Abstract
Background: The bioavailability of orally administered drugs is markedly affected by the expression and function of metabolizing enzymes and drug transporters both in the liver and the gastrointestinal tract. The study revises and complements existing findings on the distribution of drug transporters in the first-pass effect organs.
Methods: Tissue samples were obtained from 9 healthy organ donors (one duodenal, two jejunal, one ileal, one colonic and one hepatic). A validated LC-MS/MS-based targeted proteomics. and qPCR methods have been used for the simultaneous absolute quantification of ATP-binding cassette (ABC: ABCB1, ABCC2, ABCC3, ABCC4, ABCG2) and solute carrier (SLC: ASBT, NTCP, BSEP, MCT1, OATP1A2, OATP1B1, OATP1B3, OATP2B1, OCT1, OCT3, OAT2, PEPT1, SLC22A18, MATE1) transporters.
Results: The gene expression and protein abundance pattern varied substantially between intestinal and hepatic samples. BSEP, MATE1, NTCP, OAT2, OATP1A2, OATP1B1 and OATP1B3 were only determined in hepatic tissues. Distribution of the transporters was not homogenous along the length of the human intestine. Nearly all drug transporters detected in the gastrointestinal tract showed their highest abundance in the jejunum, followed in most cases by ileum, duodenum and colon.
Conclusion: Our data may contribute to an improved understanding of hepatic and intestinal processes governing drug transport. The knowledge about intra-subject variability in the expression of intestinal and hepatic drug transporters may improve the PBPK-based prediction for orally administered drugs. The study was funded a grant by the National Science Centre, Cracow, Poland UMO-2015/17/B/NZ7/03066
