Rifampicin Induces Gene, Protein, and Activity of P-Glycoprotein (ABCB1) in Human Precision-Cut Intestinal Slices

Area of Science:

• Pharmacology and Toxicology
• Drug Metabolism and Transport

Background:

• P-glycoprotein (ABCB1) limits drug absorption and is a key site for drug-drug interactions.
• Drug-induced ABCB1 expression reduces drug bioavailability, but reliable human models for induction testing are lacking.
• Regulatory agencies currently lack standardized in vitro/ex vivo testing recommendations for ABCB1-inducing drugs.

Purpose of the Study:

• To evaluate human precision-cut intestinal slices (hPCISs) as a model for assessing drug-induced ABCB1 expression.
• To determine if rifampicin induces functional ABCB1 expression in hPCISs over 24- and 48-hour incubation periods.
• To characterize the dynamic changes in ABCB1 gene expression and its correlation with PXR levels.

Main Methods:

• Incubation of hPCISs in William's Medium E for 48 hours to assess viability and baseline ABCB1 activity.
• Treatment of hPCISs with 30 μM rifampicin to induce ABCB1 expression.
• Measurement of ABCB1 gene expression, protein levels, and efflux activity at 24 and 48 hours post-treatment.

Main Results:

• hPCISs maintained morphology, ATP content, and ABCB1 efflux activity during 48-hour incubation.
• Rifampicin significantly increased ABCB1 gene expression, protein levels, and efflux activity in hPCISs.
• ABCB1 induction peaked at different times among donors, and induction extent correlated with intestinal PXR mRNA levels.

Conclusions:

• hPCISs are a viable experimental model for evaluating the ABCB1-inducing potency of drugs in the human intestine.
• This model can be utilized under conditions similar to those used for inhibition studies, facilitating drug interaction assessments.
• hPCISs offer a valuable tool for complex experimental evaluations of drug-drug interactions, contributing to improved drug safety.