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BACKGROUND: P-glycoprotein (P-gp), an ABC transport protein contributes to the interpatient pharmacokinetic and pharmacodynamic variability of calcineurin inhibitors(CNI), tacrolimus(TAC) and cyclosporine (CYA). ABCB1 encodes P-gp and the single nucleotide polymorphisms (SNP) 1236C>T, 2677G>T/A, 3435C>T may alter protein expression or function. Our objective was to examine the association of ABCB1 haplotypes, sex and race with chronic CNI adverse effects (AE) in renal transplant recipients (RTR). METHODS: A meta-analysis of 3 prospective observational studies was completed in 149 stable RTR [GFR= 51 ±17 ml/min/1.73m2] using identical inclusion and exclusion criteria in 62 African Americans (AA) and 81 Caucasians (C) treated with CYA (troughs: 50- 150 ng/ml) and mycophenolate mofetil or TAC (troughs: 5-10 ng/ml) and mycophenolate sodium. Each RTR had AE assessed using standardized objective scales by study physicians. A Cumulative AE ratio was determined using 14 AE. Separate gastrointestinal (GI), central nervous system (CNS), and aesthetic AE ratios were also assessed. DNA from peripheral blood mononuclear cells was collected to characterize ABCB1 SNPs completed on 11/15/12. Haplotype computation and association with AE was completed by THESIAS program on 12/3/12. RESULTS: All genotypes were in Hardy-Weinberg equilibria. AA had a greater frequency of the C-G-C haplotype (SNPs: 1236-2677-3435) compared to C (71.6% vs. 44.2%; p<0.001). A gender difference was noted for Cumulative (p<0.001); GI (p=0.046); aesthetic (p=0.0002) and CNS (p=0.051) AE ratios with greater AE ratios in females. The Aesthetic AE ratio was associated with haplotype T-T-C (p=0.008). Haplotype C-T-T was associated with increased GI AE ratio (p=0.02) though the effect was not significant when sex was included as a covariate (p=0.13). Race had no associations with AE. CONCLUSION: RTR receiving CNI based immunosuppression within the therapeutic range exhibited interpatient variability in AE with associations to sex and ABCB1 haplotypes.
Pharmacy and Pharmaceutical Sciences
Poster originally presented at the March 2013 American Society Clinical Pharmacology and Therapeutics meeting.
Brazeau, Daniel A.; Meaney, Calvin; Chang, Shirley; Venuto, Rocco; Leca, Nick; Gundroo, Aijaz; Morse, Sarah; Consiglio, Joseph; Cooper, Louise; and Tornatore, Kathleen, "Sex and Haplotype Associations with Adverse Effects of Calcineurin Inhibitors Post-Renal Transplant" (2013). Pharmaceutical Sciences Faculty Posters. Poster 2.