Theoretical Considerations on Quantitative Prediction of Drug-Drug Interactions

• HISAKA Akihiro

  Pharmacology and Pharmacokinetics, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo

• OHNO Yoshiyuki

  Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo

• YAMAMOTO Takehito

  Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo

• SUZUKI Hiroshi

  Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo

Abstract

  The prediction of drug-drug interactions (DDIs) associated with change in clearance for metabolism is reviewed, particularly focusing on pharmacokinetic theories for prediction based on in vitro and in vivo observation. First, there is discussion about how quantitative determination of the contribution of major clearance pathways is fundamental for the accurate prediction of DDIs. Secondly, the concentrations of causative drugs at sites of interactions are discussed. Although DDIs have been predicted from in vitro pharmacokinetic parameters based on predicted hepatic unbound concentrations of inhibitors and inducers, there are noticeable discrepancies between predicted and observed magnitudes of these DDIs. To solve these issues, a method for the prediction of unbound hepatic concentration is proposed based on theoretical considerations. Finally, a pharmacokinetic model to describe the intestinal first pass metabolism is considered, particularly focusing on the importance of the Q_gut model. Although this Q_gut model was proposed as an empirical model, theoretical considerations suggest that the model is regarded as a physiologically-based pharmacokinetic model that can predict significance of intestinal DDIs. Theoretical considerations proposed in the present article may be helpful for future analysis of DDIs.<br>

Journal

• Drug Metabolism and Pharmacokinetics

  Drug Metabolism and Pharmacokinetics 25 (1), 48-61, 2010

  The Japanese Society for the Study of Xenobiotics

Keywords

• drug-drug interaction
• pharmacokinetics
• clinical pharmacokinetics
• <i>in vitro-in vivo</i> extrapolation
• drug metabolism
• physiological pharmacokinetics
• cytochrome P450

Details

• CRID: 1390282680158273664
• NII Article ID: 10027581845
• NII Book ID: AA1162652X
• DOI: 10.2133/dmpk.25.48
• COI: 1:CAS:528:DC%2BC3cXlsVSmuro%3D
• ISSN: 18800920
• ISSN: 13474367
• PubMed: 20208388
• Web Site: http://api.elsevier.com/content/article/PII:S1347436715300057?httpAccept=text/xml
• Web Site: http://api.elsevier.com/content/article/PII:S1347436715300057?httpAccept=text/plain
• Web Site: https://search.jamas.or.jp/link/ui/2010252953
• Text Lang: en
• Data Source:
  • JaLC
  • Crossref
  • PubMed
  • CiNii Articles
• Abstract License Flag: Disallowed