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The CYP3A4*22 C>T single nucleotide polymorphism is associated with reduced midazolam and tacrolimus clearance in stable renal allograft recipients

The Pharmacogenomics Journal volume 15, pages 144–152 (2015)Cite this article

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Abstract

Tacrolimus, a dual substrate of CYP3A4 and CYP3A5 has a narrow therapeutic index and is characterized by high between-subject variability in oral bioavailability. This study investigated the effects of the recently described CYP3A4*22 intron 6 C>T single nucleotide polymorphism on in vivo CYP3A4 activity as measured by midazolam (MDZ) clearance and tacrolimus pharmacokinetics in two cohorts of renal allograft recipients, taking into account the CYP3A5*1/*3 genotype and other determinants of drug disposition. In CYP3A5 non-expressers, the presence of one CYP3A4*22T-allele was associated with a 31.7–33.6% reduction in MDZ apparent oral clearance, reflecting reduced in vivo CYP3A4 activity. In addition, at ⩾12 months after transplantation, steady-state clearance of tacrolimus was 36.8% decreased compared with homozygous CYP3A4*22CC-wild type patients, leading to 50% lower dose requirements. Both concurrent observations in stable renal allograft recipients are consistent with a reduced in vivo CYP3A4 activity for the CYP3A4*22T-allele.

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Acknowledgements

We thank our study nurses C Beerten, J De Vis, M Dubois, I Laenen, A Swinnen, H Wielandt and A Willems for their great efforts in this study and A Herelixcka for managing the clinical database. We also thank M Dekens, G Lemmens, K Vandormael, E Vanhalewyck and K Verstraete of the laboratory of Nephrology for their excellent technical assistance. The continued support of all colleagues of the Leuven Collaborative Group for Renal Transplantation is much appreciated. Last but not least, a special thanks to all renal transplant recipients who participated in this study. H de Jonge and D Kuypers received a grant from the Fund for Scientific Research Flanders (FWO Vlaanderen).

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Authors and Affiliations

  1. Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium

    H de Jonge, H de Loor & D R J Kuypers

  2. Department of Clinical Chemistry, University Medical Center, Rotterdam, The Netherlands

    L Elens & R H van Schaik

  3. Cliniques Universitaires Saint-Luc – UCL, Laboratory of Analytical Biochemistry & Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Brussels, Belgium

    L Elens

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  1. H de Jonge
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  4. R H van Schaik
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Correspondence to D R J Kuypers.

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de Jonge, H., Elens, L., de Loor, H. et al. The CYP3A4*22 C>T single nucleotide polymorphism is associated with reduced midazolam and tacrolimus clearance in stable renal allograft recipients. Pharmacogenomics J 15, 144–152 (2015). https://doi.org/10.1038/tpj.2014.49

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