de Jonge, H.
Elens, Laure
[UCL]
de Loor, H.
van Schaik, R. H.
Kuypers, D. R. J.
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.The Pharmacogenomics Journal advance online publication, 7 October 2014; doi:10.1038/tpj.2014.49.
Bibliographic reference |
de Jonge, H. ; Elens, Laure ; de Loor, H. ; van Schaik, R. H. ; Kuypers, D. R. J.. The CYP3A4*22 C>T single nucleotide polymorphism is associated with reduced midazolam and tacrolimus clearance in stable renal allograft recipients.. In: The Pharmacogenomics Journal, Vol. 15, no. 2, p. 144-152 (2015) |
Permanent URL |
http://hdl.handle.net/2078.1/157810 |