Do drug transporter (ABCB1) SNPs and P-glycoprotein function influence cyclosporine and macrolides exposure in renal transplant patients? Results of the pharmacogenomic substudy within the symphony study

Abstract

SummaryThe function of the efflux pump P-glycoprotein (Pgp) and ABCB1 single nucleotide polymorphisms (SNPs) should be considered as important tools to deepen knowledge of drug nephrotoxicity and disposition mechanisms. The aim of this study is to investigate the association of C3435T, G2677T, C1236T, and T129C ABCB1 SNPs with Pgp activity and exposure to different immunosuppressive drugs in renal transplant patients. Patients included in the Symphony Pharmacogenomic substudy were genotyped for ABCB1 SNPs. According to the design, patients were randomized into four immunosuppressive regimens: low and standard dose of cyclosporine (n = 30), tacrolimus (n = 13), and sirolimus (n = 23) concomitantly with mycophenolate and steroids. Pgp activity was evaluated in PBMC using the Rhodamine 123 efflux assay. TT carrier patients on C3435T, G2677T, and C1236T SNPs (Pgp-low pumpers) showed lower Pgp activity than noncarriers. Pgp-high pumpers treated with cyclosporine showed lower values of Pgp function than macrolides. There was a negative correlation between cyclosporine AUC and Pgp activity at 3 months. Results did not show any correlation between tacrolimus and sirolimus AUC and Pgp activity at 3 months. We found an important role of the ABCB1 SNPs Pgp function in CD3 + peripheral blood lymphocytes from renal transplant recipients. Pgp activity was influenced by cyclosporine but not macrolides exposure.

CYP3A4∗18B and CYP3A5∗3 polymorphisms contribute to pharmacokinetic variability of cyclosporine among healthy Chinese subjects

“…Specifically, women and patients with at least one CYP3A5⁄1 or CYP3A4⁄18B allele would require significantly higher doses of cyclosporine to reach target drug levels than patients with the CYP3A5⁄3 or CYP3A4⁄1 alleles. What our study neglected to address is how P-glycoprotein (P-gp) activity may affect the bioavailability of cyclosporine (Llaudó et al, 2013). Specifically, patients with a CT or CC nucleotide exchange in exon 26 (C3435T) with high P-gp activity may result in decreased bioavailability of cyclosporine.…”

Testing of candidate single nucleotide variants associated with paclitaxel neuropathy in the trial NCCTG N08C1 (Alliance)

“…ABCB1, also known as MDR1 (multidrug resistant gene), is a part of the ABC transporter superfamily. It encodes a P‐glycoprotein (Pgp), which was first described in multi‐drug resistant cells . It is involved in absorption, disposition, and metabolism of drugs .…”

Influence of cyclosporine and everolimus on the main mycophenolate mofetil pharmacokinetic parameters

“…It has been shown that in the patients with a CT or CC nucleotide exchange (high pumpers) in exon 26 (C3435T) with high Pgp activity on the apical surface of intestinal enterocytes, more CsA is removed from the cells, which results in decreased bioavailability. [49] In this context, patients (high pumpers) treated with low doses of CsA would show lower drug exposure and this could affect MPA AUC exposure. [17,49] …”

“…[49] In this context, patients (high pumpers) treated with low doses of CsA would show lower drug exposure and this could affect MPA AUC exposure. [17,49] …”