title: Sex differences in cyclosporine pharmacokinetics and ABCB1 gene expression in mononuclear blood cells in African American and Caucasian renal transplant recipients.
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.
authors.affiliation: 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; Division of Nephrology, Department of Medicine, School of Medicine and Biomedical Sciences, Erie County Medical Center, University at Buffalo, Buffalo, NY, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Tornatore
authors.forename: Daniel
authors.initials: D
authors.lastname: Brazeau
authors.forename: Kiran
authors.initials: K
authors.lastname: Dole
authors.forename: Ryan
authors.initials: R
authors.lastname: Danison
authors.forename: Gregory
authors.initials: G
authors.lastname: Wilding
authors.forename: Nicolae
authors.initials: N
authors.lastname: Leca
authors.forename: Aijaz
authors.initials: A
authors.lastname: Gundroo
authors.forename: Kathryn
authors.initials: K
authors.lastname: Gillis
authors.forename: Julia
authors.initials: J
authors.lastname: Zack
authors.forename: Robin
authors.initials: R
authors.lastname: DiFrancesco
authors.forename: Rocco C
authors.initials: RC
authors.lastname: Venuto
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000008:administration & dosage / Q000235:genetics*; D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D015992:Body Mass Index; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D011241:Prednisone / Q000008:administration & dosage; D012737:Sex Factors; D044465:White People / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D011241:Prednisone
keywords: ABCB1 gene expression; P-glycoprotein; cyclosporine pharmacokinetics; immunosuppression pharmacology; race; renal transplantation; sex