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

Shinji Kobuchi, Keizo Fukushima, Yuta Maeda, Takatoshi Kokuhu, Hidetaka Ushigome, Norio Yoshimura, Nobuyuki Sugioka, Kanji Takada

4Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan..
Department of Clinical Pharmacokinetics, Fac- ulty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan.
Department of Clinical Pharmacokinetics, Fac- ulty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan;.
Department of Hospital Pharmacy, Kyoto Prefectural Uni- versity of Medicine, Kyoto, Japan;.
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan.
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan;.

DOI: 10.4236/ijcm.2013.410078                

Abstract

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.

Keywords

Pharmacokinetics; Bile Duct Stricture; Tacrolimus; Drug Metabolism; Total Bilirubin; Therapeutic Drug Monitoring

Conflicts of Interest

The authors declare no conflicts of interest.

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