Abstract
BackgroundThe expression and activity of P-glycoproteins due to genetic or environmental factors may have a significant impact on drug disposition, drug effectiveness or drug toxicity. Hence, characterization of drug disposition over a wide range of conditions of these membrane transporters activities is required to better characterize drug pharmacokinetics and pharmacodynamics. This work aims to improve our understanding of the impact of P-gp activity modulation on tissue distribution of P-gp substrate.MethodsA PBPK model was developed in order to examine activity and expression of P-gp transporters in mouse brain and heart. Drug distribution in these tissues was first represented by a well-stirred (WS) model and then refined by a mechanistic transport-based (MTB) model that includes P-gp mediated transport of the drug. To estimate transport-related parameters, we developed an original three-step procedure that allowed extrapolation of in vitro measurements of drug permeability to the in vivo situation. The model simulations were compared to a limited set of data in order to assess the model ability to reproduce the important information of drug distributions in the considered tissues.ResultsThis PBPK model brings insights into the mechanism of drug distribution in non eliminating tissues expressing P-gp. The MTB model accounts for the main transport mechanisms involved in drug distribution in heart and brain. It points out to the protective role of P-gp at the blood-brain barrier and represents thus a noticeable improvement over the WS model.ConclusionBeing built prior to in vivo data, this approach brings an interesting alternative to fitting procedures, and could be adapted to different drugs and transporters.The physiological based model is novel and unique and brought effective information on drug transporters.
Highlights
The expression and activity of P-glycoproteins due to genetic or environmental factors may have a significant impact on drug disposition, drug effectiveness or drug toxicity
The most studied ATP binding cassette (ABC) membrane transporters is the P-glycoprotein (P-gp), which is a multidrug resistance (MDR) protein encoded by the ATP-binding cassette B1 (ABCB1) gene
P-gp transporters have a regulator function by limiting penetration of drugs in brain, heart, placenta, ovaries, and testes tissues. This has been shown in vivo on wild type (WT), mdr1a(-) and mdr1a/1b(-/-) knockout (KO) mice, which are mice lacking genes encoding for drug-transporting P-gp [3]
Summary
The expression and activity of P-glycoproteins due to genetic or environmental factors may have a significant impact on drug disposition, drug effectiveness or drug toxicity. P-gp transporters have a regulator function by limiting penetration of drugs in brain, heart, placenta, ovaries, and testes tissues This has been shown in vivo on wild type (WT), mdr1a(-) and mdr1a/1b(-/-) knockout (KO) mice, which are mice lacking genes encoding for drug-transporting P-gp [3]. It has been demonstrated that modulation of the expression and/or activity of these transporters due to genetic or environmental factors may have a significant impact on drug disposition, drug effectiveness or drug toxicity [9,10,11]. Characterization of drug disposition over a wide range of conditions of ABC membrane transporters activities is required to better characterize drug pharmacokinetics and pharmacodynamics
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