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 (13-DMT) and 15-O-desmethyl tacrolimus (15-DMT), 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 twenty (11 with diabetes) and thirty-two (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 exposure to tacrolimus or metabolites were higher in diabetic patients. CYP3A4*1B carriers and CYP3A5 expressers, independently or when considered 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. Nondiabetic 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.

Effects of the CYP3A4*1B Genetic Polymorphism on the Pharmacokinetics of Tacrolimus in Adult Renal Transplant Recipients: A Meta-Analysis

“…[ 21 ] and Chitnis, S D et al . [ 29 ] reported that CYP3A4*1/*1 recipients exhibited higher tacrolimus trough concentrations and C 0 /Dose ratios than CYP3A4*1B carriers in CYP3A5 expressers ( CYP3A5*1/*1 or CYP3A5*1/*3 ); Tavira, B et al . [ 22 ] reported that, relative to CYP3A4*1B carriers stratified by CYP3A5 (expressers or non-expressers respectively), CYP3A4*1/*1 recipients required lower tacrolimus doses, and exhibited higher tacrolimus trough concentrations and C 0 /dose ratios, which suggests a significant role of the CYP3A4*1B .…”

Pharmacokinetics of Total and Unbound Prednisone and Prednisolone in Stable Kidney Transplant Recipients With Diabetes Mellitus

“…CYP3A4*1B and CYP3A5*3 were genotyped as described previously [17]. Two common polymorphisms in HSD11B1 gene (rs12086634 and rs846910) were determined by TaqMan ® allelic discrimination assay (Life Technologies, Foster, CA) using an Applied Biosystems 7500 Real-Time PCR system (Life Technologies) according to manufacturer's instructions.…”

Multidrug Resistance-Associated Protein 2 (MRP2/ABCC2) Haplotypes Significantly Affect the Pharmacokinetics of Tacrolimus in Kidney Transplant Recipients

“…[15] In brief, sample preparation involved the addition of 800 μL of ZnSO4 (17.28 g/L): methanol (30:70, v/v) containing the internal standard (ascomycin, 100 ng/mL) to a 200 μL aliquot of EDTA anticoagulated whole blood, calibration standards or quality control samples. Samples were vortex mixed, centrifuged (13,000 rpm for 10 minutes at 4°C), and 50 μL of supernatant was injected onto an HPLC column (4.6 × 150 mm, 3.5 μm, Eclipse Zorbax XDB -C8, Agilent Technologies) maintained at 65°C.…”