Iwamoto K, Watanabe J, Satoh M, Deguchi N, Sugiyama H
Biochem Pharmacol. 1986 Apr 1;35(7):1149-52. doi: 10.1016/0006-2952(86)90152-8.
The effect of age on the hepatic clearance of propranolol was studied by perfusing the liver isolated from 3- to 104-week-old rats. Propranolol levels in the recirculating perfusate declined biexponentially with time in all age groups. When the liver isolated from 7-week-old rats was perfused with propranolol (1 microgram/ml, 100 ml), hepatic clearance of this drug by the perfused liver (CLperf) increased from 0.589 to 1.14 ml X min-1 X (g liver)-1 with the increase of the perfusion flow rate from 1.0 to 2.0 ml X min-1 X (g liver)-1, confirming evidence of "perfusion-limited" hepatic clearance for this drug. Furthermore, there was no initial concentration(dose)-dependence in CLperf up to 2.5 micrograms/ml (i.e. 250 micrograms/organ). The effect of age on CLperf was then investigated by perfusing the isolated liver with 1.0 micrograms/ml propranolol at 2.0 ml X min-1 X (g liver)-1. Elimination of this drug from the perfusion medium was relatively rapid in 5- to 7-week-old rats, yielding the highest CLperf in these relatively young rats [approximately 1.0 to 1.1 ml X min-1 X (g liver)-1]. In contrast, CLperf values in both immature and older rats were 0.5 ml X min-1 X (g liver)-1 or less. The in vitro intrinsic hepatic clearance estimated in 5- and 7-week-old rats was about ten times as high as that in 104-week-old rats.
通过灌注从3至104周龄大鼠分离的肝脏，研究了年龄对普萘洛尔肝清除率的影响。在所有年龄组中，再循环灌注液中普萘洛尔水平随时间呈双指数下降。当用普萘洛尔（1微克/毫升，100毫升）灌注从7周龄大鼠分离的肝脏时，随着灌注流速从1.0增加到2.0毫升·分钟⁻¹·（克肝脏）⁻¹，灌注肝脏对该药物的肝清除率（CLperf）从0.589增加到1.14毫升·分钟⁻¹·（克肝脏）⁻¹，证实了该药物“灌注受限”肝清除率的证据。此外，在高达2.5微克/毫升（即250微克/器官）时，CLperf没有初始浓度（剂量）依赖性。然后通过以2.0毫升·分钟⁻¹·（克肝脏）⁻¹的流速用1.0微克/毫升普萘洛尔灌注分离的肝脏，研究年龄对CLperf的影响。在5至7周龄大鼠中，该药物从灌注介质中的消除相对较快，在这些相对年轻的大鼠中产生最高的CLperf[约1.0至1.1毫升·分钟⁻¹·（克肝脏）⁻¹]。相比之下，未成熟和老年大鼠的CLperf值均为0.5毫升·分钟⁻¹·（克肝脏）⁻¹或更低。5周龄和7周龄大鼠的体外肝内在清除率估计比104周龄大鼠高约10倍。
