P-gp Transport Kinetics – Compound-specific Selection of in vitro Assay Design and Kinetic Parameter Estimation
This September, Cyprotex, along with our colleagues at Genentech and Novartis, ran a complimentary webinar series on drug transporters. This blog focuses on the second webinar of the series presented by Birk Poller PhD of Novartis, entitled ‘P-gp Transport Kinetics – Compound-specific Selection of in vitro Assay Design and Kinetic Parameter Estimation’. If you missed our first blog in this series, you can catch up by reading here.
P-glycoprotein (P-gp) is a plasma membrane bound protein of the ATP Binding Cassette (ABC) superfamily (isoform; ABCB1) which acts as a drug transporter by actively exporting drugs out of the cell. As a clinically relevant drug transporter, P-gp is located in many pharmacokinetic-related organs such as the gastrointestinal (GI) tract, liver, kidney and blood-brain barrier (BBB) and therefore can impact on the absorption, distribution, metabolism and elimination of drugs that are substrates. Functionally, acting as a unidirectional efflux pump that moves substrates against their concentration gradients, P-gp limits the cellular exposure of many drugs and other substances and, due to the role in drug disposition, it is recommended by the FDA that potential drug candidates be assessed for their potential as either substrates or inhibitors of P-gp.
This webinar describes a systematic comparison of in vitro methods, including polarised cell monolayer (transwell) and cellular uptake assays, used to obtain robust and reproducible transport kinetic parameters (Km and Vmax) for P-gp which may be critical for the prediction of the clinical impact. Furthermore, compound-specific guidance, based on the BDDCS (Biopharmaceutical Drug Disposition Classification System) is discussed for the selection of assay types and analysis methods for optimum efflux transporter kinetic parameter estimation.
More information on the work covered by this presentation can be found in the following research paper:
- Examining P-gp efflux kinetics guided by the BDDCS – Rational selection of the in vitro assay designs and mathematical models (Riede et al., (2019) European Journal of Pharmaceutical Science 132: 132-141).
If you missed out on our webinar series or if you would like the opportunity to watch the webinars again, please click on the links below: