Plasma metabolomic profiling reveals factors associated with dose-adjusted trough concentration of tacrolimus in liver transplant recipients

Abstract

Inter- and intrapatient variability of tacrolimus exposure is a vital prognostic risk factor for the clinical outcome of liver transplantation. New factors or biomarkers characterizing tacrolimus disposition is essential for optimal dose prediction in recipients of liver transplant. The aim of the study was to identify potential plasma metabolites associated with the dose-adjusted trough concentration of tacrolimus in liver transplant recipients by using a global metabolomic approach. A total of 693 plasma samples were collected from 137 liver transplant recipients receiving tacrolimus and regular therapeutic drug monitoring. Untargeted metabolomic analysis was performed by ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry. Univariate and multivariate analyses with a mixed linear model were conducted, and the results showed that the dose-adjusted tacrolimus trough concentration was associated with 31 endogenous metabolites, including medium- and long-chain acylcarnitines such as stearoylcarnitine (β = 0.222, p = 0.001), microbiota-derived uremic retention solutes such as indolelactic acid (β = 0.194, p = 0.007), bile acids such as taurohyodeoxycholic acid (β = −0.056, p = 0.002), and steroid hormones such as testosterone (β = 0.099, p = 0.001). A multiple linear mixed model including 11 metabolites and clinical information was established with a suitable predictive performance (correlation coefficient based on fixed effects = 0.64 and correlation coefficient based on fixed and random effects = 0.78). These data demonstrated that microbiota-derived uremic retention solutes, bile acids, steroid hormones, and medium- and long-chain acylcarnitines were the main metabolites associated with the dose-adjusted trough concentration of tacrolimus in liver transplant recipients.