Masten L W
Drug Alcohol Depend. 1979 Sep;4(5):381-90. doi: 10.1016/0376-8716(79)90070-x.
Following the repeated oral administration of l-alpha-acetylmethadol (LAAM) employing a dose (28 mg/kg per day) shown to induce its own metabolism by three- to four-fold, mice exhibited a rapid development of cellular tolerance and physical dependence which correlated on a temporal basis with this self-induction of LAAM metabolism. Evidence of cellular tolerance included significant elevations in the LAAM oral LD50, LAAM ICV (intracerebroventricular) LD50, LAAM oral AD50 and the LAAM ICV AD50 following repeated administration of this narcotic. Since the ICV parameters and the morphine AD50 were elevated over water control values, cellular tolerance appeared to play an important role in explaining the elevations noted for the oral parameters because the former were not influenced by changes in the rate of LAAM metabolism. Moreover, SKF-525A, a microsomal enzyme inhibitor, had little effect on the LAAM oral LD50 and the LAAM oral AD50, further indicating a minor role for dispositional tolerance. It is concluded that the induction noted for repeated oral LAAM administration most likely is responsible for generating more potent metabolites which in turn act to produce the cellular tolerance and physical dependence in these mice through constant exposure of the CNS.
以每天28毫克/千克的剂量重复口服左旋 - α - 乙酰美沙醇（LAAM），该剂量已显示可诱导其自身代谢增加三到四倍，小鼠表现出细胞耐受性和身体依赖性的快速发展，这在时间上与LAAM代谢的这种自我诱导相关。细胞耐受性的证据包括在重复给予这种麻醉剂后，LAAM口服半数致死量（LD50）、LAAM脑室内（ICV）半数致死量、LAAM口服半数有效剂量（AD50）和LAAM脑室内半数有效剂量显著升高。由于脑室内参数和吗啡半数有效剂量相对于水对照组值升高，细胞耐受性似乎在解释口服参数升高方面起重要作用，因为前者不受LAAM代谢速率变化的影响。此外，微粒体酶抑制剂SKF - 525A对LAAM口服半数致死量和LAAM口服半数有效剂量影响很小，进一步表明处置耐受性的作用较小。得出的结论是，重复口服LAAM所观察到的诱导作用很可能是产生了更有效的代谢产物，这些代谢产物反过来通过持续作用于中枢神经系统而在这些小鼠中产生细胞耐受性和身体依赖性。
