The impact of CYP3A5 and MDR1 polymorphisms on tacrolimus dosage requirements and trough concentrations in pediatric renal transplant recipients.
Previous international studies demonstrated significant heterogeneity in the tacrolimus (TAC) dose required to attain target blood concentrations, attributed to both genetic and ethnic factors. While the majority of previous reports on adult recipients of renal, heart and liver transplants have shown a significant effect of CYP3A5FNx013 single nucleotide polymorphisms (SNPs) on TAC pharmacokinetics (PKs), the impact of multidrug resistance protein 1 (MDR1) and SNPs remains controversial. Yet, similar data of TAC in pediatric populations, in whom the intra- and inter-subject variations are likely to be even greater, is currently limited. We aimed to examine the influence of various CYP3A5 and MDR1 genotypes on TAC dose requirements and PKs in the Jordanian pediatric renal transplant population. Thirty-eight patients were genotyped for CYP3A5FNx011 and FNx013 and MDR1 C3435T. Dose-adjusted trough concentrations (C 0 /D) and daily doses (D) were compared among different CYP3A5 and MDR1 genotypes in the early and maintenance phases post-transplant. Surprisingly, there were no significant differences in D, C 0 or C 0 /D among the genotypes of CYP3A5 or MDR1 polymorphisms in either the early or the maintenance phase after transplantation, whereas after combining the C 0 /D levels of MDR1 C allele expressers, noticeably lower TAC levels were observed as compared with the TT genotype. However, the difference became not significant beyond 3 months. Based on a pharmacogenetic evaluation, the independent impact of CYP3A5 SNPs on TAC PKs was not evident, demonstrating the need for further large-scale studies.
Department of Clinical Pharmacy, Pharmacy College, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia.
Sireen
S
Shilbayeh
Rawan
R
Zmeili
Reham Issa
RI
Almardini
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000293:Adolescent; D002648:Child; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus