Author(s): Mariano Ferraresso [*] aff1 aff2 , Stefano Turolo aff3 , Mirco Belingheri aff3 , Amedea Silvia Tirelli aff4 , Ivan Cortinovis aff2 aff5 , Silvano Milani aff2 aff5 , Alberto Edefonti aff3 , Luciana Ghio aff3
ABCB1; CYP3A4; CYP3A5; mRNA; pediatric kidney transplant; peripheral blood mononuclear cells; SXR; tacrolimus
Adult and pediatric organ transplants have greatly benefited from tacrolimus (TAC) therapy but, despite good clinical results, TAC management still requires considerable effort to distinguish therapeutic from toxic effects [ 1,2 ]. Although trough blood TAC concentrations closely correlate with the area under the concentration-time curve, a tenfold variability in pharmacokinetic parameters is frequently observed after a fixed dose [3 ]. TAC is almost completely metabolized in the liver and, to a lesser extent, in intestinal mucosa via CYP3A isoenzymes CYP3A4 and CYP3A5 and it is also a substrate for P-gp, a transmembrane efflux pump which affects drug absorption and excretion, predominantly expressed in intestinal epithelial cells and biliary canalicular cells [4 ]. Recently, a significant role of genetics on TAC pharmacokinetics was emphasized by several authors. SNPs of CYP3A5 would have a significant impact on TAC metabolism [5,6 ] while role of MDR1 variants is more controversial [7-9 ]. In addition, a great interest is newly aroused by the nuclear hormone receptors which functionally regulate the induction of many genes. The steroids and xenobiotics receptor (SXR) is responsible for the upregulation of CYP3A and ABCB1 enzymes, and its expression is also upregulated by steroids [10,11 ]. Therefore, this nuclear receptor seems to be a valid candidate for explaining the pharmacokinetic variability of TAC. Another important issue to be taken into consideration for its relevance when dealing with a young population is that epigenetic factors may play a major role in the regulation of gene expression over the different age groups [12,13 ]. Large changes in the activity of the various CYP3A isoenzymes, SXR and MDR1 are known to occur during human development [14,15 ] Thus, the possibility of age-dependent variations in TAC pharmacokinetics enhanced during growth may be also considered. The purpose of this study was to evaluate the relationship between patients' age and the main pathways involved in TAC metabolism, as measured by the amount of nuclear mRNA specific for SXR, CYP3A and ABCB1 proteins in the peripheral blood mononuclear cells (PBMCs) of a young population with renal transplant receiving TAC as calcineurin inhibitor.
Patients & methods
This retrospective study included a youngster kidney transplant group with a functionally stable graft for at least 6 months after transplant. Data were obtained from our electronic database that contains all of the information relating to admissions and outpatient visits of our entire transplant population. From our records, we selected a cohort of patients that have maintained stable kidney function and matched the following clinical parameters: a negative history of acute or chronic rejection episodes, maintenance of the initial immunosuppressive therapy without modification except per protocol and absence at all times in their therapy of drugs that can significantly modify TAC metabolism, such as antivirals or antifungals. We...