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.

Effects of UGT1A1, CYP3A5 and ABCB1 Genetic Variants on Pharmacokinetics of Antihistamine Drug Mizolastine in Chinese Healthy Volunteers

“…Twenty-four healthy male Chinese Han ethnic volunteers were recruited for the mizolastine pharmacokinetics evaluation. The mean age, average weight and body mass index of the 24 volunteers were 25.60 (22)(23)(24)(25)(26)(27)(28)(29) years old, 65.71 (58-80) kg and 22.12 (19.51-21.15) kg/m 2 , respectively. All of them were non-smokers and in good health as evaluated by physical examination and laboratory evaluation before entering the study.…”

“…ABCB1 gene encodes P-glycoprotein (P-gp, or multidrug-resistance protein 1, MDR1). One of the most widely studied functional SNPs in ABCB1 gene is C3435T (rs1045642, ILe 1145ILe) in exon 26 [25], which also has a higher frequency in Chinese population than that in other ethnic groups including Caucasian and African populations [26][27][28]. Other research groups have reported of a correlation between genetic polymorphisms of allergic response proteins, such as IgE receptor (FCERIA) and component 5a receptor 1 (C5AR1), and the therapeutic efficacy or side effects of mizolastine in vivo [29][30][31].…”

Sex differences in transplantation

“…Tornatore et al recently reported that females have lower expression of the gene that encodes P-glycoprotein (ABCB1) in peripheral blood mononuclear cells. 14 These data suggest that females may have reduced efflux activity of calcineurin inhibitors leading to greater intracellular drug exposure. One possibility of the reduced risk of chronic allograft failure in females, therefore, is that females have higher intracellular concentrations of calcineurin inhibitors when plasma drug concentrations are kept the same.…”

Cyclosporine use in Hematopoietic Stem Cell Transplantation: Pharmacokinetic Approach

“…Although some showed sex-associated difference in CsA distribution and metabolism, with controversial results [98][99][100][101], others found no gender related significant distinction [87,102].…”