Research ArticlesMethodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption
Section snippets
Abbreviations used:
- AUC
area under the plasma concentration-time curve
- FG,
fraction of dose escaping the enterocyte intact
- FH
fraction of dose escaping hepatic metabolism
- CYP
cytochrome
- taf,
transporter abundance factor
- caf,
CYP abundance factor
INTRODUCTION
Poor absorption characteristics of many new chemical entities is one of the major causes of failure of compounds at the early development stages.1 As the oral route is the most favourable route of drug administration, with over 70% of dosage forms taking the oral form,2 the small intestine must be recognised as a vital and key barrier to efficacious delivery into the systemic circulation. The ability to predict the rate and extent of absorption of compounds following oral administration may be
METHODS
The aim was to develop a research tool capable of predicting the fraction of dose escaping epithelial cells intact (FG) and the temporal distribution of drug ab orally. Compounds with a range of intestinal metabolic (CYP3A) and efflux (P-glycoprotein) clearances were used in the development of the model. The model predicts in vivo absorption from in vitro data on permeability. Additionally scaling of in vitro parameters to human in vivo situation, the inclusion of pH and geometrical parameters
Prediction of the Impact of P-Glycoprotein Efflux and CYP3A Metabolism on FG
Irrespective of the extent of P-glycoprotein-mediated transport, increasing the apparent permeability (PappAB) to increase FG (Fig. 2a). For drugs with an efflux ratio of between 1 and 2, increasing permeability increased FG to 1. For drugs with efflux ratios of 4 or greater FG increased but did not reach 1. In all cases, the most rapid increase in FG occurred at low PappAB levels, that is increasing PappAB from 10 × 10−6 cm/s to 20 × 10−6 cm/s (Fig. 2a).
An increase in FG occurred for drugs
DISCUSSION
A limited number of pharmacokinetic models have examined the influence of efflux and metabolism on oral drug absorption. Ito et al.48 considered the influence of P-glycoprotein and CYP3A metabolism on intestinal extraction within a single ‘lumped’ intestinal compartment whereas Cong et al.49 have developed intricate intestinal models incorporating segregated flow within the intestinal tissues. However, these models lack physiological distribution of metabolic enzyme and efflux transporter along
CONCLUSION
Traditionally, simplistic compartmental models, lacking physiological descriptors of the small intestine, have been used to describe intestinal-drug availability. However, these types of models have often been found to inadequately predict intestinal drug distribution, largely as a result of not accounting for the heterogeneous physiological makeup of the intestine. Elaborate models such as those proposed by Cong et al.,49 whilst physiologically accurate, remain challenging in their application
ACKNOWLEDGEMENTS
The work was funded by a consortium of pharmaceutical companies (GlaxoSmithKline, Eli Lilly, Novartis, Pfizer and Servier) within the Centre for Applied Pharmacokinetic Research at the University of Manchester.
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2014, European Journal of Pharmaceutical SciencesCitation Excerpt :These studies have employed blot densitometry techniques to evaluate relative expression differences between samples after calibration against a reference ‘housekeeper’ protein. Meta-analyses evaluating the regional heterogeneity of intestinal transporter expression from multiple literature sources, using immunoblot densitometry and mRNA-based expression, have been undertaken to incorporate expression-based transporter functionality into mechanistic intestinal models (Badhan et al., 2009; Bolger et al., 2009; Darwich et al., 2010; Harwood et al., 2013). It is common when using relative expression techniques to normalize the expression of transporters along the intestine to a single reference compartment, i.e. the proximal ileal or jejunal segments (Bolger et al., 2009; Darwich et al., 2010; Harwood et al., 2013).