Association between cyclosporine concentration and genetic polymorphisms of CYP3A5 and MDR1 during the early stage after renal transplantation.
OBJECTIVE
Cyclosporine (CsA) has a narrow therapeutic range, and its pharmacokinetic characteristics vary among individuals. It also is a substrate for cytochrome P450 (CYP) 3A and P-glycoprotein, the product of the multidrug resistance 1 (MDR1) and CYP3A5 genes. Some of the single nucleotide polymorphisms (SNPs) in these genes are associated with deficient protein expression and reduced in vivo activity. We postulated that in renal transplant recipients, these SNPs should be associated with interindividual variations in CsA pharmacokinetics.


METHODS
In 88 Iranian renal transplant patients receiving CsA, CYP3A5 and MDR1 genotypes were determined by polymerase chain reaction, followed by restriction fragment length polymorphism analysis. Whole blood trough CsA concentrations were measured by radioactive immunosorbent assay. The dose-adjusted concentration (ng/mL per mg/kg/d) was calculated at 1 day (+/-2 days), 7 days, and 1 month after transplantation.


RESULTS
The MDR-1 wild-type genotype (3435CC) was observed in 17 patients (19%), whereas 45 patients (51%) were heterozygous (3435CT), and 26 patients (30%) were homozygous (3435 TT) for the mutation. In the days immediately after transplantation, we found a correlation between the concentration/dose ratio and the exon 26 MDR single nucleotide polymorphisms (33.3+/-15.24 microg mg/L/kg in the CT group vs 44.1+/-28.4 microg mg/L/kg in the TT group, P=.019). This ratio was significantly higher in subjects homozygous for the mutation (3435TT). This significant difference was not seen 1 week or 1 month after transplantation. All patients had the CYP3A5*3/*3 genotype, so no differences among the CYP3A5*1/*3 genotypes were found.


CONCLUSIONS
MDR-1 (3435CC) polymorphisms are associated with CsA pharmacokinetics and dose requirements in the first few days after renal transplantation. Pharmacogenetic methods could be used to help select the initial dosage and individualize immunosuppressive therapy. According to our results, the major genotype of our recipients is CYP3A5*3/*3. According to the literature, the recommended starting dosage of CsA is 9-14 mg/kg/day; however, the Iranian population has a good response with lower dosages (3-5 mg/kg/day), which may be explained by genetic differences.
Azarpira
N
N
The Organ Transplant Research Center, Nemazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran. negarazarpira@yahoo.com
Aghdaie
M H
MH
Behzad-Behbahanie
A
A
Geramizadeh
B
B
Behzadi
S
S
Malekhoseinie
S A
SA
Raisjalal
G H
GH
Rahsaz
M
M
Pourgholami
A
A
Sagheb
F
F
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D016572:Cyclosporine / Q000493:pharmacokinetics* / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A