ABCB1 p.Trp212*
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[hide] Association of genetic polymorphisms in the influx... Ther Drug Monit. 2011 Apr;33(2):244-50. Yamakawa Y, Hamada A, Nakashima R, Yuki M, Hirayama C, Kawaguchi T, Saito H
Association of genetic polymorphisms in the influx transporter SLCO1B3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia.
Ther Drug Monit. 2011 Apr;33(2):244-50., [PMID:21311410]
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This study explored the association of 14 single nucleotide polymorphisms in three genes coding for influx transporters (SLC22A1, SLCO1B1, and SLCO1B3), two genes coding for efflux transporters (ABCB1 and ABCG2), and four genes coding for enzymes (CYP2C9, CYP2C19, CYP2D6, and CYP3A5) with the pharmacokinetics of imatinib in Japanese patients with chronic myeloid leukemia. Pharmacokinetic parameters were estimated by a population pharmacokinetic analysis based on 622 plasma samples from 34 patients at steady state. Approximately 4.6-fold variability in individual clearance was observed (range, 3.4-15.5 L/hr). The individual estimated clearance was significantly increased in patients with the SLCO1B3 334GG genotype (median value +/- standard deviation, 9.5 +/- 3.1 L/hr; n = 19) compared with SLCO1B3 334TT and TG genotypes (7.0 +/- 3.1 L/hr; n = 15) (P = 0.019). Patients with the ABCB1 3435CC genotype had significantly higher imatinib clearance (12.7 +/- 3.0 L/hr; n = 7) compared with patients with ABCB1 3435CT and TT genotypes (7.9 +/- 2.7 L/hr; n = 27) (P = 0.035). In conclusion, the present study suggests that single nucleotide polymorphisms of the influx transporter SLCO1B3 and the efflux transporter ABCB1 were functionally associated with individual variability of imatinib pharmacokinetics in Japanese patients with chronic myeloid leukemia.
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77 Individual Clearance of Imatinib as a Function of Variant Genotypes Allele Region Effect* Number of Patients Allele Frequency† WT Het Var p q SLC22A11022C.T Exon6 P341L 24 8 2 0.82 0.18 SLCO1B1521T.C Exon6 V174A 26 7 1 0.87 0.13 SLCO1B3334T.G Exon3 S112A 5 10 19 0.29 0.71 ABCB11236C.T Exon12 G412G 5 19 10 0.43 0.57 ABCB12677G.T/A Exon21 A893S/T 10 14 10 0.50 0.50 ABCB13435C.T Exon26 I1145I 7 21 6 0.51 0.49 ABCG2421C.A Exon5 Q141K 21 13 0 0.81 0.19 CYP2C9430C.T Exon3 R144C 34 0 0 1.00 0.00 CYP2C91075A.C Exon7 I359L 33 1 0 0.99 0.01 CYP2C19636G.A Exon5 W212X 27 7 0 0.90 0.10 CYP2C19681G.A Exon4 Splice defect 16 13 5 0.66 0.34 CYP2D6100C.T Exon1 P34S 13 16 5 0.62 0.38 CYP2D61846G.A Exon4 Splice defect 34 0 0 1.00 0.00 CYP3A56986A.G Intron3 Splice defect 2 12 20 0.24 0.76 Allele Clearance 6 SD (L/hr) P WT Het Var WT vs Het vs Var WT + Het vs Var WT vs Het + Var SLC22A11022C.T 8.8 6 2.9 8.2 6 3.5 8.3 6 3.5 0.973 0.913 0.926 SLCO1B1521T.C 8.7 6 3.1 8.3 6 2.0 5.5 0.304 0.235 0.288 SLCO1B3334T.G 5.7 6 2.3 7.4 6 2.4 9.5 6 3.1 0.046 0.019 0.071 ABCB11236C.T 11.7 6 3.1 8.1 6 2.7 8.2 6 3.2 0.277 0.642 0.196 ABCB12677G.T/A 9.8 6 3.2 8.1 6 2.5 8.0 6 3.3 0.494 0.445 0.270 ABCB13435C.T 12.7 6 3.0 7.9 6 2.4 9.2 6 3.5 0.058 0.581 0.035 ABCG2421C.A 7.9 6 3.1 9.5 6 2.8 N/A 0.446 N/A 0.462 CYP2C9430C.T 8.3 6 3.0 N/A N/A N/A N/A N/A CYP2C91075A.C 8.6 6 3.0 10.0 N/A 0.508 N/A 0.647 CYP2C19636G.A 8.1 6 2.8 9.7 6 3.3 N/A 0.242 N/A 0.257 CYP2C19681G.A 8.6 6 3.6 9.5 6 2.6 7.0 6 1.1 0.473 0.252 0.852 CYP2D6100C.T 7.3 6 3.2 8.2 6 2.4 12.7 6 3.3 0.190 0.089 0.276 CYP2D61846G.A 8.3 6 3.0 N/A N/A N/A N/A N/A CYP3A56986A.G 6.3 6 1.0 7.9 6 3.4 9.4 6 2.8 0.285 0.323 0.175 *Number represents amino acid codon.
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ABCB1 p.Trp212* 21311410:77:564
status: NEW