Lack of effect of nizatidine on drug metabolism.
Lack of effect of nizatidine on drug metabolism.
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尼扎替丁对药物代谢缺乏影响。
DOI：
10.3109/00365528709094481
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发表时间：
1987
期刊：
影响因子：
--
通讯作者：
U. Klotz
中科院分区：
文献类型：
--
作者：
U. Klotz
H2受体拮抗剂是世界上使用最广泛的药物之一，由于许多患者同时接受各种其他药物治疗，因此研究新的H2受体拮抗剂如尼扎替丁的相互作用潜力非常重要。已有文献表明，西咪替丁通过与细胞色素P-450系统结合，抑制多种药物的肝排泄。因此，我们在体内外研究了尼扎替丁对药物代谢的影响。以大鼠肝微粒体为模型，研究了尼扎替丁和其他四种H_2受体阻滞剂(西咪替丁、奥美替丁、雷尼替丁、法莫替丁)对三种标志酶(芳烃羟基酶、7-乙氧基香豆素-O-脱乙基酶、7-乙氧基间苯二酚-O-脱乙基酶)活性的影响。西咪替丁和奥美替丁对上述三种代谢反应均表现出明显的剂量依赖性抑制作用，而尼扎替丁只有在很高浓度时才表现出微弱的抑制作用。同样，只有西咪替丁和奥美替丁才能与人肝微粒体的细胞色素P-450结合，而尼扎替丁不影响结合光谱。研究了尼扎替丁300 mg/d夜间给药对9名健康受试者安定(10 mg，po)的药代动力学影响。尼扎替丁的消除半衰期(+/-SD)为35.3+/-24.2h(对照组)和37.3+/-18.3h(+nizatidine)，血浆总清除量为28.2+/-12.0ml/min(对照组)和26.7+/-10.4ml/min(+nizatidine)。尼扎替丁对主要代谢物--去甲基安定的形成也没有影响。
H2-receptor antagonists are among the most widely-used drugs in the world and, since many patients receive a variety of other drugs concomitantly, it is important to investigate the interaction potential of new H2-receptor antagonists such as nizatidine. It is well documented that cimetidine can inhibit the hepatic elimination of many drugs by binding to the cytochrome P-450 system. Therefore we investigated in vitro and in vivo the effects of nizatidine on drug metabolism. With rat liver microsomes the effects of nizatidine and four other H2-blockers (cimetidine, oxmetidine, ranitidine, famotidine) on the activity of three marker enzymes (aryl-hydrocarbon-hydroxylase, 7-ethoxycoumarin-O-deethylase, 7-ethoxy-resorufin-O-deethylase) were tested. While cimetidine and oxmetidine exhibited marked and dose-dependent inhibition of all three metabolic reactions, nizatidine showed some weak inhibition only at very high concentrations. Similarly, binding to cytochrome P-450 of human liver microsomes could be seen only with cimetidine and oxmetidine, whereas nizatidine did not affect the binding spectra. In nine healthy mal volunteers the pharmacokinetics of diazepam (10 mg po) was studied under the influence of nizatidine (300 mg day nocte). Nizatidine had no significant effect on the hepatic elimination of diazepam, as characterized by its elimination half-life (mean +/- SD) of 35.3 +/- 24.2 h (control) and 37.3 +/- 18.3 h (+ nizatidine) or its total plasma clearance of 28.2 +/-12.0 ml/min (control) and 26.7 +/- 10.4 ml/min (+ nizatidine). The formation of the major metabolite-desmethyldiazepam-was also unaffected by nizatidine.(ABSTRACT TRUNCATED AT 250 WORDS)