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ADME/Pharmacokinetics

All newly developed drugs coming onto the market have been tested with regard to their absorption, distribution, metabolism and excretion/clearance (ADME testing). Thus, early evaluation of pharmacokinetics has become pivotal for new drug discovery and lead optimization and considerable effort is expended in new drug research to avoid the development of numerous compounds showing promising pharmacological activity but will eventually fail for reasons related to bioavailability, toxicity, or drug-drug interactions (e.g. activation/inhibition of CYP proteins).

In addition to affecting its own metabolism and clearance rate, drugs can affect the rate of clearance of other, simultaneously administered drugs, causing severe or even fatal drug-drug interactions (DDI). Besides being degraded and cleared, some drugs can also be activated - primarily by liver CYP450 enzymes - to form potent metabolites either with the desired efficacy or with unwanted, adverse side effects.

Liver diseases as well as kidney dysfunctions may have complex effects on metabolism and clearance of drugs and their metabolites , biotransformation, and pharmacokinetics. Pathogenetic factors include alterations in intestinal absorption, plasma protein binding, hepatic metabolism and extraction ratio, liver blood flow, biliary excretion, enterohepatic circulation, and renal clearance.Thus, measurement of clinically relevant markers of liver and kidney functions that may indicate hepatotoxic or nephrotoxic effects of a drug candidate or disease-related decrease of its efficacy is an important issue in drug development.