Iwamoto K, Watanabe J, Araki K, Deguchi N, Sugiyama H
J Pharm Pharmacol. 1985 Jul;37(7):466-70. doi: 10.1111/j.2042-7158.1985.tb03041.x.
The effect of age on hepatic clearance of propranolol was investigated in male Wistar rats (3 to 104 weeks old). Pharmacokinetic analysis of the plasma propranolol data obtained after i.v. dosage (1.0 mg kg-1) indicated that both the elimination rate constant and the volume of distribution decreased with age between weeks 5 and 11, after when the distribution volume remained almost constant. The elimination rate constant was reduced consistently with age after 15 weeks. Total body clearance of the drug was reduced extensively with age between weeks 5 and 11 (94 to 43 ml min-1 kg-1) and decreased gradually thereafter. The plasma free fraction of propranolol also decreased with age, falling from more than 20% in 3 to 5 weeks-old rats to about 10% in rats of 52 to 104 weeks. In immature rats the renal clearance was approximately 5 to 12% of the total body clearance. Intrinsic hepatic clearance for unbound propranolol also decreased with age between weeks 7 and 24. As expected from the evidence that propranolol has a high extraction ratio, the extent of its hepatic clearance was significantly dependent on the liver blood flow. These data suggest that the age-dependent decrease in hepatic clearance of propranolol is largely due to a reduction of the elimination rate that might be accompanied by the age-dependent decrease in liver blood flow.
在雄性Wistar大鼠（3至104周龄）中研究了年龄对普萘洛尔肝清除率的影响。静脉注射剂量（1.0 mg kg-1）后获得的血浆普萘洛尔数据的药代动力学分析表明，在第5至11周之间，消除速率常数和分布容积均随年龄降低，之后分布容积几乎保持恒定。15周后，消除速率常数随年龄持续降低。在第5至11周之间，药物的总体清除率随年龄大幅降低（从94降至43 ml min-1 kg-1），此后逐渐下降。普萘洛尔的血浆游离分数也随年龄降低，从3至5周龄大鼠的20%以上降至52至104周龄大鼠的约10%。在未成熟大鼠中，肾清除率约为总体清除率的5%至12%。未结合普萘洛尔的肝内在清除率在第7至24周之间也随年龄降低。鉴于普萘洛尔具有高提取率的证据，其肝清除程度显著取决于肝血流量。这些数据表明，普萘洛尔肝清除率随年龄的降低很大程度上是由于消除速率的降低，这可能伴随着肝血流量随年龄的降低。
