Murthy S S, Nelson W L, Shen D D, Power J M, Cahill C M, McLean A J
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Drug Metab Dispos. 1991 Nov-Dec;19(6):1093-100.
The effect of verapamil co-administration on the hepatic first-pass clearance of metoprolol was investigated in dogs. Plasma concentration-time course of metoprolol enantiomers and urinary recovery of oxidative metabolites were determined after a single iv (0.51 mg/kg) and an oral (1.37 mg/kg) dose of deuterium-labeled pseudoracemic metoprolol, with or without concomitant administration of racemic verapamil (3 mg/kg). Verapamil inhibited both the systemic and oral clearance of metoprolol by about 50-70%. The first-pass effect of metoprolol was completely abolished after co-administration of verapamil, reflecting a marked alteration in the degree of hepatic extraction of metoprolol from intermediate to low. The hepatic clearance of metoprolol was slightly (S)-enantioselective (R/S ratio = 0.89 +/- 0.04) in control dogs. Inhibition of hepatic clearance of metoprolol by verapamil was selective towards (S)-metoprolol, such that the enantioselectivity in hepatic clearance toward (S)-metoprolol disappeared following verapamil co-administration (R/S ratio = 1.01 +/- 0.05). Urinary metabolite profiles indicated that O-demethylation and N-dealkylation were the major pathways of oxidative metabolism in the dog. alpha-Hydroxymetoprolol was a minor metabolite in urine. N-Dealkylation showed a strong preference for (S)-metoprolol, whereas O-demethylation and alpha-hydroxylation exhibited a modest selectivity toward (R)-metoprolol; hence, the slight (S)-enantioselectivity in the overall hepatic clearance. Comparison of metoprolol metabolite formation clearances in the absence or presence of verapamil co-administration showed that all three oxidative pathways were inhibited by 60-80%. The greater inhibition of hepatic clearance observed with (S)-metoprolol as compared to (R)-metoprolol was attributed to a significant (S)-enantioselective inhibition in the O-demethylation of metoprolol by verapamil.
在犬体内研究了维拉帕米联合给药对美托洛尔肝脏首过清除率的影响。在给予氘标记的伪外消旋美托洛尔单次静脉注射（0.51mg/kg）和口服（1.37mg/kg）剂量后，测定了美托洛尔对映体的血浆浓度-时间过程以及氧化代谢产物的尿回收率，给药时伴有或不伴有消旋维拉帕米（3mg/kg）。维拉帕米使美托洛尔的全身清除率和口服清除率均降低约50%-70%。维拉帕米联合给药后，美托洛尔的首过效应完全消除，这反映出美托洛尔肝脏摄取程度从中等变为低等的显著改变。在对照犬中，美托洛尔的肝脏清除率对（S）-对映体有轻微选择性（R/S比值 = 0.89±0.04）。维拉帕米对美托洛尔肝脏清除率的抑制对（S）-美托洛尔具有选择性，因此在维拉帕米联合给药后，肝脏对（S）-美托洛尔清除率的对映体选择性消失（R/S比值 = 1.01±0.05）。尿代谢产物谱表明，O-去甲基化和N-脱烷基化是犬体内氧化代谢的主要途径。α-羟基美托洛尔是尿液中的次要代谢产物。N-脱烷基化对（S）-美托洛尔有强烈偏好，而O-去甲基化和α-羟基化对（R）-美托洛尔有适度选择性；因此，在总体肝脏清除率中存在轻微的（S）-对映体选择性。比较有无维拉帕米联合给药时美托洛尔代谢产物形成清除率，结果显示所有三种氧化途径均被抑制60%-80%。与（R）-美托洛尔相比，（S）-美托洛尔的肝脏清除率受到更大抑制，这归因于维拉帕米对美托洛尔O-去甲基化有显著的（S）-对映体选择性抑制作用。
