Influence of Race on P-Glycoprotein Function in Peripheral Blood Mononuclear Cells
1NYS Center of Excellence in Bioinformatics & Life Science, School of Pharmacy, Buffalo
2Flow Cytometry Laboratories, Roswell Park Cancer Institute, Buffalo
3Biostatistics, School of Public Health, Buffalo
4University of New England
School of Pharmacy, Portland, ME
5Medicine, School of Medicine
University at Buffalo, Buffalo, NY.
Meeting: 2015 American Transplant Congress
Abstract number: 438
Keywords: Gene polymorphism, Immunosuppression, Kidney transplantation, P-glycoprotein
Session Information
Session Name: Concurrent Session: Immune Monitoring II
Session Type: Concurrent Session
Date: Tuesday, May 5, 2015
Session Time: 4:00pm-5:30pm
Presentation Time: 5:00pm-5:12pm
Location: Terrace IV
Purpose: African Americans (AA) renal transplant recipients (RTR) have poorer long term allograft survival compared to Caucasians(C) which may be attributed to racial differences in calcineurin inhibitor pharmacology. P-glycoprotein (P-gp), an ABC transporter expressed in liver, gut, kidney and peripheral blood mononuclear cells (PBMCs), modulates tacrolimus (TAC) pharmacokinetics and intracellular pharmacology impacting overall patient response. ABCB1 encodes for P-gp with a primary variant (TTT) associated with altered function compared to wild-type (CGC). This study evaluated P-gp function in PBMCs in AA and C males(M) and females(F) at troughs and 4 hours after TAC with ABCB1 haplotypes in RTR.
Methods: P-gp function in PBMC was quantitated in 67 stable RTR receiving tacrolimus (trough: 7.2 ± 1.9 ng/ml) and mycophenolic acid immunosuppression for ≥ 6 months. The P-gp function was quantified by flow cytometric measurement of cyclosporine (CYA, 2.5 ¯o;M) -reversible efflux of the P-gp substrate, DiOC2(3) by % change of Mean Fluorescent Intensity (MFI) with CYA (% δMFI-CYA) at TAC trough (0 hours) and 4 hours(peak). A 50% increase in %δMFI-CYA correlates with significant P-gp function based on P-gp-expressing cell line models. ABCB1 single nucleotide polymorphisms: c.1236C>T (rs1128503), c.2677G>T (rs2032582), and c.3435C>T (rs1045642) were determined and haplotype associations estimated by THESIAS.
Results: P-gp function are summarized in table by race and sex. A significant race effect was found. The patients with variant TTT had 29% increased P-gp function (p=0.057) at the TAC peak with no race or gender effects.
| Time (hrs) | AAM (n=22) | AAF (n=13) | CM (n=16) | CF (n=16) | P Value |
| 0 | 82.0(57.1) | 44.2(21.6) | 88.4(47.7) | 120.6(106.8) | Race: 0.012 |
| 4 | 83.6(46.8) | 52.2(32.7) | 83.8 (39.3) | 108.4(87.0) | Race x Sex:0.104 |
CONCLUSION: P-gp function in PBMC demonstrated race effects with reduced function in AA RTR. Measurement of P-glycoprotein function in PBMC may provide insight into interpatient variability in intracellular tacrolimus pharmacology.
To cite this abstract in AMA style:
Tornatore K, Minderman H, O'Loughlin K, Attwood K, Brazeau D, Venuto R. Influence of Race on P-Glycoprotein Function in Peripheral Blood Mononuclear Cells [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/influence-of-race-on-p-glycoprotein-function-in-peripheral-blood-mononuclear-cells/. Accessed November 21, 2024.« Back to 2015 American Transplant Congress