Variability in intestinal drug metabolizing enzymes and transporters in Crohn's disease and potential impact on oral drug absorption.

Abstract

Aims: The aim of study was to generate quantitative data on the abundance of drug-metabolizing enzymes and transporters (DMETs) in inflamed and non-inflamed Crohn's disease (CD) ileum and colon, for incorporation into physiologically based pharmacokinetic (PBPK) models, enabling prediction of oral drugs' pharmacokinetics (PK) perturbation in CD patients.

Methods: Homogenate fractions were processed from 13 inflamed (six ileum and seven colon) and seven non-inflamed (two ileum and five colon) CD and 10 healthy (five ileum and five colon) tissues from deceased subjects by calcium chelation elution, and protein abundances determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics and compared with healthy values. PBPK simulation was applied to predict the potential effect of altered DMET profiles on the PK of oral drugs.

Results: All investigated proteins showed trends for reduced expression in inflamed and non-inflamed CD samples relative to healthy individuals. Significant downregulation (P < 0.05) was observed for CYP3A4, AOX1, NAT1 and several SULTs in inflamed ileum as well as UGT1A10, NAT1, BCRP and several SULTs in inflamed and non-inflamed colon. Inter-individual variability was generally higher in CD, with exceptions, for most targets (up to 146%CV in inflamed ileum and up to 169% in histologically normal colon tissues). Integration of abundance data into a verified PBPK model of CD showed a considerable (≥2-fold; CD predicted relative to healthy predicted) change in systemic drug exposure for 10 drugs examined.

Conclusions: CD inflammation significantly suppresses the expression of intestinal DMETs, which, together with changes in other system parameters, can alter the fate of drugs taken orally in these patients. Virtual patients within a PBPK framework, informed by the measured DMET ranges in the intestine, may serve as a guide for dose adjustment in the absence of dedicated clinical studies.