title: Concentration of tacrolimus and major metabolites in kidney transplant recipients as a function of diabetes mellitus and cytochrome P450 3A gene polymorphism.
abstract: 1. Disposition of tacrolimus and its major metabolites, 13-O-desmethyl tacrolimus and 15-O-desmethyl tacrolimus, was evaluated in stable kidney transplant recipients in relation to diabetes mellitus and genetic polymorphism of cytochrome P450 (CYP) 3A. 2. Steady-state concentration-time profiles were obtained for 12-hour or 2-hour post-dose, in 20 (11 with diabetes) and 32 (24 with diabetes) patients, respectively. In addition, single nucleotide polymorphisms of the following genes: CYP3A4 (CYP3A4: CYP3A4*1B, -392A > G), 3A5 (CYP3A5: CYP3A5*3, 6986A > G) and P-glycoprotein (ABCB1: 3435C > T) were characterized. 3. Dose-normalized concentrations of tacrolimus or metabolites were higher in diabetic patients. CYP3A4*1B carriers and CYP3A5 expressers, independently or when assessed as a combined CYP3A4-3A5 genotype, had significantly lower dose-normalized pre-dose (C0/dose) and 2-hour post-dose (C2/dose) concentrations of tacrolimus and metabolites. Non-diabetic patients with at least one CYP3A4*1B and CYP3A5*1 allele had lower C0/dose as compared to the rest of the population. 4. Genetic polymorphism of CYP3A5 or CYP3A4 influence tacrolimus or metabolites dose-normalized concentrations but not metabolite to parent concentration ratios. The effect of diabetes on tacrolimus metabolism is subject to debate and requires a larger sample size of genetically stratified subjects.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Shripad D
authors.initials: SD
authors.lastname: Chitnis
authors.forename: Ken
authors.initials: K
authors.lastname: Ogasawara
authors.forename: Björn
authors.initials: B
authors.lastname: Schniedewind
authors.forename: Reginald Y
authors.initials: RY
authors.lastname: Gohh
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Akhlaghi
mesh_terms: D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D003920:Diabetes Mellitus / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000378:metabolism*
chemical_list: D007166:Immunosuppressive Agents; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus