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Transporter‐Mediated Drug–Drug Interactions Involving OATP Substrates: Predictions Based on In Vitro Inhibition Studies
Author(s) -
Yoshida K,
Maeda K,
Sugiyama Y
Publication year - 2012
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2011.351
Subject(s) - transporter , drug , pharmacology , pharmacokinetics , efflux , chemistry , organic anion transporting polypeptide , drug drug interaction , in vitro , plasma concentration , organic anion transporter 1 , drug interaction , medicine , biochemistry , gene
Transporter‐mediated drug–drug interactions (DDIs) are among the most important of the clinically relevant pharmacokinetic DDIs. We investigated the validity of a static prediction of area under the plasma concentration–time curve (AUC) ratios (AUCRs; AUC with inhibitor /AUC control ) using in vitro inhibition profiles, and selected the types of assumptions that improved the prediction accuracy with minimizing false‐negative predictions. We used data from 58 DDI studies involving 12 substrates of hepatic organic anion–transporting polypeptides (OATPs). With original assumptions regarding the maximal increase in intestinal availability, maximum unbound concentration at the inlet to the liver, and inhibition of only the hepatic uptake process, the predicted AUCRs were comparable to those reported within a two/threefold error margin in 44/52 studies, whereas in 16 studies, the predictions were judged to be false‐negatives. When the inhibitory effects on both hepatic uptake and efflux/metabolisms were considered, the overall prediction accuracy became worse, although the false‐negative prediction decreased to 11 studies. This illustrates that if appropriate assumptions are selected, unnecessary clinical DDI studies can be reasonably avoided. Clinical Pharmacology & Therapeutics (2012); 91 6, 1053–1064. doi: 10.1038/clpt.2011.351