home > news > 2011 > february > new paper explores current hot topic in pharmacokinetics
New paper explores current hot topic in pharmacokinetics
Date: 01 Feb 2011
A new paper entitled ‘Interplay of Metabolism and Transport in Determining Oral Drug Absorption and Gut Wall Metabolism: A Simulation Assessment Using the “Advanced Dissolution, Absorption, Metabolism (ADAM)” Model’ explores a current hot topic in pharmacokinetics. The article investigates the impact of intestinal drug permeability and transport via P-glycoprotein P-gp (P-gp; MDR1/ABCB1) and intestinal metabolism (CYP3A) interplay on oral drug bioavailability in relation to the well-defined Biopharmaceutics Classification System (BCS), used routinely in the pharmaceutical industry. The authors of the paper are from The University of Uppsala, Simcyp Limited and the University of Manchester.
A mechanistic modelling and simulation approach using Simcyp’s Advanced Dissolution Absorption and Metabolism (ADAM) model was employed to investigate the impact of P-gp and CYP3A on fraction absorbed (fa) and the fraction of drug escaping gut metabolism (FG). The results of over 8000 simulations show that increasing CYP3A intrinsic clearance (CLint) reduces FG while increasing P-gp CLint reduces fa and also reduces FG under certain parameter conditions. However, the reduced FG is restricted to a limited area of parameter space. This adds valuable information to the role of GI tract transporters on drug metabolism in addition to highlighting the feasibility of using this model for assessing the complex interplay between multiple elements.
The paper demonstrates that employment of robust in vitro data and advanced physiological modelling can be utilised to identify the sensitivity of certain parameters key to determining oral bioavailability. The results are related to the BCS used in early discovery, and emphasises how a scientist in a discovery setting can investigate the in vivo relevance of mechanistically challenging pharmacokinetic concepts from early discovery in vitro data.
The abstract and full text options for the paper can be found here.