title: The CYP3A4*22 C>T single nucleotide polymorphism is associated with reduced midazolam and tacrolimus clearance in stable renal allograft recipients.
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.
authors.affiliation: Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: de Jonge
authors.affiliation: 1] Department of Clinical Chemistry, University Medical Center, Rotterdam, The Netherlands [2] Cliniques Universitaires Saint-Luc - UCL, Laboratory of Analytical Biochemistry & Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Brussels, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Elens
authors.affiliation: Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: de Loor
authors.affiliation: Department of Clinical Chemistry, University Medical Center, Rotterdam, The Netherlands.
authors.forename: R H
authors.initials: RH
authors.lastname: van Schaik
authors.affiliation: Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
authors.forename: D R J
authors.initials: DR
authors.lastname: Kuypers
mesh_terms: D000483:Alleles; D003430:Cross-Sectional Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016559:Tacrolimus / Q000493:pharmacokinetics
chemical_list: D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam; D016559:Tacrolimus