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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, METHODS, RESULTS. Meshes: ATP Binding Cassette Transporter, Subfamily B, ATP Binding Cassette Transporter, Subfamily B, Member 1, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Genotype, Graft Rejection, Humans, Immunosuppressive Agents, Interleukin-2, Kidney Transplantation, Polymorphism, Single Nucleotide, Tacrolimus.
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Do genetic polymorphisms in ABCB1 influence the pharmacodynamics of tacrolimus? Context: Tacrolimus has a large interindividual pharmacokinetic variability, and quantification of its effect is difficult. It is a substrate of ABCB1, an efflux pump expressed more on CD8 T cells than on CD4 T cells. The ABCB1 3435C>T single-nucleotide polymorphism (SNP) has been associated with interindividual differences in ABCB1 activity and may influence drug efficacy. Here the influence of this SNP on the biological effect of tacrolimus was studied. Rhodamine (Rh123) efflux was used to study ABCB1 activity, with or without the addition of the ABCB1 inhibitor verapamil. Intracellular interleukin (IL) 2 production in T cells was used to measure the pharmacodynamic effect of tacrolimus after phorbol-12-myristate-13-acetate/ionomycin stimulation of whole blood. In addition, the ABCB1 genotype of 36 tacrolimus-treated renal transplant patients was related to ABCB1 activity and tacrolimus efficacy. The mean Rh123 efflux was higher in CD8 T cells compared with CD4 T cells: 40% versus 19% of cells, respectively (P < 0.001). Verapamil almost completely blocked Rh123 efflux (to 1.8% of CD4 T cells and 0.5% of CD8 T cells), whereas tacrolimus did not change Rh123 efflux. Tacrolimus 10 ng/mL reduced the production of IL-2 in CD4 and CD8 T cells by 28.9% and 45.4% (P < 0.05). Tacrolimus-mediated inhibition of IL-2 was enhanced by verapamil (P < 0.05). This effect on tacrolimus pharmacodynamics was associated with ABCB1 3435C>T SNP in renal transplant patients: verapamil reduced the percentage of IL-2-producing CD4 and CD8 T cells by 14% and 22% in patients with the CC genotype (P < 0.05) but not in patients with the TT genotype. Moreover, the ratio of tacrolimus C0 over the percent of IL-2-producing CD8 T cells in CC genotype patients was significantly higher compared with TT genotype patients (P < 0.05), showing a smaller pharmacodynamic effect in CC genotype patients.
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The ABCB1 3435C>T SNP influences ABCB1 activity of T cells and the pharmacodynamic effect of tacrolimus in kidney transplant patients. Final Decision: yes