Lintz W, Erlaçin S, Frankus E, Uragg H
Arzneimittelforschung. 1981;31(11):1932-43.
Following p.o. administration of 14C-labelled rac.-1-(e)-(m-methoxyphenyl)-2-(e)-dimethylaminomethyl-cyclohexan-1-(a)-ol hydrochloride (tramadol hydrochloride, CG 315, Tramal) to mice, hamsters, rats, guinea pigs, rabbits, dogs and man the metabolic pathways were investigated and the results compared. After synthesis of the reference substances the metabolites were identified by co-chromatography using both TLC (thin-layer chromatography) and HPLC (high-performance liquid chromatography) methods, by co-crystallization and by gas chromatography-mass spectrometry. In all species the main metabolic pathways are N- and O-demethylation (phase I reactions) and conjugation of O-demethylated compounds (phase II reactions). 11 metabolites are known, 5 arising by phase I reactions (M1 to M5) and 6 by phase II reactions (glucuronides and sulfates of M1, M4 and M5). The 5 phase I metabolites are mono-O-demethyl-tramadol (M1), mono-N-demethyl-tramadol (M2), di-N-demethyl-tramadol (M3), tri-N,O-demethyl-tramadol (M4) and di-N,O-demethyl-tramadol (M5). The biotransformation scheme of tramadol is qualitatively identical in man, dog, rabbit, guinea pig, rat, hamster and mouse. In all species M1 and M1-conjugates, M5 and M5-conjugates and M2 are the main metabolites, whereas M3, M4 and M4-conjugates were only formed in minor quantities. Following p.o. administration to man and animals 14C-tramadol are rapidly and almost completely absorbed. The unchanged drug and metabolites are mainly excreted via kidneys. The cumulative renal excretion of total radioactivity accounts for approximately 90% in man and varies from 86 to 100% in mouse, hamster, rat, guinea pig, rabbit and dog; the residual of the applied radioactivity appears in the feces. Apparently tramadol is metabolized much more rapidly in animals than in man. For that reason there are appreciable differences between man and animals in the amount of tramadol excreted unchanged in the urine (about 30% and 1% of the p.o. dose, respectively). After incubation with beta-glucuronidase and arylsulfatase at least 81% of the excreted radioactivity could be extracted from the urine of man animals (with the exception of the guinea pig and the rabbit). In man all extractable metabolites were identified.
给小鼠、仓鼠、大鼠、豚鼠、兔子、狗和人经口给予14C标记的消旋-1-(反式)-(间甲氧基苯基)-2-(反式)-二甲基氨基甲基-环己烷-1-(顺式)-醇盐酸盐（盐酸曲马多，CG 315，曲马多）后，研究了其代谢途径并比较了结果。合成参考物质后，通过使用薄层色谱（TLC）和高效液相色谱（HPLC）方法的共色谱法、共结晶法和气相色谱-质谱法鉴定代谢物。在所有物种中，主要代谢途径是N-去甲基化和O-去甲基化（I相反应）以及O-去甲基化化合物的结合（II相反应）。已知有11种代谢物，5种由I相反应产生（M1至M5），6种由II相反应产生（M1、M4和M5的葡糖醛酸苷和硫酸盐）。5种I相代谢物是单-O-去甲基曲马多（M1）、单-N-去甲基曲马多（M2）、二-N-去甲基曲马多（M3）、三-N,O-去甲基曲马多（M4）和二-N,O-去甲基曲马多（M5）。曲马多在人、狗、兔子、豚鼠、大鼠、仓鼠和小鼠中的生物转化模式在定性上是相同的。在所有物种中，M1及其结合物、M5及其结合物和M2是主要代谢物，而M3、M4及其结合物仅少量形成。给人和动物经口给药后，14C-曲马多迅速且几乎完全被吸收。未变化的药物和代谢物主要通过肾脏排泄。总放射性的累积肾排泄在人中约占90%，在小鼠、仓鼠、大鼠、豚鼠、兔子和狗中为86%至100%；施用放射性的残余物出现在粪便中。显然，曲马多在动物中的代谢比在人中快得多。因此，人和动物在尿中未变化排泄的曲马多量上存在明显差异（分别约为口服剂量的30%和1%）。用β-葡糖醛酸酶和芳基硫酸酯酶孵育后，至少81%的排泄放射性可从人及动物（豚鼠和兔子除外）的尿液中提取出来。在人中鉴定出了所有可提取的代谢物。
