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

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.