[Application and development of in vitro metabolism study at early drug discovery stage].
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Drug metabolism studies, including in vivo and in vitro metabolism studies, are significant in the design of candidate compounds and screening of lead compounds at drug discovery/development stages. Compared with in vivo metabolism studies, in vitro metabolism studies have the advantages of rapidity, simplicity, without consumption of large amounts of samples and animals. Moreover, it is convenient for researchers to observe the selective interaction between compound and target. Therefore, in vitro metabolism studies are appropriate for high throughput screening of compounds which are lack of metabolism information and have been widely used during drug discovery stages. This article briefly introduced the application of in vitro drug metabolism studies based on the metabolic stability, reaction phenotyping and metabolic drug-drug interactions, aiming to raise valuable evaluation strategies for innovative drug discovery in China.Keywords:
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Abstract Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. High metabolic lability usually leads to poor bioavailability and high clearance. Formation of active or toxic metabolites will have an impact on the pharmacological and toxicological outcomes. There is also potential for drug–drug interactions with coadministered drugs due to inhibition and/or induction of drug metabolism pathways. Hence, optimization of the metabolic liability and drug–drug interaction potential of the new chemical entities are some of the most important steps during the drug discovery process. The rate and site(s) of metabolism of new chemical entities by drug metabolizing enzymes are amenable to modulation by appropriate structural changes. Similarly, the potential for drug–drug interactions can also be minimized by appropriate structural modifications to the drug candidate. However, the optimization of the metabolic stability and drug–drug interaction potential during drug discovery stage has been largely by empirical methods and by trial and error. Recently, a lot of effort has been applied to develop predictive methods to aid the optimization process during drug discovery and development. This article reviews the role of drug metabolism in drug discovery and development. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 5, 397–411, 2001
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Drug discovery and development is an expensive process with a high attrition rate.Cytochrome P450(CYP) induction and inhibition mediated drug-drug interaction of drug candidates serves as one of the reasons for such attrition.Consequently a great effort is paid to identify those compounds that influence pharmacokinetic parameters of other drugs,which may lead to drug-drug interactions.CYP plays a central role in metabolism and biosynthesis of a wide range of exogenous and endogenous compounds.CYP induction mediated drug-drug interactions may result in an increased metabolic clearance for coadministrated drugs,and subsequently affect their effectiveness and safety.Assessment of CYP induction potential for drug candidates has become an integral part of new drug discovery and development.This article reviews the current understanding on CYP induction mediated drug-drug interaction and its clinical implications,along with the in vitro and in vivo methodologies for assessment of the induction potential of new drug candidates.
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Along with minimal toxicity, good drug metabolism and pharmacokinetic (DMPK) properties are essential for the clinical success of a drug candidate. A major cause of failure of orally administered drugs during their development is the discovery that in humans they have low intestinal absorption and/or high clearance causing low and variable bioavailability. In addition, drug interactions and the presence of active metabolites can prevent or complicate their successful development. With poor pharmacokinetics it can be difficult to achieve a suitable dosage regimen for the required pharmacodynamic action. The main role of DMPK in discovery is, therefore, the prediction of human pharmacokinetics and metabolism. Reducing the rate of attrition during drug discovery and development is now considered essential, particularly as it is now possible to screen an ever-greater number of compounds.
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The in vitro intrinsic clearances (CLint, in vitro) of P450-mediated reactions obtained by using human liver microsomes were compared with the in vivo intrinsic clearances (CLint, in vivo) which were calculated from pharmacokinetic data in literature. Although CLint, in vitro and CLint, in vivo agreed well with each other for most of the drugs investigated, more than 10-fold differences were observed for some drugs, indicating the possible involvement of the first-pass metabolism in the gut and/or interindividual variability in the hepatic metabolism. The AUCoral and bioavailability of YM796, a compound being developed for the treatment of dementia, were well predicted from in vitro metabolic studies taking the non-linear first-pass metabolism into consideration. Furthermore, we have tried to predict in vivo drug-drug interactions from in vitro data on drug metabolism obtained from the literature. Assuming the same unbound concentration of the inhibitor in the liver and in plasma, the degree of increase in the AUC caused by the metabolic inhibition was underestimated for some of the drug combinations. The transport study using isolated rat hepatocytes indicated that the contribution of the active transport of the inhibitors such as quinidine, erythromycin etc. into the hepatocytes is not so large. The drug-drug interactions involving the gastrointestinal absorption process may have to be considered for the more precise prediction.
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Predicting human pharmacokinetics (PK) such as clearance (CL) and volume of distribution (Vd) is a critical component of drug discovery. These predictions are mainly performed by in vitro-in vivo extrapolation (IVIVE) using human biological samples, such as hepatic microsomes and hepatocytes. However, some issues with this process have arisen, such as inconsistencies between in vitro and in vivo findings; the integration of predicted CYP, non-CYP and transporter-mediated human PK; and the difficulty of evaluating very metabolically stable compounds. Various approaches to solving these issues have been reported. Allometric scaling using experimental animals has also often been used. However, this method has also shown many problems due to interspecies differences, albeit that various correction methods have been proposed. Another approach involves the production of chimeric mice with humanized liver via the transplantation of human hepatocytes into mice. The livers of these mice are repopulated mostly with human hepatocytes and express human drug-metabolizing enzymes and drug transporters, suggesting that these mice are useful for solving the issues of IVIVE and allometric scaling, and more reliably predicting human PK. In this review, we summarize human PK prediction methods using IVIVE, allometric scaling and chimeric mice with humanized liver, and discuss the utility of predicting human PK in drug discovery by comparing these chimeric mice with IVIVE and allometric scaling.
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Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
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