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Foti RS , Tyndale RF , Garcia KL , Sweet DH , Nagar S , Sharan S , Rock DA
"Target-Site" Drug Metabolism and Transport
Drug Metab Dispos. 2015 May 18;43(8) :1156-68
PMID: 25986849 URL: http://www.ncbi.nlm.nih.gov/pubmed/25986849
AbstractThe recent symposium on "Target-Site" Drug Metabolism and Transport that was sponsored by the American Society for Pharmacology and Experimental Therapeutics at the 2014 Experimental Biology meeting in San Diego is summarized in this report. Emerging evidence has demonstrated that drug metabolizing enzyme and transporter activity at the site of therapeutic action can affect the efficacy, safety and metabolic properties of a given drug, with potential outcomes including altered dosing regimens, stricter exclusion criteria or even the failure of a new chemical entity in clinical trials. Drug metabolism within the brain, for example, can contribute to metabolic activation of therapeutic drugs such as codeine as well as the elimination of potential neurotoxins in the brain. Similarly, the activity of oxidative and conjugative drug metabolizing enzymes in the lung can have an effect on the efficacy of compounds such as resveratrol. In addition to metabolism, the active transport of compounds into or away from the site of action can also influence the outcome of a given therapeutic regimen or disease progression. For example, OAT3 is involved in the initiation of pancreatic beta-cell dysfunction and may have a role in how uremic toxins enter pancreatic beta-cells and ultimately contribute to the pathogenesis of gestational diabetes. Finally, it is likely that a combination of target-specific metabolism and cellular internalization may have a significant role in determining the pharmacokinetics and efficacy of antibody-drug conjugates, a finding which has resulted in the development of a host of new analytical methods that are now used for characterizing the metabolism and disposition of antibody-drug conjugates. Taken together, the research summarized herein can provide for an increased understanding of potential barriers to drug efficacy and allow for a more rational approach for developing safe and effective therapeutics.
NotesFoti, Robert S Tyndale, Rachel F Garcia, Kristine L P Sweet, Douglas H Nagar, Swati Sharan, Satish Rock, Dan A Drug Metab Dispos. 2015 May 18. pii: dmd.115.064576.