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Sex differences in cyclosporine pharmacokinetics and ABCB 1 gene expression in mononuclear blood cells in African American and Caucasian renal transplant recipients
Author(s) -
Tornatore Kathleen M.,
Brazeau Daniel,
Dole Kiran,
Danison Ryan,
Wilding Gregory,
Leca Nicolae,
Gundroo Aijaz,
Gillis Kathryn,
Zack Julia,
DiFrancesco Robin,
Venuto Rocco C.
Publication year - 2013
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.123
Subject(s) - pharmacokinetics , peripheral blood mononuclear cell , pharmacology , medicine , mycophenolic acid , efflux , bioavailability , pharmacodynamics , endocrinology , transplantation , biology , in vitro , biochemistry , genetics
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 (AUC 0–12 /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.