Pharmacokinetics and Drug Metabolism

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. 

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Berellini G, Cruciani G, Mannhold R. Pharmacophore, drug metabolism, and pharmacokinetics models on non-peptide ATi, AT2, and AT1/AT2 angiotensin II receptor antagonists. J Med Chem 2005 48 4389-99. 

D. K. Design of drugs involving the concepts and theories of drug metabolism and pharmacokinetics. 

Van de Waterbeemd, H. High-throughput and in silico techniques in drug metabolism and pharmacokinetics. Curr. Opin. Drug Dis. Dev. 2002, 5, 33-43. 

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... 

A second area of drug discovery and development in which enzyme reactions play a critical role is in the study of drug metabolism and pharmacokinetics. The elimination of xenobiotics, including drug molecules, from systemic circulation is driven by metabolic transformations that are entirely catalyzed by enzymes. Table 1.2 lists some of the enzyme-catalyzed transformations of xenobiotics that commonly contribute to drug molecule elimination. These biotransformation reactions... 

Roberts, S. A., High-throughput screening approaches for investigating drug metabolism and pharmacokinetics, Xenobiotica 31, 557-589 (2001). 

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. 

White RE. High-throughput screening in drug metabolism and pharmacokinetic support of dmg discovery. Annu Rev Pharmacol Toxicol 2000 40 133-157. 

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

The drug discovery and development processes are time consuming and costly endeavors. It has been reported that on average it takes 10 to 15 years and costs more than 800 million to bring a molecule from discovery to market.12 Compounds fail for various reasons. One that accounts for a reported 40% of failures in clinical trials is poor pharmacokinetics.3 In an effort to improve the number of compounds that exhibit optimal absorption, distribution, metabolism, elimination (ADME), and pharmacokinetic (PK) properties and reach development, drug metabolism and pharmacokinetic scientists continually implement new technologies and compound screening approaches. 

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. 

High-Throughput Quantitative Pharmaceutical Analysis in Drug Metabolism and Pharmacokinetics Using Liquid Chromatography-Mass Spectrometry... 

Masubuchi, Y. (2006) Metabolic and non-metabolic factors determining troglitazone hepatotoxicity a review. Drug Metabolism and Pharmacokinetics, 21 (5), 347-356. 

Exploratory Drug Metabolism Department of Drug Metabolism and Pharmacokinetics... 

Smith, D., Schmid, E. and Jones, B. (2002) Do drug metabolism and pharmacokinetic departments make any contribution to drug discovery Clinical Pharmacokinetics, 41, 1005-1019. 

Smith, D.A., Jones, B.C. and Walker, D.K. (1996) Design of drugs involving the concepts and theories of drug metabolism and pharmacokinetics. Medicinal Research Reviews, 16, 243-266. 

Caldwell, G.W., Masucci, J.A., Yan, Z. and Hageman, W. (2004) Allometric scaling of pharmacokinetic parameters in drug discovery Can human CL Vss and tl/2 be predicted from in-vivo rat data European Journal of Drug Metabolism and Pharmacokinetics, 29, 133-143. 

F. Hoffmann-La Roche Ltd Drug Metabolism and Pharmacokinetics Department Modeling and Simulation Group Grenzacher Strasse 124 4070 Basel S vitzerland... 

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