BACKGROUND: Interindividual heterogeneity in expression of ABCB1 gene has been suspected to be one of the factors resulting in cyclosporin (CsA) pharmacokinetic variation. The present study explored the association of ABCB1 SNPs on CsA dose requirements and dose-adjusted C2 levels (CsA level/daily dose requirement) in renal allograft recipients. METHODS: Daily doses (mg/kg/day) and dose-adjusted C2 levels (microg/mL per mg/kg/day) at 1 and 3 months for 155 recipients on CsA therapy were compared according to allelic status of ABCB1 c.1236C>T, c. 2064-76T>A, c.2677G>T and c.3435C>T. RESULTS: Dose-adjusted C2 levels were lower in ABCB1 c.2677G>T GG genotype as compared to GT/TT genotypes at 1 and 3 months, suggesting that for a given dose their CsA blood concentration is lower (p=0.009 and p=0.043). GG genotype was further associated with lower allograft survival as revealed by Kaplan-Meier analysis (p=0.021). CONCLUSIONS: Identification of ABCB12677GG patients may have a clinically significant impact on allograft outcome and may be helpful in providing pre-transplant pharmacogenetic information to individualize CsA dosing.
BACKGROUND: Interindividual heterogeneity in expression of ABCB1 gene has been suspected to be one of the factors resulting in cyclosporin (CsA) pharmacokinetic variation. The present study explored the association of ABCB1 SNPs on CsA dose requirements and dose-adjusted C2 levels (CsA level/daily dose requirement) in renal allograft recipients. METHODS: Daily doses (mg/kg/day) and dose-adjusted C2 levels (microg/mL per mg/kg/day) at 1 and 3 months for 155 recipients on CsA therapy were compared according to allelic status of ABCB1 c.1236C>T, c. 2064-76T>A, c.2677G>T and c.3435C>T. RESULTS: Dose-adjusted C2 levels were lower in ABCB1 c.2677G>T GG genotype as compared to GT/TT genotypes at 1 and 3 months, suggesting that for a given dose their CsA blood concentration is lower (p=0.009 and p=0.043). GG genotype was further associated with lower allograft survival as revealed by Kaplan-Meier analysis (p=0.021). CONCLUSIONS: Identification of ABCB12677GG patients may have a clinically significant impact on allograft outcome and may be helpful in providing pre-transplant pharmacogenetic information to individualize CsA dosing.
Authors: Abdullah M Al-Mohizea; Khalid M Alkharfy; Khawla M Bagulb; Amal M Alghamdi; Fahad I Al-Jenoobi; Saleh Al-Muhsen; Rabih Halwani; Mohammad Khalid Parvez; M Khalid Parvez; Mohammed S Al-Dosari Journal: Mol Biol Rep Date: 2012-10-07 Impact factor: 2.316