Kronbach T, Fischer V, Meyer U A
Department of Pharmacology, Biocenter of the University, Basel, Switzerland.
Clin Pharmacol Ther. 1988 Jun;43(6):630-5. doi: 10.1038/clpt.1988.87.
The rate of formation of the three initial metabolites of cyclosporine metabolism has been determined in liver microsomes of 15 kidney transplant donors. Interindividual variation in metabolite formation was considerable but all three metabolites varied in parallel. An antiserum raised against a steroid-inducible rat cytochrome P-450 (P-450 PCN) strongly inhibited the formation of these metabolites. Immunoquantitation of the protein recognized by a monoclonal antibody reacting with human cytochromes P-450 of the P-450III gene family, homologues of rat P-450 PCN and rabbit P-4503C, revealed a high degree of correlation with microsomal cyclosporine metabolism. The data suggest that this cytochrome P-450 is the major cyclosporine-metabolizing enzyme in human liver. The substrate specificity and the known inducers and inhibitors of this cytochrome P-450 explain several clinically observed drug interactions with cyclosporine.
在15名肾移植供体的肝微粒体中测定了环孢素代谢的三种初始代谢产物的形成速率。代谢产物形成的个体间差异相当大，但所有三种代谢产物均呈平行变化。一种针对类固醇诱导的大鼠细胞色素P - 450（P - 450 PCN）产生的抗血清强烈抑制这些代谢产物的形成。用与P - 450III基因家族的人细胞色素P - 450、大鼠P - 450 PCN的同源物和兔P - 4503C反应的单克隆抗体识别的蛋白质的免疫定量显示，其与微粒体环孢素代谢高度相关。数据表明，这种细胞色素P - 450是人类肝脏中环孢素的主要代谢酶。这种细胞色素P - 450的底物特异性以及已知的诱导剂和抑制剂解释了临床上观察到的几种与环孢素的药物相互作用。
