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为探讨美多心安代谢物总体水平在β相缓慢下降的机理,采用离体单向灌流大鼠肝脏（IPRL）研究美多心安及其代谢物在肝脏中的处置。在IPRL中,美多心安输入液浓度为74.80μmol／L时,metoprololacid在输出液中的浓度经过（60±10）min才达到稳态,远远大于美多心安及其它两种代谢物。α-hydroxymetoprolol和O-demethyl-metoprolol达到稳态所需的时间（分别为20.3±14.5,11.3±76,和8.7±1.2min）。在使用不含有美多心安的Krebe缓冲液的灌流清洗期间,metoPrololacid的每克肝脏的清除率为0.4±0.2ml／min,远低于美多心安,每克肝脏。α-hydroxymetoprolol和O-demethylmetoprolol的相应值分别为6.3±1.1,0.8±0.2和1.1±0.1ml／min。反之,metoprololacid转运出肝细胞的半衰期长达102±36.2min,远远大于美多心安,α-hydroxymetoprolol和O-demethylmetoprolol所需的时间为5.1±3.5,7.4±1.9和7.3±1.9。。因此,实验结果表明肝静脉窦基股可能是metoprololacid的扩散屏障,metoprololacid从肝细胞中转运出来的极低效率,可以作为解释美多心安代谢物血浆总体浓度保持稳定的机理之一。
To investigate the mechanism of the slow down of the total metabolites of melatonin in β-phase, we investigated the treatment of metoprolol and its metabolites in the liver using unidirectional perfusion rat liver (IPRL). In the IPRL, Metoprololacid reached the steady-state at the concentration of 74.80 μmol / L in the effluent for 60 ± 10 min, much greater than Metoprolol and the other two metabolites. The time required for α-hydroxymetoprolol and O-demethyl-metoprolol to reach steady state (20.3 ± 14.5, 11.3 ± 76, and 8.7 ± 1.2 min, respectively). During perfusion purging with Krebe’s buffer, which contains no Metoprolol, metoPrololacid has a clearance rate of 0.4 ± 0.2 ml / min per gram of liver, far lower than Metoprolol, per gram of liver. The corresponding values for α-hydroxymetoprolol and O-demethylmetoprolol were 6.3 ± 1.1, 0.8 ± 0.2 and 1.1 ± 0.1 ml / min, respectively. In contrast, the half-life of metoprololacid translocating out of hepatocytes was as long as 102 ± 36.2 min, much longer than 5.1 ± 3.5, 7.4 ± 1.9 and 7.3 ± 1.9 for metoprolol, α-hydroxymetoprolol and O-demethylmetoprolol. . Therefore, the experimental results show that hepatic sinusoidal basal ganglia may be the diffusion barrier of metoprololacid, and the extremely low efficiency of metoprololacid transport from hepatocytes may serve as a mechanism to explain the steady plasma total concentration of metoprolol metabolites.