Kellner H M, Volz M, Badder E, Kürzel G U, Eckert H G
Pharma Research, Hoechst AG, Frankfurt/Main, Federal Republic of Germany.
J Hepatol. 1991;13 Suppl 3:S48-61; discussion S62. doi: 10.1016/0168-8278(91)90008-y.
The studies were performed in healthy male rats and in one male dog after oral and intravenous administration of [2-carbamoyl-14C]HOE 077. HOE 077 wa rapidly and completely absorbed after oral administration. In blood, tmax was at about 0.5 h and cmax 2.63 +/- 0.92 micrograms equivalents/g in rats (5 mg/kg), and 18.1 micrograms equivalents/g in the dog (15 mg/kg). The predominant half-lives for total radioactivity were in the range of 1 h in the rats and 2 h in the dog, independent of the route of administration. The radioactivity was distributed throughout the body. The highest concentrations were detected in kidneys and liver. Urine (75% of dose) was the main route of excretion after oral and intravenous administration. The radioactivity was almost entirely eliminated 2 days after administration. The compound was intensively metabolized by rat and dog. While the parent compound was the major component in plasma at early time after dosage, more than ten metabolites, accompanied by only small amounts of original substance, were detected in the urine of the first study day. In faeces only metabolites were found. The known metabolites are assumed to be formed by oxidative degradation of the alkylic side chains of the molecule, preferably that in the 2-position of the pyridine ring. The main metabolite in the dog urine was a 2-hydroxyethyl derivative (M4), and in the rat a hippuric acid analogue of HOE 077 (M6). The pyridine carboxylic acid in 2-position of the side chain of HOE 077 (M2) was the predominant metabolite in faeces of rat and dog. In both animal species, more than 80% of the administered radioactivity had been identified. In rats with liver damage caused by treatment with CCl4 the amount of parent compound increased and the rates of formation of metabolites were lower than in normal rats. This can be interpreted as a consequence of the diminished number of hepatocytes able to metabolize HOE 077.
这些研究在健康雄性大鼠以及一只雄性犬口服和静脉注射[2-氨基甲酰基-¹⁴C]HOE 077后进行。HOE 077口服给药后迅速且完全吸收。在大鼠（5 mg/kg）中，血药达峰时间（tmax）约为0.5小时，血药峰浓度（cmax）为2.63±0.92微克当量/克，在犬（15 mg/kg）中为18.1微克当量/克。总放射性的主要半衰期在大鼠中为1小时左右，在犬中为2小时，与给药途径无关。放射性分布于全身。在肾脏和肝脏中检测到最高浓度。口服和静脉给药后，尿液（剂量的75%）是主要排泄途径。给药后2天放射性几乎完全消除。该化合物在大鼠和犬体内被大量代谢。给药后早期血浆中母体化合物是主要成分，但在研究首日的尿液中检测到十多种代谢物，仅伴有少量原物质。在粪便中仅发现代谢物。已知代谢物被认为是由分子的烷基侧链，优选吡啶环2位的侧链经氧化降解形成的。犬尿液中的主要代谢物是2-羟乙基衍生物（M4），大鼠尿液中的主要代谢物是HOE 077的马尿酸类似物（M6）。HOE 077侧链2位的吡啶羧酸（M2）是大鼠和犬粪便中的主要代谢物。在两种动物中，已鉴定出超过80%的给药放射性。在用四氯化碳处理导致肝损伤的大鼠中，母体化合物的量增加，代谢物的形成速率低于正常大鼠。这可以解释为能够代谢HOE 077的肝细胞数量减少的结果。
