A comparison of the inhibitory effects of roxatidine acetate hydrochloride and cimetidine on cytochrome P-450-mediated drug-metabolism in mouse hepatic microsomes and in man in vivo.
A comparison of the inhibitory effects of roxatidine acetate hydrochloride and cimetidine on cytochrome P-450-mediated drug-metabolism in mouse hepatic microsomes and in man in vivo.
复制标题
盐酸罗沙替丁与西咪替丁对小鼠肝微粒体和人体体内细胞色素 P-450 介导的药物代谢的抑制作用比较。
DOI：
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发表时间：
1987
期刊：
影响因子：
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通讯作者：
H. Shimakawa
中科院分区：
文献类型：
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作者：
K. Morita;H. Konishi;T. Ono;H. Shimakawa
本文比较了新的H_2受体拮抗剂盐酸罗沙替丁（ROX）和西咪替丁（CIM）对小鼠肝微粒体和人体内氧化药物代谢酶系统的抑制作用。CIM对小鼠肝微粒体睾酮6 β-、7 α-和16 α-羟化酶、氨基比林N-脱甲基酶和苯胺羟化酶的活性有明显的抑制作用，抑制常数（Ki）为0.2-3.49 mM，ROX对各酶活性的抑制作用较CIM弱，Ki值为CIM的12 ~ 100倍。CIM给出II型差谱，解离常数（Ks）为10.4和111 μ M，而ROX给出反向I型差谱，Ks为55.6 μ M。尿中6 β-羟基皮质醇（6 β-OHF）与17-羟基皮质类固醇（17-OHCS）的比值，作为人体药物氧化代谢能力的指标，在口服CIM 800 mg/d后1-3 d，下降了25-35%。在口服150 mg/d ROX治疗期间，该比率没有显著变化。这些结果表明，ROX表现出较低的亲和力细胞色素P-450和较低的抑制效力的药物代谢酶在肝微粒体比CIM。
The inhibitory effects of roxatidine acetate hydrochloride (ROX), a new H2-receptor antagonist, on the oxidative drug-metabolizing enzyme system in mouse hepatic microsomes and in man in vivo were compared with those of cimetidine (CIM). CIM markedly inhibited testosterone 6 beta-, 7 alpha- and 16 alpha-hydroxylase, aminopyrine N-demethylase and aniline hydroxylase activities in mouse hepatic microsomes with inhibition constants (Ki) of 0.2-3.49 mM. ROX exhibited much weaker inhibitory effects on each enzyme activity with 12 to 100-fold higher values of Ki than those of CIM. CIM gave type II difference spectra with dissociation constants (Ks) of 10.4 and 111 microM while ROX gave reverse type I difference spectra with Ks of 55.6 microM. The ratio of 6 beta-hydroxycortisol (6 beta-OHF) to 17-hydroxy corticosteroids (17-OHCS) in urine, used as an indicator of oxidative drug-metabolizing capacity in man, was decreased by 25-35% of the original level on 1-3 d after oral treatment with 800 mg/d of CIM. The ratio was not significantly changed during oral treatment with 150 mg/d of ROX. These results indicate that ROX exhibits a lower affinity for cytochrome P-450 and a lower inhibitory potency on the drug-metabolizing enzymes in hepatic microsomes than does CIM.