Research on Organ Correlation of Drug Metabolic Activities by Gene Technology

点击翻译按钮获取中文摘要

Pharmacokinetic difference among patients is a critical problem for the success of drug therapy. Especially, marked interindividual difference is found in drug metabolism and quantitative method should be developed for evaluating and predicting the pharmacokinetic characteristics of an individual patient. The purpose of the present study is to clarify the factors affecting the pharmacokinetic variabilities from the standpoint of organ correlation and to develop its evaluation method by means of gene technology. We have investigated the pharmacokinetics of three drugs in renal disease.1. Losartan : Losartan, which undergoes oxidative metabolism by CYP2C9 and CYP3A4 to produce an active metabolite, was administered to rats with acute renal failure (ARF). After oral administration of losartan, AUC of losartan was significantly increased in rats with ARF.On the other hand, serum concentration of active metabolite in ARF was lower than that in control. I.v. study of losartan showed that the … More total body clearance of losartan was lower in rats with ARF than that in control rats. Furthermore, slower formation rate of losartan metabolite in hepatic microsome fraction prepared from ARF rats than that from control rats indicated the reduced metabolic activity associated with ARF.2. Cefoperazone : Cefoperazone is mainly eliminated from the body by biliary excretion of unchanged drug. I.v. study of cefoperazone showed the decreased clearance in rats with ARF.It was suggested the change of hepatic transport system of drugs in ARF.3. N-acetylprocainamide (NAPA) : NAPA undergoes renal tubular secretion by organic cation transport system. Renal clearance study of NAPA in various kinds of renal disease models showed that renal disease affected the renal excretion of NAPA and renal clearance of N-methylnicotinamide is useful for predicting NAPA excretion.These results indicate the importance of organ correlation concept for evaluating the effect of disease states on pharmacokinetics of various drugs. Less