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   PDF    HTML     3,286 Downloads   5,288 Views   Citations


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.

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S. Kobuchi, K. Fukushima, Y. Maeda, T. Kokuhu, H. Ushigome, N. Yoshimura, N. Sugioka and K. Takada, "Effects of Cholestasis on Whole Blood Concentration of Tacrolimus, an Immunosuppressant, in Living-Related Liver Transplant Recipients," International Journal of Clinical Medicine, Vol. 4 No. 10, 2013, pp. 432-439. doi: 10.4236/ijcm.2013.410078.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] T. Kino, H. Hatanaka, M. Hashimoto, M. Nishiyama, T. Goto, M. Okuhara, M. Kohsaka, H. Aoki and H. Imanaka, “FK-506, a Novel Immunosuppressant Isolated from a Streptomyces. I. Fermentation, Isolation, and Physico-Chemical and Biological Characteristics,” The Journal of Antibiotics (Tokyo), Vol. 40, No. 9, 1987, pp. 1249-1255.
[2] T. Kino, H. Hatanaka, S. Miyata, N. Inamura, M. Nishiyama, T. Yajima, T. Goto, M. Okuhara, M. Kohsaka, H. Aoki, et al., “FK-506, a Novel Immunosuppressant Isolated from a Streptomyces. II. Immunosuppressive Effect of FK-506 in Vitro,” The Journal of Antibiotics (Tokyo), Vol. 40, No. 9, 1987, pp. 1256-1265.
[3] G. L. Plosker and R. H. Foster, “Tacrolimus: A Further Update of Its Pharmacology and Therapeutic Use in the Management of Organ Transplantation,” Drugs, Vol. 59, No. 2, 2000, pp. 323-389.
[4] E. M. Haddad, V. C. McAlister, E. Renouf, R. Malthaner, M. S. Kjaer and L. L. Gluud, “Cyclosporin versus Tacrolimus for Liver Transplanted Patients,” Cochrane Database System Review, Vol. 4, 2006, CD005161.
[5] C. E. Staatz and S. E. Tett, “Clinical Pharmacokinetics and Pharmacodynamics of Tacrolimus in Solid Organ Transplantation,” Clinical Pharmacokinetics, Vol. 43, No. 10, 2004, pp. 623-653.
[6] M. Naesens, D. R. Kuypers and M. Sarwal, “Calcineurin Inhibitor Nephrotoxicity,” Clinical Journal of the American Society of Nephrology, Vol. 4, No. 2, 2009, pp. 481-508. http://dx.doi.org/10.2215/CJN.04800908
[7] Tacrolimus (Prograf®), “Drug Information,” Astellas Pharma Inc., Tokyo, 2013.
[8] R. P. Kershner and W. E. Fitzsimmons, “Relationship of FK506 Whole Blood Concentrations and Efficacy and Toxicity after Liver and Kidney Transplantation,” Transplantation, Vol. 62, No. 7, 1996, pp. 920-926.
[9] P. McMaster, D. F. Mirza, T. Ismail, G. Vennarecci, P. Patapis and A. D. Mayer, “Therapeutic Drug Monitoring of Tacrolimus in Clinical Transplantation,” Therapeutic Drug Monitoring, Vol. 17, No. 6, 1995, pp. 602-605.
[10] G. W. Boswell, I. Bekersky, J. Fay, J. Wingard, J. Antin, D. Weisdorf, R. Maher, W. Fitzsimmons and R. Nash, “Tacrolimus Pharmacokinetics in BMT Patients,” Bone Marrow Transplant, Vol. 21, No. 1, 1998, pp. 23-28.
[11] W. J. Jusko, W. Piekoszewski, G. B. Klintmalm, M. S. Shaefer, M. F. Hebert, A. A. Piergies, C. C. Lee, P. Schechter and Q. A. Mekki, “Pharmacokinetics of Tacrolimus in Liver Transplant Patients,” Clinical Pharmacology & Therapeutics, Vol. 57, 1995, pp. 281-290.
[12] R. J. Stratta, R. P. Wood, A. N. Langnas, R. R. Hollins, K. J. Bruder, J. P. Donovan, D. A. Burnett, R. P. Lieberman, G. B. Lund, T. J. Pillen, et al., “Diagnosis and Treatment of Biliary Tract Complications after Orthotopic Liver Transplantation,” Surgery, Vol. 106, 1989, pp. 675-683.
[13] J. W. Ostroff, “Post-Transplant Biliary Problems,” Gastrointestinal Endoscopy Clinics of North America, Vol. 11, 2001, pp. 163-183.
[14] D. M. Minich, R. Havinga, F. Stellaard, R. J. Vonk, F. Kuipers and H. J. Verkade, “Intestinal Absorption and Postabsorptive Metabolism of Linoleic Acid in Rats with Short-Term Bile Duct Ligation,” American Journal of Physiology-Gastrointestinal and Liver Physiology, Vol. 279, No. 6, 2000, pp. G1242-G1248.
[15] R. J. Sokol, M. Devereaux, R. Khandwala and K. O’Brien, “Evidence for Involvement of Oxygen Free Radicals in Bile Acid Toxicity to Isolated Rat Hepatocytes,” Hepatology, Vol. 17, No. 5, 1993, pp. 869-881.
[16] G. Poli, “Pathogenesis of Liver Fibrosis: Role of Oxidative Stress,” Molecular Aspects of Medicine, Vol. 21, No. 3, 2000, pp. 49-98.
[17] G. Tahan, H. Akin, F. Aydogan, S. S. Ramadan, O. Yapicier, O. Tarcin, H. Uzun, V. Tahan and K. Zengin, “Melatonin Ameliorates Liver Fibrosis Induced by Bile-Duct Ligation in Rats,” Canadian Journal of Surgery, Vol. 53, 2010, pp. 313-318.
[18] S. Eguchi, M. Takatsuki, A. Soyama, M. Hidaka, I. Muraoka and T. Kanematsu, “Use of Stepwise versus Straightforward Clamping of Biliary Drainage Tubes after Living-Donor Liver Transplantation: A Prospective, Randomized Trial,” Journal of Hepato-Biliary-Pancreatic Surgery, Vol. 19, No. 4, 2012, pp. 379-381.
[19] M. L. Shiffman, R. L. Carithers Jr., M. P. Posner and E. W. Moore, “Recovery of Bile Secretion Following Orthotopic Liver Transplantation,” Journal of Hepatology, Vol. 12, No. 3, 1991, pp. 351-361.
[20] R. Venkataramanan, A. Jain, V. S. Warty, K. Abu-Elmagd, M. Alessiani, J. Lever, A. Krajak, J. Flowers, S. Mehta, S. Zuckerman, et al., “Pharmacokinetics of FK 506 in Transplant Patients,” Transplant Proceedings, Vol. 23, No. 6, 1991, pp. 2736-2740.
[21] M. Fukudo, I. Yano, S. Masuda, M. Goto, M. Uesugi, T. Katsura, Y. Ogura, F. Oike, Y. Takada, H. Egawa, S. Uemoto and K. Inui, “Population Pharmacokinetic and Pharmacogenomic Analysis of Tacrolimus in Pediatric Living-Donor Liver Transplant Recipients,” Clinical Pharmacology & Therapeutics, Vol. 80, 2006, pp. 331-345. http://dx.doi.org/10.1016/j.clpt.2006.06.008
[22] R. A. Koster, E. C. Dijkers and D. R. Uges, “Robust, High-Throughput LC-MS/MS Method for Therapeutic Drug Monitoring of Cyclosporine, Tacrolimus, Everolimus, and Sirolimus in Whole Blood,” Therapeutic Drug Monitoring, Vol. 31, No. 1, 2009, pp. 116-125.
[23] U. Christians, F. Braun, N. Kosian, M. Schmidt, H. M. Schiebel, L. Ernst, C. Kruse, M. Winkler, I. Holze, A. Linck, et al., “High Performance Liquid Chromatography/ Mass Spectrometry of FK 506 and Its Metabolites in Blood, Bile, and Urine of Liver Grafted Patients,” Transplant Proceedings, Vol. 23, 1991, pp. 2741-2744.
[24] M. Antignac, J. S. Hulot, E. Boleslawski, L. Hannoun, Y. Touitou, R. Farinotti, P. Lechat and S. Urien, “Population Pharmacokinetics of Tacrolimus in Full Liver Transplant Patients: Modelling of the Post-Operative Clearance,” European Journal of Clinical Pharmacology, Vol. 61, No. 5-6, 2005, pp. 409-416.
[25] S. Kobuchi, K. Fukushima, Y. Maeda, T. Kokuhu, H. Ushigome, N. Yoshimura, N. Sugioka and K. Takada, “Effects of Bile Duct Stricture on the Pharmacokinetics of the Immunosuppressant Tacrolimus in Rats,” Interactive Medicinal Chemistry, in press.

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