Genetic Polymorphisms in CYP3A5 and MDR1 Genes and Their Correlations With Plasma Levels of Tacrolimus and Cyclosporine in Renal Transplant Recipients

Abstract

Immunosuppressive drugs, such as tacrolimus (FK506) and cyclosporine (CsA), play an essential role in graft survival, preventing rejection. Large interindividual differences in drug-metabolizing enzymes as well as in drug transporters make the task of reaching the optimal concentrations difficult. The bioavailability of CsA and FK506 seems to be associated with the cytocrhome P450 IIIA (CYP3A) gene. It has also been described that the Multi Drug Resistance 1 (MDR1) gene that encodes for polyglycoprotein-P (P-gp) may influence the metabolizing action of FK506 and CsA. Therefore, we sought, to correlate single nucleotide polymorphisms (SNPs) in the CYP3A and MDR1 genes with the concentrations of FK506 and CsA. For this purpose we analyzed 2 groups of renal transplant recipients by sequencing: one receiving a CsA immunosuppressive regime, and other, an FK506-immunosuppression. This study showed that subjects in the FK506 group who had encoded the 1236CϾT substitution in the MDR1 gene displayed 44.4% higher drug concentrations compared with ("wild-type") individuals. Individuals carrying the 2677GϾT,A mutation showed FK506 concentrations that were 44.7% higher than the wild-type individuals. Concerning the CsA group, individuals carrying the 22915AϾC substitution displayed CsA concentrations 52.1% higher than wild-type individuals.

Increased Hospital Stay and Allograft Disfunction in Renal Transplant Recipients with Cyp2c19 AA Variant in SNP rs4244285

“…This was especially observed according to recipients' genotype, but seems to be also observed according to the donor's, although in a less significant way. Many publications, including our own, have found statistically significant correlations between this SNP and tacrolimus and/or cyclosporine C 0 /D c (Hesselink et al, 2003;Jun et al, 2009;Mendes et al, 2009;Herrero et al, 2010a;Herrero et al, 2010b;López-Montenegro et al, 2010;Jacobson et al, 2011;Jordán de Luna et al, 2011;Galiana et al, 2012). Even some researchers, working groups, and consortia recommend guidelines for initial dose adjustment with this SNP (Haufroid et al, 2006;Provenzani et al, 2009;Kuypers et al, 2010;Thervet et al, 2010;Becquemont et al, 2011;Jacobson et al, 2011;Passey et al, 2011;Singh et al, 2011;Tang et al, 2011;Tavira et al, 2011;Zhu et al, 2011), but always followed by TDM.…”

Clinical Pharmacokinetics of Oral Versus Sublingual Administration of Tacrolimus in Adult Liver Transplant Recipients

“…After oral administration of TAC, gut and hepatic metabolism by cytochrome P450 microsomal enzymes (CYP3A), and P-glycoprotein (P-gp) efflux at the gut, result in low TAC bioavailability. 4 Sublingual administration of TAC, bypassing gut processes, may provide comparable drug bioavailability and desired trough blood concentrations compared to the oral route even with lower drug dosages.…”

Interactions between Tacrolimus and Metronidazole in a renal transplant patient

“…P-gp, may be the target site of the tacrolimusmetronidazole interaction. It is located throughout the epithelial cells of the jejunum, kidney, pancreas, and liver and has significant role in Tac metabolism [16,17]. There is no evidence that confirms that Met may be an inhibitor or substrate of P-gp, but, according to previous reports, Met may interfere with Tac clearance [11].…”

“…There is no evidence that confirms that Met may be an inhibitor or substrate of P-gp, but, according to previous reports, Met may interfere with Tac clearance [11]. If the P-gp efflux pump is inhibited by Met, this can increase Tac trough concentration [16] Page et al assumed that, mucosa permeability may be changed as a result of intestinal infection. They based their assumption on the fact, that Clostridium difficile can invade and rupture the intestinal epithelium and change the permeability of the mucosa in this manner.…”