European Journal of Clinical Pharmacology

, Volume 71, Issue 9, pp 1091–1097 | Cite as

Effect of CYP3A5 and ABCB1 polymorphisms on the interaction between tacrolimus and itraconazole in patients with connective tissue disease

  • Masaru Togashi
  • Takenori Niioka
  • Atsushi Komatsuda
  • Mizuho Nara
  • Shin Okuyama
  • Ayumi Omokawa
  • Maiko Abumiya
  • Hideki Wakui
  • Naoto Takahashi
  • Masatomo Miura
Pharmacokinetics and Disposition

Abstract

Purpose

The aim of this study was to investigate the effect of itraconazole (ITCZ), a potent inhibitor of CYP3A4 and P-glycoprotein, on the blood concentration 12 h after tacrolimus administration (C 12h) in relation to CYP3A5 6986A>G and ABCB1 3435C>T genotype status in patients with connective tissue disease (CTD).

Methods

Eighty-one CTD patients taking tacrolimus (Prograf®) once daily at night (2100 hours) were enrolled in this study. Whole blood samples were collected 12 h after tacrolimus administration at steady state.

Results

The dose-adjusted tacrolimus C 12h with or without ITCZ co-administration was significantly higher in patients with CYP3A5*3/*3 than in those with the CYP3A5*1 allele [CYP3A5 *1/*1 vs. *1/*3 vs. *3/*3 = 1.67 vs. 2.70 vs. 4.83 ng/mL/mg (P = 0.003) and 0.68 vs. 0.97 vs. 2.20 ng/mL/mg (P < 0.001), respectively], but differences were not observed for ABCB1 genotypes. However, there was no difference in the increase rate of the dose-adjusted C 12h of tacrolimus between CYP3A5 or ABCB1 genotypes (P = 0.378 and 0.259). On the other hand, reduction of the estimated glomerular filtration rate exhibited a correlation with the C 12h of tacrolimus after ITCZ co-administration (r = −0.482, P = 0.009).

Conclusions

In CYP3A5*3/*3 patients, because the metabolic pathway for tacrolimus occurs only through CYP3A4, the combination with ITCZ seems to lead to a higher risk of acute renal dysfunction. Therefore, we suggest that the target blood tacrolimus concentration be set as low as possible through dose-adjustment for patients with the CYP3A5*3/*3 allele.

Keywords

Itraconazole Tacrolimus CYP3A5 polymorphism Drug-drug interaction Connective tissue disease 

Notes

Acknowledgments

This work was supported by a grant (No. 26460189) from the Japan Society for the Promotion of Science, Tokyo, Japan.

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

228_2015_1901_MOESM1_ESM.docx (27 kb)
ESM 1 Figure 1 Study profile. Diagram shows patient disposition in treatment groups with and without co-administration of itraconazole. (DOCX 26 kb)
228_2015_1901_MOESM2_ESM.docx (50 kb)
ESM 2 Table 2 Median blood concentration and dose of tacrolimus with or without itraconazole. (DOCX 50 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Masaru Togashi
    • 1
  • Takenori Niioka
    • 2
  • Atsushi Komatsuda
    • 1
  • Mizuho Nara
    • 1
  • Shin Okuyama
    • 3
  • Ayumi Omokawa
    • 4
  • Maiko Abumiya
    • 2
  • Hideki Wakui
    • 5
  • Naoto Takahashi
    • 1
  • Masatomo Miura
    • 2
  1. 1.Department of Hematology, Nephrology, RheumatologyAkita University Graduate School of MedicineAkitaJapan
  2. 2.Department of PharmacyAkita University HospitalAkitaJapan
  3. 3.Center for Kidney Disease and TransplantationAkita University HospitalAkitaJapan
  4. 4.Department of General Internal Medicine and Clinical Laboratory MedicineAkita University Graduate School of MedicineAkitaJapan
  5. 5.Department of Life Science, Graduate School of Engineering and Resource ScienceAkita UniversityAkitaJapan

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