Advanced Age-Related Changes in Intestinal Drug Transporters and Metabolising Enzymes: A Targeted Proteomics Study

This study examines the influence of aging on the protein abundance of key drug transport proteins (DTPs) and drug-metabolizing enzymes (DMEs). Duodenal and colonic biopsies were collected from 58 volunteers aged 19-85 years who underwent routine endoscopic procedures. Targeted mass spectrometry-based proteomics was used to quantify the abundance of major ATP-binding cassette (ABC) and solute carrier (SLC) transporters, as well as cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes involved in drug disposition. Multiple regression analysis was employed to assess the effects of age, sex, and sex-specific age effects on DTP and DME expression, providing insight into potential age-related variability in intestinal drug metabolism and transport. The analysis revealed significant age-related changes in duodenal protein abundance, with age coefficients ranging from -0.36 to 0.51. Specifically, a decrease in duodenal abundance with age was observed for carboxylesterase 2 (CES2), peptide transporter 1 (PEPT1), and villin-1. Additionally, a significant age-dependent increase in the duodenal abundance of breast cancer resistance protein (BCRP), multidrug resistance-associated proteins 1, 3, 4 (MRP1, MRP3, MRP4) and permeability-glycoprotein (P-gp) was observed. No significant impact of sex or sex-specific age effects was detected. These findings provide novel insights into the aging human proteome and may inform future research in this area.