Research on Organ Correlation of Drug Metabolic Activities by Gene Technology

利用基因技术研究药物代谢活性的器官相关性

• 批准号: 11672211
• 负责人: YASUHARA Masato
• 金额: $ 2.3万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672211/
• 关键词: organ correlation; drug metabolism; acute renal failure; pharmacokinetics; losartan; cefoperazone; N-acetylprocainamide

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

患者之间的药代动力学差异是药物治疗成功的关键问题。尤其是药物代谢存在明显的个体差异，应建立定量的方法来评价和预测个体的药代动力学特征。本研究的目的是从器官相关性的角度阐明影响药代动力学变异的因素，并利用基因技术建立其评价方法。我们研究了三种药物在肾脏疾病中的药代动力学。氯沙坦：在急性肾功能衰竭(ARF)大鼠中应用氯沙坦，它通过细胞色素P450 2 C9和细胞色素P3A4的氧化代谢产生活性代谢物。口服氯沙坦后，急性肾衰大鼠的AUC显著增加，血清活性代谢物浓度明显低于对照组。静脉注射。氯沙坦的研究表明，…氯沙坦在ARF大鼠体内的清除量明显低于对照组。此外，ARF大鼠肝微粒体中氯沙坦代谢物的形成速度慢于对照组大鼠，表明ARF大鼠的代谢活性降低。头孢哌酮：头孢哌酮主要通过未改变药物的胆汁排泄从体内排出。静脉注射。对头孢哌酮的研究表明，ARF大鼠体内清除率降低，提示ARF对药物的肝转运系统有一定的影响。N-乙酰普鲁卡因胺(NAPA)：NAPA通过有机阳离子转运系统进行肾小管分泌。在不同肾脏疾病模型上对NAPA的肾脏清除研究表明，肾脏疾病影响了NAPA的肾脏排泄，N-甲基烟酰胺的肾脏清除有助于预测NAPA的排泄。这些结果表明，器官相关性概念对于评价疾病状态对各种药物药代动力学的影响具有重要意义。较少

项目成果

Y.-L.HE: "Quantitative estimation of renal clearance of N-acetylprocainamide in rats with various experimental acute renal failure"Eur.J.Pharm.Sci.. (in press). (2001)

Y.-L.HE：“各种实验性急性肾衰竭大鼠中 N-乙酰普鲁卡因酰胺肾清除率的定量评估”Eur.J.Pharm.Sci..（出版中）。

H.Katayama, M.Yasuhara, R.Hori: "Effect of acute renal failure on the disposition of cefoperazone."J.Pharm.Pharmacol.. 51(3). 361-366 (1999)

H.Katayama、M.Yasuhara、R.Hori：“急性肾衰竭对头孢哌酮处置的影响。”J.Pharm.Pharmacol.. 51(3)。

H KATAYAMA: "Effect of acute renal failure on the disposition of cefoperazone"J.Pharm.Pharmacol.. 51(3). 361-366 (1999)

H KATAYAMA：“急性肾功能衰竭对头孢哌酮处置的影响”J.Pharm.Pharmacol.. 51(3)。

JUN-ICHI KUNIMASA: "Pharmacokinetics and pharmacological Effects of Recombinant Human Granulocyte-Colony-stimulating Factor Conjugated to Poly(Styrene-Co-maleic acid) in Rat"J. Pharm. Pharmacol.. 51(7). 777-782 (1999)

JUN-ICHI KUNIMASA：“重组人粒细胞集落刺激因子与聚苯乙烯-马来酸共轭物在大鼠体内的药代动力学和药理作用”J.

J.KUNIMASA: "Pharmacokinetics and pharmacological effect of recombinant human granulocyte-colony-stimulating factor conjugated to"J.Pharm.Pharmacol.. 51(7). 777-782 (1999)

J.KUNIMASA：“与重组人粒细胞集落刺激因子结合的药代动力学和药理作用”J.Pharm.Pharmacol.. 51(7)。