Microdose Cocktail Study Reveals the Activity and Key Influencing Factors of <scp>OATP1B</scp> , P‐Gp, <scp>BCRP,</scp> and <scp>CYP3A</scp> in End‐Stage Renal Disease Patients

OATP1B, P-gp, BCRP, and CYP3A are the most contributing drug-metabolizing enzymes or transporters (DMETs) for commonly prescribed medication. Their activities may change in end-stage renal disease (ESRD) patients with large inter-individual variabilities (IIVs), leading to altered substrate drug exposure and ultimately elevated safety risk. However, the changing extent and indictive influencing factors are not quantified so far. Here, a microdose cocktail regimen containing five sensitive substrate drugs (pitavastatin, dabigatran etexilate, rosuvastatin, midazolam, and atorvastatin) for these DMETs was administrated to Chinese healthy volunteers and ESRD patients. Drug pharmacokinetics profiles were determined, together with physiological, pharmacogenetic, and gut microbiome signature. Population pharmacokinetic and machine learning model were established to identify key influencing factors and quantify their contribution to drug exposure change. The exposure of pitavastatin, dabigatran, rosuvastatin, and atorvastatin increased to 1.8-, 3.1-, 1.1-, and 1.3-fold, respectively, whereas midazolam exposure decreased by 72% in ESRD patients. Notably, in addition to disease state, the relative abundance of genus Veillonella and Clostridium_XIVb were firstly identified as significant influencing factors for PTV and RSV apparent clearance, respectively, suggesting their indicative role for OATP and BCRP activity evaluation. Moreover, several genera were found to strongly associate with drug clearance and reduce unexplained IIVs. Accordingly, it was estimated that OATP1B and intestine P-gp activity decreased by 35-75% and 29-44%, respectively, whereas BCRP and CYP3A4 activity may upregulate to some extent. Our study provides a quantitative and mechanistic understanding of individual DMET activity and could support precision medicine of substrate drugs in ESRD patients.