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Review-articles-on-pharmacokinetics

After absorption, the drug is distributed to tissues via the blood, including kidney and liver, and excreted into the urine and bile. Highly lipophilic drugs, generally considered to exhibit a high pharmacological activity, are often metabolized by drug-metabolizing enzymes and converted to more hydrophilic metabolites for excretion. Given that metabolism is a key factor in lipophilic drug elimination, identification of the respective drug-metabolizing enzymes can lead to a better understanding of the pharmacokinetics of new drugs. Pharmacokinetics is therefore regarded as one of the most essential processes in new drug research and development to maximize drug efficacy and avoid the risk of interactions with concomitant drugs or inter-individual differences. This paper summarizes experiences linked with the identification of non-P450 enzymes in Daiichi Sankyo, based on: 1) drug interaction: acyl peptide hydrolase involved in the interaction of valproic acid with a combination of carbapenem antibiotics, and alcohol dehydrogenase 4 involved in tivantinib metabolism, 2) prodrug: carboxymethylenebutenolidase and paraoxogenase 1 involved in generating the active form of olmesartan medoxomil, and Raf kinase inhibitor protein catalyzing prasugrel as a bioactivation hydrolase, 3) a new enzyme identification method: CS-0777 phosphate phosphatase.

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