P-Glycoprotein Function: Association with Race, Gender and Tacrolimus Pharmacokinetics.
1Translational Pharmacology Research, School of Pharmacy, Buffalo
2Flow Cytometry Laboratory, Roswell Park Cancer Institute, Buffalo
3Biostatistics, School of Public Health, Buffalo
4Medicine, School of Medicine;UB, Buffalo.
Meeting: 2016 American Transplant Congress
Abstract number: 335
Keywords: African-American, Immunosuppression, Kidney transplantation, P-glycoprotein
Session Information
Date: Monday, June 13, 2016
Session Name: Concurrent Session: Medication Errors, Variability and Adherence
Session Time: 4:30pm-6:00pm
Presentation Time: 5:06pm-5:18pm
Location: Room 302
Background: Long term allograft survival remains poorer in African American(AA) renal transplant recipients(RTR) compared to Caucasians(C) and may be due 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(PK) and intracellular pharmacology. This study evaluated PBMC P-gp function and TAC PK in 33 AA and 32 C male(M) and female(F) RTR who received TAC and mycophenolic acid.
Methods: A steady-state 12-hour PK study determined TAC trough(C0), dose-adjusted area under the concentration time curve 0-4 hours(AUC0-4), apparent clearance(CL) and lean body weight (LBW)-normalized CL in stable RTR >6 months post-transplant. TAC dosage was adjusted using C0 range of 4-9 ng/ml. P-gp function was quantified by flow cytometric measurement of cyclosporine (CYA, 2.5 [micro]M)-reversible efflux of P-gp substrate, DiOC2(3) by % change of Mean Fluorescent Intensity(MFI) with CYA(% [Delta]MFI-CYA) pre-TAC(0 hours), 4, 8 and 12 hours after TAC and evaluated with AUC % [Delta]MFI-CYA.
Results: Significant race-gender effects in TAC dose, CL, AUC and AUC%[Delta]MFI-CYA were noted with reduced P-gp function and more rapid CL in AAF. P-gp function was a significant covariate influencing TAC AUC0-4(p=0.042).
| Mean[SD] | AAF | AAM | CF | CM | P Value |
| eGFR[ml/min/1.74m2] | 49.9(13.4) | 57.4(13.4) | 49.8(11.5) | 64.4(16.2) | 0.019 |
| Tac Dose[mg] | 5.0(1.7) | 3.7(1.6) | 2.7(1.2) | 2.2(0.7) | <0.001 |
| Tac C0[ng/ml] | 7.2(1.8) | 7.3(1.9) | 6.7(1.7) | 6.2(1.2) | NS |
| CL[L/hr] | 40.0(16.8) | 28.2(13.3) | 22.2(8.9) | 21.3(6.7) | <0.001 |
| CL/LBW | 0.81(0.35) | 0.45(0.24) | 0.48(0.20) | 0.32(0.10) | <0.001 |
| Tac AUC0-4/Dose[ng.hr/ml/mg] | 13.9(6.9) | 18.8(8.9) | 24.2(12.4) | 21.3(7.7) | 0.027 |
| AUC%ΔMFI-CYA | 649(281) | 945(440) | 1393(1071) | 1088(601) | 0.029 |
Conclusion: P-gp function is associated with a race-gender effect and reduced P-gp function in AA. Clinical use of troughs to adjust TAC dose does not consider factors that influence variability in intracellular TAC concentration. P-glycoprotein function assessment may provide insight into more individualized tacrolimus immunosuppression among RTR.
CITATION INFORMATION: Tornatore K, Minderman H, Attwood K, O'Loughlin K, Venuto R. P-Glycoprotein Function: Association with Race, Gender and Tacrolimus Pharmacokinetics. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:
Tornatore K, Minderman H, Attwood K, O'Loughlin K, Venuto R. P-Glycoprotein Function: Association with Race, Gender and Tacrolimus Pharmacokinetics. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/p-glycoprotein-function-association-with-race-gender-and-tacrolimus-pharmacokinetics/. Accessed March 6, 2021.« Back to 2016 American Transplant Congress