Importance of target-mediated drug disposition for small molecules.

Autor: Smith DA; Department of Chemistry, University of Cape Town, Cape Town, South Africa., van Waterschoot RAB; Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Switzerland. Electronic address: robert.van_waterschoot@roche.com., Parrott NJ; Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Switzerland., Olivares-Morales A; Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Switzerland., Lavé T; Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Switzerland., Rowland M; Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, University of Manchester, Manchester, UK.
Jazyk: angličtina
Zdroj: Drug discovery today [Drug Discov Today] 2018 Dec; Vol. 23 (12), pp. 2023-2030. Date of Electronic Publication: 2018 Jun 19.
DOI: 10.1016/j.drudis.2018.06.010
Abstrakt: Target concentration is typically not considered in drug discovery. However, if targets are expressed at relatively high concentrations and compounds have high affinity, such that most of the drug is bound to its target, in vitro screens can give unreliable information on compound affinity. In vivo, a similar situation will generate pharmacokinetic (PK) profiles that deviate greatly from those normally expected, owing to target binding affecting drug distribution and clearance. Such target-mediated drug disposition (TMDD) effects on small molecules have received little attention and might only become apparent during clinical trials, with the potential for data misinterpretation. TMDD also confounds human microdosing approaches by providing therapeutically unrepresentative PK profiles. Being aware of these phenomena will improve the likelihood of successful drug discovery and development.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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