Drug disposition protein quantification in matched human jejunum and liver from donors with obesity

Abstract

Mathematical models, such as physiologically based pharmacokinetic (PBPK) models, are used to predict e.g., drug disposition and toxicity. However, populations differ in the abundance of proteins involved in these processes. To improve the building and refinement of such models, they must take into account these inter-individual variabilities. In this study, we used global proteomics to characterize the protein composition of jejunum and liver from 37 donors with obesity enrolled in the COCKTAIL study. Liver protein levels from the 37 donors were further compared with those from donors without obesity. We quantified thousands of proteins and could present the expression of several drug-metabolizing enzymes, for the first time, in jejunum, many of which belong to the cytochrome P450 (e.g., CYP2U1) and the amine oxidase [flavin-containing] (e.g., MAOA) families. Although we show that many metabolizing enzymes had greater expression in liver, others had higher expression in jejunum (such as, MAOA and CES2), indicating the role of the small intestine in extrahepatic drug metabolism. We further show that proteins involved in drug disposition are not correlated in the two donor-matched tissues. These proteins also do not correlate with physiological factors such as BMI, age, and inflammation status in either tissue. Furthermore, the majority of these proteins are not differently expressed in donors with or without obesity. Nonetheless, inter-individual differences were considerable, with implications for personalized prediction models and systems pharmacology.

Drug disposition protein quantification in matched human jejunum and liver from donors with obesity