Association between CYP3A5 genotypes in graft liver and increase in tacrolimus biotransformation from steroid treatment in living-donor liver transplant patients

Keiko Hosohata, Miwa Uesugi, Sachiyo Hashi, Mio Hosokawa, Ken Ichi Inui, Kazuo Matsubara, Kohei Ogawa, Yasuhiro Fujimoto, Toshimi Kaido, Shinji Uemoto, Satohiro Masuda

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

We retrospectively examined whether cytochrome P450 (CYP) 3A5 genotypes are associated with high-dose steroid pulse treatment-induced functional gain of tacrolimus biotransformation in livingdonor liver transplant patients. Concentrations of tacrolimus and its 3 primary metabolites, 13-O-demethyl tacrolimus (M-I), 31-O-demethyl tacrolimus (M-II), and 15-O-demethyl tacrolimus (M-III), were measured in trough blood samples from 18 liver transplant patients, by liquid chromatographytandem mass spectrometry/mass spectrometry (LC-MS/MS). In patients engrafted with a CYP3A5*1-carrying liver but not with a CYP3A5*3/*3-carrying liver, the concentration/dose ratio of tacrolimus significantly fell after therapy, while ratios of M-I/tacrolimus, M-II/tacrolimus, and M-III/tacrolimus were significantly higher after therapy than before (p = 0.032, p = 0.023, and p = 0.0078, respectively). After steroid pulse therapy, the concentration of tacrolimus measured by immunoassay was significantly higher than that measured by LCMS/MS in patients engrafted with a CYP3A5*1-carrying liver, but not those engrafted with a CYP3A5*3/*3-carrying liver. This suggests that the increased ratio of tacrolimus metabolites/tacrolimus can be explained by induction of CYP3A5 via high-dose steroid pulse therapy. Further, the concentrations of tacrolimus measured by the immunoassays were overestimated, partly because of cross-reactivity of the monoclonal antibody they incorporated to detect tacrolimus, with the increased metabolites in patients with a CYP3A5*1-carrying graft liver.

Original languageEnglish
Pages (from-to)83-89
Number of pages7
JournalDrug Metabolism and Pharmacokinetics
Volume29
Issue number1
DOIs
Publication statusPublished - Jan 1 2014
Externally publishedYes

Fingerprint

Cytochrome P-450 CYP3A
Living Donors
Tacrolimus
Biotransformation
Steroids
Genotype
Transplants
Liver
Therapeutics
Immunoassay
Tandem Mass Spectrometry

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

Cite this

Association between CYP3A5 genotypes in graft liver and increase in tacrolimus biotransformation from steroid treatment in living-donor liver transplant patients. / Hosohata, Keiko; Uesugi, Miwa; Hashi, Sachiyo; Hosokawa, Mio; Inui, Ken Ichi; Matsubara, Kazuo; Ogawa, Kohei; Fujimoto, Yasuhiro; Kaido, Toshimi; Uemoto, Shinji; Masuda, Satohiro.

In: Drug Metabolism and Pharmacokinetics, Vol. 29, No. 1, 01.01.2014, p. 83-89.

Research output: Contribution to journalArticle

Hosohata, Keiko ; Uesugi, Miwa ; Hashi, Sachiyo ; Hosokawa, Mio ; Inui, Ken Ichi ; Matsubara, Kazuo ; Ogawa, Kohei ; Fujimoto, Yasuhiro ; Kaido, Toshimi ; Uemoto, Shinji ; Masuda, Satohiro. / Association between CYP3A5 genotypes in graft liver and increase in tacrolimus biotransformation from steroid treatment in living-donor liver transplant patients. In: Drug Metabolism and Pharmacokinetics. 2014 ; Vol. 29, No. 1. pp. 83-89.
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abstract = "We retrospectively examined whether cytochrome P450 (CYP) 3A5 genotypes are associated with high-dose steroid pulse treatment-induced functional gain of tacrolimus biotransformation in livingdonor liver transplant patients. Concentrations of tacrolimus and its 3 primary metabolites, 13-O-demethyl tacrolimus (M-I), 31-O-demethyl tacrolimus (M-II), and 15-O-demethyl tacrolimus (M-III), were measured in trough blood samples from 18 liver transplant patients, by liquid chromatographytandem mass spectrometry/mass spectrometry (LC-MS/MS). In patients engrafted with a CYP3A5*1-carrying liver but not with a CYP3A5*3/*3-carrying liver, the concentration/dose ratio of tacrolimus significantly fell after therapy, while ratios of M-I/tacrolimus, M-II/tacrolimus, and M-III/tacrolimus were significantly higher after therapy than before (p = 0.032, p = 0.023, and p = 0.0078, respectively). After steroid pulse therapy, the concentration of tacrolimus measured by immunoassay was significantly higher than that measured by LCMS/MS in patients engrafted with a CYP3A5*1-carrying liver, but not those engrafted with a CYP3A5*3/*3-carrying liver. This suggests that the increased ratio of tacrolimus metabolites/tacrolimus can be explained by induction of CYP3A5 via high-dose steroid pulse therapy. Further, the concentrations of tacrolimus measured by the immunoassays were overestimated, partly because of cross-reactivity of the monoclonal antibody they incorporated to detect tacrolimus, with the increased metabolites in patients with a CYP3A5*1-carrying graft liver.",
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