ABCMdb

PMID: 18334920

Haenisch S, May K, Wegner D, Caliebe A, Cascorbi I, Siegmund W
Influence of genetic polymorphisms on intestinal expression and rifampicin-type induction of ABCC2 and on bioavailability of talinolol.
Pharmacogenet Genomics. 2008 Apr;18(4):357-65., [PubMed]

Sentences

No. Mutations Sentence Comment

7 ABCC2 p.Val417Ile The variant ABCC2 1249G > A (V417I), however, was associated with lower oral bioavailability (P = 0.001), and increased residual clearance of intravenous talinolol (P = 0.021). Login to comment 8 ABCC2 p.Val417Ile Intestinal ABCC2 mRNA and protein expression were upregulated by rifampicin treatment, a genetic influence could be detected in only four cases heterozygote for 3563T > A or 4544G > A. Conclusion The 1249G > A (V417I) polymorphism is obviously associated with higher activity of the intestinal transporter. Login to comment 17 ABCC2 p.Val417Ile ABCC2 p.Cys1515Tyr ABCC2 p.Val1188Glu So far, the polymorphism -24C > T in the 50 -untranslated region, the nonsynonymous single nucleotide polymorphisms (SNPs) c.1249G > A (V417I), c.3563T > A (V1188E), c.4544G > A (C1515Y), and the synonymous SNPs 1446C > G (Thr482Thr) and 3972C > T (I1324I) were subjects of evaluations [15-17]. Login to comment 38 ABCC2 p.Arg768Trp ABCC2 p.Val417Ile ABCC2 p.Ser789Phe ABCC2 p.Ala1450Thr Genotyping The ABCC2 SNPs -24C > T (rs717620), c.1249G > A (V417I, rs2273697), c.2302C > T (Arg768Trp), c.2366C > T (Ser789Phe), c.3972C > T (I1324I, rs3740066), c.4348G > A (Ala1450Thr) were genotyped using PCR-restriction fragment length polymorphism (RFLP) analysis. Login to comment 47 ABCC2 p.Cys1515Tyr ABCC2 p.Val1188Glu ABCC2 p.Arg1181Leu ABCC2 p.Thr486Ile The SNPs -24C > T (rs717620), -23G > A (rs17216156) in the 50 -UTR, c.1446C > G (T482T), recently described by Niemi et al. [17], c.1457C > T (T486I, rs45518933), c.3542G > T (R1181L, rs8187692), c.3561G > A (E1187E, rs45622934), c.3563T>A (V1188E rs17222723), c.4544G>A (C1515Y, rs8187710) were determined by pyrosequencing using the PSQ 96HS system (Biotage, Uppsala, Sweden). Login to comment 99 ABCC2 p.Val417Ile Talinolol disposition After oral administration of talinolol, the AUC was significantly associated with the nonsynonymous ABCC2 polymorphism 1249G > A (V417I) in a gene-dose-related manner (P = 0.005). Login to comment 112 ABCC2 p.Val417Ile With regard to the activity of ABCC2, however, the nonsynonymous variant 1249G > A (V417I) seems to be associated with increased activity of the efflux transporter as evidenced by significantly decreased bioavailability of b1-selective blocker talinolol in carriers of the variant allele. Login to comment 128 ABCC2 p.Val417Ile ABCC2 1249G > A leads to an exchange of valine to isoleucine at position 417 of the transmembrane protein domain 1. Login to comment 135 ABCC2 p.Val417Ile In-vitro transport studies in recombinant Lewis lung carcinoma porcine kidney cells, however, did not suggest differences Table 6 Influence of ABCC2 1249G > A (V417I) on disposition of talinolol after intravenous infusion (10 mg/30 min) and oral administration of 100 mg in 31 healthy white subjects All participants GG GA AA Intravenous Oral Intravenous Oral Intravenous Oral Intravenous Oral N 31 31 18 18 11 11 2 2 AUC (ng Â h/ml) 1385.6 ± 229 3131 ± 757 1400 ± 223 3420 ± 708 1380 ± 232 2910 ± 485a 1320 ± 417 1750 ± 695a,b F (%) - 68.9 ± 14.6 - 75.1 ± 12.0 - 63.2 ± 9.3 - 44.3 ± 29.7a t1/2 (h) 12.9 ± 2.3 13.7 ± 2.2 12.6 ± 1.7 13.3 ± 1.5 13.5 ± 3.1 14.1 ± 2.9 11.9 ± 0.6 15.5 ± 3.2 CLR (ml/min) 188 ± 57 169 ± 54.1 183 ± 52 159 ± 40 199 ± 59 186 ± 72 167 ± 123 169 ± 58 CLM (ml/min) 4.6 ± 3.2 - 4.84 ± 3.97 - 4.29 ± 2.04 - 4.68 ± 1.85 - CLres (ml/min) 179 ± 51 - 180 ± 58 - 169 ± 37 - 226 ± 0.54b - AUC, area under the concentration-time curve; CLM, metabolic clearance; CLR, renal clearance; CLres, residual clearance; F, bioavailability; t1/2, half-life. Login to comment 140 ABCC2 p.Val417Ile Duodenal ABCC2 expression and function Haenisch et al. 363 in V417I dependent transport [18]. Login to comment 161 ABCC2 p.Val417Ile The 1249G > A (V417I) polymorphism, however, is obviously associated with higher activity of the intestinal transporter as evidenced by gene-dose related decrease of oral absorption and increased residual clearance of talinolol. Login to comment