Pharmacogenetics of calcineurin inhibitors in renal transplantation.
Cyclosporine A and tacrolimus (Tac) are inmunosuppresive drugs with a narrow therapeutic range. Underdosing is associated with organ rejection, whereas overdosing could result in toxicity. Therapeutic drug monitoring at different postdose times is necessary to maintain the blood concentrations within a target window. These calcineurin inhibitors are characterized by a broad interindividual pharmacokinetics variability, which makes the determination of the initial dose difficult. In a patient receiving a dose, the amount of the drug that is measured in the blood determines its bioavailability, which depends on the absorption, biotransformation, and elimination of the drug. These processes are primarily controlled by efflux pumps and enzymes of the cytochrome P (CYP) 450 family. DNA variants at the genes encoding these proteins contribute to the interindividual heterogeneity for calcineurin inhibitors metabolism. Cyclosporine A and Tac are metabolized by CYP3A4 and CYP3A5, and several single nucleotide polymorphisms in the two genes have been associated with differences in drug clearance. Carriers of the CYP3A5 wild-type allele have a higher CYP3A5 expression compared with individuals who are homozygous for a common DNA variant that affects gene splicing (CYP3A5*3). For renal transplant recipients receiving Tac, homozygotes for this nonexpression allele would exhibit significantly lower Tac clearance and may require a lower dose to remain within the blood target concentration compared with CYP3A5 expressors. To date, this CYP3A5 variant is the only reported genetic factor to predict the appropiate starting dosage of Tac, avoiding overdosing and improving the outcome of renal transplantation.
Coto
Eliecer
E
Genética Molecular, Redinren, and Fundación Renal, Hospital Universitario Central de Asturias, Oviedo, Spain. eliecer.coto@sespa.princast.es
Tavira
Beatriz
B
D017398:Alternative Splicing; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004247:DNA / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D014644:Genetic Variation; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology*; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000627:therapeutic use
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D004247:DNA; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus