monkeys permitted use of this animal model to generate samples after a high dose for structure elucidation. Liquid chromatography/mass spectrometry (LC/MS) analysis of monkey urine samples indicated that the four polar metabolites were two pairs of diastereoisomeric glucuronides whose molecular weight differed by two daltons. Enzyme hydrolysis, cochromatography, and LC/MS experiments resulted in the identification of a hydroxylated cyclic amide as one of the aglycones, which formed a pair of diastereoisomeric glucuronides after conjugation. Data also suggested that a dihydroxycyclic amide formed by the reduction of the ketone group that joins the phenyl rings formed the second pair of diastereoisomeric glucuronides. Further, incubation of various reference standards in control (blank) urine and buffer with and without creatinine indicated that the hydroxy cyclic amide released from enzyme hydrolysis can undergo ex vivo transformations to a condensation product between creatinine and an alpha-keto acid derivative of the hydroxy cyclic amide that is formed by oxidation and ring opening. Further experiments with a dihydroxylated cyclic amide after reduction of the keto function indicated that it too can form a creatinine conjugate.
在6名健康男性受试者单次口服50毫克剂量后，对一种口服活性、强效、非甾体、非麻醉性镇痛药14C-溴芬酸的代谢情况进行了研究。放射性物质吸收迅速，给药后1.0±0.5小时达到平均最大血浆浓度（Cmax）为4.9±1.8微克当量/毫升。原形药物是血浆中发现的主要成分，血浆中未检测到主要代谢物。6名受试者中的4名在4天内回收的总放射性分别平均占剂量的82.5%和13.2%，分别存在于尿液和粪便中。尿液排泄迅速；大部分放射性物质在最初8小时内排出。在0至24小时尿液样本中检测到5个放射性色谱峰、1个环状酰胺和4个极性代谢物。人类和食蟹猴之间代谢物谱的相似性使得可以使用这种动物模型在高剂量后生成样本以进行结构解析。对猴尿样本的液相色谱/质谱（LC/MS）分析表明，4个极性代谢物是两对非对映异构葡糖醛酸苷，其分子量相差2道尔顿。酶水解、共色谱和LC/MS实验导致鉴定出一种羟基化环状酰胺为糖苷配基之一，其在结合后形成一对非对映异构葡糖醛酸苷。数据还表明，由连接苯环的酮基还原形成的二羟基环状酰胺形成了第二对非对映异构葡糖醛酸苷。此外，将各种参考标准品在含和不含肌酐的对照（空白）尿液和缓冲液中孵育表明，酶水解释放的羟基环状酰胺可在体外转化为肌酐与羟基环状酰胺的α-酮酸衍生物之间的缩合产物，该α-酮酸衍生物是通过氧化和开环形成的。对酮功能还原后的二羟基化环状酰胺进行的进一步实验表明，它也可以形成肌酐缀合物。
