Sex differences in cyclosporine pharmacokinetics and ABCB1 gene expression in mononuclear blood cells in African American and Caucasian renal transplant recipients

Authors

  • Kathleen M. Tornatore PharmD,

    Corresponding author
    1. Division of Nephrology, Department of Medicine, School of Medicine and Biomedical Sciences, Erie County Medical Center, University at Buffalo, Buffalo, NY, USA
    • Department of Pharmacy Practice, Translational Pharmacology Research Core, Center of Excellence in Bioinformatics and Life Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
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  • Daniel Brazeau PhD,

    1. Pharmaceutical Genomics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
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  • Kiran Dole PharmD,

    1. Department of Pharmacy Practice, Translational Pharmacology Research Core, Center of Excellence in Bioinformatics and Life Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
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  • Ryan Danison MA,

    1. Department of Biostatistics, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, USA
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  • Gregory Wilding PhD,

    1. Department of Biostatistics, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, USA
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  • Nicolae Leca MD,

    1. Division of Nephrology, Department of Medicine, School of Medicine and Biomedical Sciences, Erie County Medical Center, University at Buffalo, Buffalo, NY, USA
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  • Aijaz Gundroo MD,

    1. Division of Nephrology, Department of Medicine, School of Medicine and Biomedical Sciences, Erie County Medical Center, University at Buffalo, Buffalo, NY, USA
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  • Kathryn Gillis PharmD,

    1. Department of Pharmacy Practice, Translational Pharmacology Research Core, Center of Excellence in Bioinformatics and Life Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
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  • Julia Zack PharmD,

    1. Department of Pharmacy Practice, Translational Pharmacology Research Core, Center of Excellence in Bioinformatics and Life Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
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  • Robin DiFrancesco MBA,

    1. Department of Pharmacy Practice, Translational Pharmacology Research Core, Center of Excellence in Bioinformatics and Life Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
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  • Rocco C. Venuto MD

    1. Division of Nephrology, Department of Medicine, School of Medicine and Biomedical Sciences, Erie County Medical Center, University at Buffalo, Buffalo, NY, USA
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Correspondence Author:

Kathleen M. Tornatore, Pharm D, FCCP, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, 219 Kapoor Hall, Buffalo, NY 14214, USA

E-mail: tornator@buffalo.edu

Abstract

Cyclosporine exhibits pharmacokinetic and pharmacodynamic variability in renal transplant recipients (RTR) attributed to P-glycoprotein (P-gp), an ABCB1 efflux transporter that influences bioavailability and intracellular distribution. Data on race and sex influences on P-gp in RTR are lacking. We investigated sex and race influences on cyclosporine pharmacokinetics and ABCB1 gene expression in peripheral blood mononuclear cells (PBMC). Fifty-four female and male African American and Caucasian stable RTR receiving cyclosporine and mycophenolic acid completed a 12-hour study. ABCB1 gene expression was assessed in PBMCs pre-dose and 4 hours after cyclosporine. Statistical analysis used mixed effects models on transformed, normalized ABCB1 expression and cyclosporine pharmacokinetics. Sex and race differences were observed for the dose-normalized area under the concentration curve (AUC0–12/Dose) [P = .0004], apparent clearance [P = .0004] and clearance/body mass index (CL/BMI) [P = .027] with slowest clearance and greatest drug exposure in females. Sex and race differences were found pre-dose and 4 hours for ABCB1 [P < .0001] with females having less expression than males. ABCB1 differences were observed between pre-dose and 4 hours [P = .0009]. Female RTR had slower cyclosporine clearance and lower ABCB1 gene expression in PBMC suggesting reduced efflux activity and greater intracellular drug exposure.

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