Effects of Cholestasis on Whole Blood Concentration of Tacrolimus, an Immunosuppressant, in Living-Related Liver Transplant Recipients

Background: To explore the effects of cholestasis on whole blood concentration of tacrolimus (TAC), an immunosup-pressant, we investigated the relationship among blood TAC concentration, bile flow, and TAC metabolites in bile, as well as the relationship between total bilirubin (T-Bil), an index of cholestasis, and blood TAC concentration, in liver transplant recipients. Methods: Data were collected retrospectively from 16 male and 19 female patients (mean age: 38 years; range: 12 -59 years) who had undergone a living-related liver transplantation at Kyoto Prefectural University of Medicine from 2004 through 2008. Analysis of TAC, demethyl-TAC, and hydroxy-TAC in bile was performed by LC-MS/MS. Results: There was no correlation between the ratio of TAC metabolite to TAC in bile (M/P) of demethyl-TAC and post operation days (POD), whereas a weak linear correlation was demonstrated between M/P of hydroxy-TAC and POD (r = －0.345). Moreover, linear correlations were not observed between M/P and the TAC trough level normalized dose (TLTAC/dose), and between TLTAC/dose and POD. A negative linear correlation was demonstrated between bile flow and T-Bil in blood (r = －0.495). Furthermore, a positive linear correlation was observed between TLTAC/dose and T-Bil (r = 0.598), whereas there was no correlation between bile flow and TLTAC/dose. Conclusions: Improvement of hepatic function and the increase of TAC clearance after postoperative day 7 did not significantly contribute to hepatic TAC metabolism, bile excretion, and TLTAC/dose. Postoperative biliary stricture from liver transplantation with/without biliary drainage caused inter-and intra-patient variability in TLTAC/dose after liver transplantation, which could be assessed by T-Bil. T-Bil in blood might be a predictive biomarker for determining the degree of bile duct stricture and TAC dose in liver transplantation patients. Along with an appropriate dosing regimen, therapeutic drug monitoring including T-Bil would be beneficial and enable individual adjustment of TAC dose in liver transplantation patients.