Consequences of genetic polymorphisms for sirolimus requirements after renal transplant in patients on primary sirolimus therapy.
Sirolimus (SRL) is a substrate for cytochromes P-450 3A and P-glycoprotein, the product of the MDR1 gene. We postulated that single nucleotide polymorphisms (SNPs) of these genes could be associated with inter-individual variations in SRL requirements. We then evaluated in 149 renal transplant recipients the effect of polymorphisms CYP3A4*1/*1B, CYP3A5*1/*3 and MDR1 SNPs in exon 12, 21 and 26 on SRL concentration/dose (C/D) ratio 3 months after sirolimus introduction. SRL C/D ratio was significantly higher in patients treated with calcineurin inhibitors. The CYP3A4*1B and CYP3A5*1 alleles were present in 17% and 21% of patients, respectively. When treated with a SRL-based therapy and low-dose steroids, patients carrying the CYP3A4*1B or the CYP3A5*1 alleles required significantly more SRL to achieve adequate blood trough concentrations (p < 0.01 and p < 0.02, respectively). None of the MDR1 SNPs was associated with the SRL concentration/dose ratio. These findings suggest that the variations in SRL requirements are secondary to both genetic and non-genetic factors including pharmacokinetic interactions. In patients with SRL-based therapy, genotyping of the CYP3As genes may help to optimize the SRL management in transplant recipients.
Anglicheau
Dany
D
Unité INSERM UMR S490, Molecular Toxicology, Centre Universitaire des Saints-Pères, Université René Descartes, Paris, France. dany.anglicheau@univ-paris5.fr
Le Corre
Delphine
D
Lechaton
Sophie
S
Laurent-Puig
Pierre
P
Kreis
Henri
H
Beaune
Philippe
P
Legendre
Christophe
C
Thervet
Eric
E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D016030:Kidney Transplantation; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020123:Sirolimus / Q000378:metabolism / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D003577:Cytochrome P-450 Enzyme System; D020123:Sirolimus