Metabolism Studies in vitro and in vivo
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In vivo Biotransformation Studies . . . . . . . . . . . . . . . . . . . . . . . . . . Perfused Organs . . . . . . . . . . . . . . . . . Organ Slices . . . . . . . . . . . . . . . . . . . . . Primary Hepatocytes . . . . . . . . . . . . Homogenates . . . . . . . . . . . . . . . . . . . . 9000g Supernatant (S9) Fractions Microsomes. . . . . . . . . . . . . . . . . . . . . . Cytosol . . . . . . . . . . . . . . . . . . . . . . . . . . Recombinant Enzymes . . . . . . . . . . Blood, Plasma and Serum . . . . . . .
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INTRODUCTION
In the era of combinatorial chemistry and high throughput screening, a huge number of hits and structural analogs potentially interesting as new chemical entities (NCEs) can be produced in a short period of time. Drug metabolism is a decisive determinant of the pharmacokinetic behavior of these compounds. Approximately three quarters of the top 200 prescribed drugs in the United States in 2002 are cleared by metabolism, one third are cleared via the kidney, while biliary clearance of unchanged drug plays only a minor role (Williams et al. 2004). In vitro biotransformation tests are one piece of the puzzle to understand the pharmacokinetic characteristics of a given compound, to optimize PK parameters and to select the most drug like compounds that will progress into development (Eddershaw 2000; Li 2004; Masimirembwa et al. 2003). Relatively recent prospect of obtaining equivalent data from in vitro and in vivo studies has provided the pharmaceutical industry with an incentive to validate in vitro models with respect to increase throughput and/or to replace animal studies where appropriate. More over, in vitro test systems are the only humanized models in early development (Coleman et al. 2001). An early assessment using animal in vitro and in vivo data together with human in vitro data allows a qualitative prediction whether humans will act in similar (path-) ways as did the animal models (Figure 1).
In vivo biotransformation studies play a role later in development in both, animals and humans (Gupta and Atul 2000; Inskeep and Day 1999; Pool 1999). Use of transgenic animals facilitates understanding the role of drug metabolizing enzymes in the organism (Gonzalez and Kimura 2003). However, animal studies cannot entirely replace clinical studies in predicting all responses in human, but, for ethical reasons, the risk to human volunteers participating in early clinical studies should be minimized (Cross and Bayliss 2000). This is supported by a variety of in vitro metabolism studies. Metabolic stability tests can be performed in higher through-put (White 2001). They allow ranking of compounds and ensure that the molecules resulting from the optimization process retain favorable metabolic properties. In addition, they give rise to set up computational models predictive for the in vitro test which helps to speed-up the selection and optimization processes although applications on the biotrans
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