DMPK, drug metabolism and

The third step is to optimize the lead molecule through iterative chemical synthesis and biological testing, aiming to obtain molecules with the required potency (typically nanomolar), selectivity, bioavailability, and DMPK (drug metabolism and pharmacokinetics) properties. This step usually requires considerable time and resources usually the synthesis of hundreds of compounds is needed to deduce a robust SAR (structure-activity relationship). Such resources can be considerably reduced and the... 

An important part of the optimization process of potential leads to candidates suitable for clinical trials is the detailed study of the absorption, distribution, metabolism and excretion (ADME) characteristics of the most promising compounds. Experience has learned that physico-chemical properties play a key role in drug metabolism and pharmacokinetics (DMPK) [1-3]. As an example, physicochemical properties relevant to oral absorption are described in Fig. 1.1. It is important to note that these properties are not independent, but closely related to each other. 

One of the major goals of computational chemistry in the field of drug metabolism and pharmacokinetics (DMPK) is the prediction of oral availability. Several computational approaches have been published to predict this important parameter, starting from the molecular structure [1-3]. However, when applied to real case studies, none of these provided totally convincing results and, correspondingly, there is a lack of any general strategy to address this problem. 

Compound related includes drug metabolism and pharmacokinetics (DMPK), safety (off-target toxicity) and selectivity, and formulation and synthesis (cost of goods)... 

A landmark study reported that 40% of failures in clinical studies were due to PK problems.1-3 This led to the need to develop drug metabolism studies that could be performed on a compound before it was recommended for development. The early drug metabolism and pharmacokinetic (DMPK) studies were used to assess the ADME/PK properties of NCEs. The major pharmaceutical companies were very successful at setting up exploratory drug metabolism departments using various models. This led to an explosion of new higher throughput ADME/PK assays that provided medicinal chemists with the necessary tools to improve the ADME/PK properties of NCEs. 

Drug metabolism and pharmacokinetic (DMPK) studies are used to show how the concentrations of the drug and its metabolites vary with the administered dose of the drug and the time from administration. They are normally carried out using suitable animal species and in humans in Phase I trials. The information obtained from animal studies is used to determine safe dose levels for use in the Phase I clinical trials in humans. However, the accuracy of the data obtained from animal tests is limited, since it is obtained by extrapolation. In addition, it is necessary to determine the dose that just saturates the absorption and elimination processes so that the toxicological and pharmacological events may be correctly interpreted. 

Drug Metabolism and Pharmacokinetics (DMPK), Cambridge, U.K. D. R. Hawkins... 

The properties that are important for drug metabolism and pharmacokinetics (DMPK) are much better understood now than they were some 10 years ago [24]. Good progress has been made in recent years toward robust modeling of a number of pharmacokinetic properties and various aspects of human drug metabolism. More and good quality data have become available for some of the important end points. However, and unfortunately, some end points are by nature very complex. These include clearance and oral bioavailability. 

To answer these needs, a series of in vitro and in vivo assays have been developed with the goal of providing these data in a time frame that is compatible with the requirements of medicinal chemists who are making the new chemical entities (NCEs). Most of the in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) screens use LC-MS or LC-MS/MS for the analytical step. As shown in Figure 12.1, one approach for using these assays is to view the process of lead optimization as passing the lead... 

Figure 6.1. Schematic showing the various departments in pharmaceutical research discovery research, chemical and pharmaceutical development, drug metabolism and pharmacokinetics (DMPK), and manufacturing quality control. Diagram Courtesy of Waters Corporation.

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