A microdose cocktail and population pharmacokinetic study suggests potentially reduced CYP3A and P-gp activities in type 2 diabetes.

BACKGROUND: Diabetes patients often exhibit suboptimal efficacy and adverse reactions, accompanied by pharmacokinetic (PK) changes, indicating drug-metabolizing enzymes and transporters (DMET) activities may change. This study aimed to determine whether type 2 diabetes affects DMET activities and quantify impact magnitude. Furthermore, gut microbiome, pharmacogenetic and demographic characteristics were assessed to elucidate the sources of inter-individual variability (IIV) in DMET activities. METHODS: The activities of CYP3A and transporters P-gp, OATP and BCRP were evaluated in type 2 diabetes patients and healthy volunteers (HVs) following a single oral dose of five probe drugs (midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin). Population pharmacokinetics (PopPK) and an exploratory machine learning (ML) analysis were employed to quantify the impact of type 2 diabetes on DMET activities. RESULTS: Based on observed PK parameters, compared to HVs, type 2 diabetes patients exhibited increased exposure to midazolam (1.38-fold), dabigatran (1.40-fold), and atorvastatin (1.93-fold), whereas pitavastatin (0.931-fold) and rosuvastatin (1.25-fold) showed no change. PopPK analysis revealed that the mean activities of CYP3A and P-gp were potentially decreased by 23% and 27%, respectively, in type 2 diabetes patients, while no changes for OATP and BCRP. Notably, unlike the direct patient population covariate for P-gp, reduced CYP3A activity was indirectly estimated from lower Salmonella abundance. Additionally, factors such as sex, BCRP genotype, and Clostridium_XlVb partly explained the IIV in probe drugs exposure. CONCLUSION: The findings regarding altered DMET activities and identified influence factors help to identify specific drug classes that may warrant closer clinical attention in type 2 diabetes patients.