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Pharmacogenetics and drug-induced nephrotoxicity in renal transplant recipients.

Zununi Vahed S, Ardalan M, Samadi N, Omidi Y - Bioimpacts (2015)

Bottom Line: The advent of calcineurin inhibitors (CNIs), as the leading immunosuppressive agents, not only has revolutionized the transplant medicine but also made it a better therapeutic intervention that guarantees the graft outcome and improves the survival rate of patients.Pharmacogenetics characteristics of CYP isoforms (CYP3A) and efflux transporters (P-gp and MRP), involved in metabolism and extracellular transportation of the immunosuppressive CNIs, can be of pivotal information in the pharmacotherapy of the renal-transplant recipients.Such information can be used for the successes clinical interventions to attain an improved drug administration strategy with reduced rates of rejection and toxicity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Research Center for Pharmaceutical Nanotechnology, School of Advanced Biomedical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran ; Chronic Kidney Disease Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran ; Research Center for Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.

ABSTRACT

Introduction: The advent of calcineurin inhibitors (CNIs), as the leading immunosuppressive agents, not only has revolutionized the transplant medicine but also made it a better therapeutic intervention that guarantees the graft outcome and improves the survival rate of patients. However, genetic polymorphism(s) in the CNIs metabolic substrates genes (CYP3A4, CYP3A5) and their transporter such as P-glycoprotein (P-gp) can influence the CNIs metabolism and elicit some possible systemic and intra-renal exposures to drugs and/or metabolites with differential risk of nephrotoxicity, jeopardizing the transplantation.

Methods: In the current study, we review the recent literatures to evaluate the effects of genetic polymorphisms of the genes involved in development of chronic calcineurin nephrotoxicity and progression of chronic allograft dysfunction (CAD) providing an extensive overview on their clinical impacts.

Results: Identifying the inherited genetic basis for the inter-individual differences in terms of drug responses and determining the risk of calcineurin-mediated nephrotoxicity and CAD allow optimized personalized administration of these agents whith minimal adverse effects.

Conclusion: Pharmacogenetics characteristics of CYP isoforms (CYP3A) and efflux transporters (P-gp and MRP), involved in metabolism and extracellular transportation of the immunosuppressive CNIs, can be of pivotal information in the pharmacotherapy of the renal-transplant recipients. Such information can be used for the successes clinical interventions to attain an improved drug administration strategy with reduced rates of rejection and toxicity.

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Mentions: In addition to the genetic polymorphisms, a multitude of epigenetic, environmental, and physiological factors are believed to influence the functional expression of CYP3A4/5 ( Fig. 2A). Altered Cyp3A4/5 enzyme activities has been shown to associate with the P450 oxidoreductase (POR*28) allele, which may reasonably delineate the variability observed in CNI pharmacokinetics.47 Moreover, nuclear receptor peroxisome proliferator-activated receptor alpha (PPARa) variants explain 8–9 % of the variability in hepatic CYP3A activity in humans.48 In the case of CYP3A5 expressers, POR*28 allele has been shown to associate with an increased in vivo activity of CYP3A5 for Tac, whereas in CYP3A5 non-expressers, POR*28 homozygosity is associated with a significant higher CYP3A4 activity for both Tac and CsA.49 In a recent study by Lunde et al., potential associations have been reported between the dose-adjusted concentrations of immunosuppressive drugs (i.e., Tac and CsA) and CYP3A5*3, CYP3A4*22, PPARA and POR*28 alleles in the renal transplant patients. The results showed that patients with POR*28 and PPARA variant alleles need respectively lower and higher doses of Tac. Furthermore, CsA was 53% higher among CYP3A4*22 carriers.50 All these findings confirm that pre-transplantation CYP3A5, POR and PPARA genotyping can improve the initial dosing of Tac to a certain extent.


Pharmacogenetics and drug-induced nephrotoxicity in renal transplant recipients.

Zununi Vahed S, Ardalan M, Samadi N, Omidi Y - Bioimpacts (2015)

© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401167&req=5

Mentions: In addition to the genetic polymorphisms, a multitude of epigenetic, environmental, and physiological factors are believed to influence the functional expression of CYP3A4/5 ( Fig. 2A). Altered Cyp3A4/5 enzyme activities has been shown to associate with the P450 oxidoreductase (POR*28) allele, which may reasonably delineate the variability observed in CNI pharmacokinetics.47 Moreover, nuclear receptor peroxisome proliferator-activated receptor alpha (PPARa) variants explain 8–9 % of the variability in hepatic CYP3A activity in humans.48 In the case of CYP3A5 expressers, POR*28 allele has been shown to associate with an increased in vivo activity of CYP3A5 for Tac, whereas in CYP3A5 non-expressers, POR*28 homozygosity is associated with a significant higher CYP3A4 activity for both Tac and CsA.49 In a recent study by Lunde et al., potential associations have been reported between the dose-adjusted concentrations of immunosuppressive drugs (i.e., Tac and CsA) and CYP3A5*3, CYP3A4*22, PPARA and POR*28 alleles in the renal transplant patients. The results showed that patients with POR*28 and PPARA variant alleles need respectively lower and higher doses of Tac. Furthermore, CsA was 53% higher among CYP3A4*22 carriers.50 All these findings confirm that pre-transplantation CYP3A5, POR and PPARA genotyping can improve the initial dosing of Tac to a certain extent.

Bottom Line: The advent of calcineurin inhibitors (CNIs), as the leading immunosuppressive agents, not only has revolutionized the transplant medicine but also made it a better therapeutic intervention that guarantees the graft outcome and improves the survival rate of patients.Pharmacogenetics characteristics of CYP isoforms (CYP3A) and efflux transporters (P-gp and MRP), involved in metabolism and extracellular transportation of the immunosuppressive CNIs, can be of pivotal information in the pharmacotherapy of the renal-transplant recipients.Such information can be used for the successes clinical interventions to attain an improved drug administration strategy with reduced rates of rejection and toxicity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Research Center for Pharmaceutical Nanotechnology, School of Advanced Biomedical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran ; Chronic Kidney Disease Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran ; Research Center for Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.

ABSTRACT

Introduction: The advent of calcineurin inhibitors (CNIs), as the leading immunosuppressive agents, not only has revolutionized the transplant medicine but also made it a better therapeutic intervention that guarantees the graft outcome and improves the survival rate of patients. However, genetic polymorphism(s) in the CNIs metabolic substrates genes (CYP3A4, CYP3A5) and their transporter such as P-glycoprotein (P-gp) can influence the CNIs metabolism and elicit some possible systemic and intra-renal exposures to drugs and/or metabolites with differential risk of nephrotoxicity, jeopardizing the transplantation.

Methods: In the current study, we review the recent literatures to evaluate the effects of genetic polymorphisms of the genes involved in development of chronic calcineurin nephrotoxicity and progression of chronic allograft dysfunction (CAD) providing an extensive overview on their clinical impacts.

Results: Identifying the inherited genetic basis for the inter-individual differences in terms of drug responses and determining the risk of calcineurin-mediated nephrotoxicity and CAD allow optimized personalized administration of these agents whith minimal adverse effects.

Conclusion: Pharmacogenetics characteristics of CYP isoforms (CYP3A) and efflux transporters (P-gp and MRP), involved in metabolism and extracellular transportation of the immunosuppressive CNIs, can be of pivotal information in the pharmacotherapy of the renal-transplant recipients. Such information can be used for the successes clinical interventions to attain an improved drug administration strategy with reduced rates of rejection and toxicity.

No MeSH data available.


Related in: MedlinePlus