Vyas K P, Kari P H, Wang R W, Lu A Y
Department of Drug Metabolism, Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
Biochem Pharmacol. 1990 Jan 1;39(1):67-73. doi: 10.1016/0006-2952(90)90649-6.
The effects of the H2-receptor antagonists, cimetidine and famotidine, on the microsomal metabolism of [14C]lovastatin were investigated. Liver microsomes were prepared from control, phenobarbital- and 3-methylcholanthrene-pretreated rats and humans (male and female). Concentration-dependent inhibition of the metabolism of lovastatin (0.1 mM) was observed with cimetidine (0.1 to 1.0 mM). In contrast, famotidine at a similar concentration was a very weak inhibitor. The formation of 6'beta-hydroxy-lovastatin, the major microsomal metabolite of lovastatin, was similarly inhibited. The results suggest that in vivo metabolic interaction with concomitantly administered lovastatin is less likely with famotidine than with cimetidine. Phenobarbital pretreatment produced 58% stimulation in overall metabolism, whereas 3-methylcholanthrene pretreatment had no effect relative to control rats (5.4 nmol/mg protein/min). Liver microsomes from phenobarbital-pretreated rats produced 67% more of the 6'beta-hydroxy-lovastatin but 63-66% less of the 3''-hydroxy and 6'-exomethylene metabolites. Liver microsomes from 3-methylcholanthrene-treated rats also produced less 3"-hydroxy-lovastatin (49%) but similar quantities of the other two metabolites. 6'beta-Hydroxy-lovastatin was a major metabolite with human liver microsomes. Interestingly with these microsomes, hydroxylation at the 3''-position of the molecule was a negligible pathway and hydrolysis to the hydroxy acid form was not observed. The formation of 6'-exomethylene-lovastatin was also catalyzed by human liver microsomes (0.5 to 0.8 nmol/mg protein/min).
研究了H2受体拮抗剂西咪替丁和法莫替丁对[14C]洛伐他汀微粒体代谢的影响。从对照、苯巴比妥和3-甲基胆蒽预处理的大鼠及人类（男性和女性）制备肝微粒体。西咪替丁（0.1至1.0 mM）对洛伐他汀（0.1 mM）的代谢呈现浓度依赖性抑制。相比之下，相似浓度的法莫替丁是一种非常弱的抑制剂。洛伐他汀的主要微粒体代谢产物6'β-羟基洛伐他汀的形成也受到类似抑制。结果表明，与西咪替丁相比，法莫替丁与同时服用的洛伐他汀在体内发生代谢相互作用的可能性较小。苯巴比妥预处理使总体代谢增加了58%，而3-甲基胆蒽预处理相对于对照大鼠无影响（5.4 nmol/mg蛋白质/分钟）。苯巴比妥预处理大鼠的肝微粒体产生的6'β-羟基洛伐他汀多67%，但3''-羟基和6'-亚甲基代谢产物少63 - 66%。3-甲基胆蒽处理大鼠的肝微粒体产生的3''-羟基洛伐他汀也较少（49%），但其他两种代谢产物的量相似。6'β-羟基洛伐他汀是人类肝微粒体的主要代谢产物。有趣的是，对于这些微粒体，分子3''-位的羟基化是一条可忽略不计的途径，且未观察到水解为羟基酸形式的情况。人类肝微粒体也催化6'-亚甲基洛伐他汀的形成（0.5至0.8 nmol/mg蛋白质/分钟）。
