ABCMdb

PMID: 16890580

Gardner ER, Burger H, van Schaik RH, van Oosterom AT, de Bruijn EA, Guetens G, Prenen H, de Jong FA, Baker SD, Bates SE, Figg WD, Verweij J, Sparreboom A, Nooter K
Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib.
Clin Pharmacol Ther. 2006 Aug;80(2):192-201., [PubMed]

Sentences

No. Mutations Sentence Comment

1 ABCG2 p.Gln141Lys Methods: Imatinib transport in vitro was studied by use of human embryonic kidney 293 cells transfected with wild-type ABCG2 and an ABCG2 Q141K clone. Login to comment 4 ABCG2 p.Gln141Lys Results: Human embryonic kidney 293 cells transfected with ABCG2 Q141K exhibited greater drug accumulation in vitro in comparison with cells expressing wild-type ABCG2 (P ‫؍‬ .028). Login to comment 26 ABCG2 p.Gln141Lys In particular, a functional single-nucleotide polymorphism (SNP) has been identified in exon 5 of the ABCG2 gene, in which a CϾA nucleotide transition at position 421 (ABCG2 421CϾA) results in a nonsynonymous variant protein with a glutamine-to-lysine amino acid substitution at codon 141 (Q141K).5 In this study we tested the hypothesis that the extensive interindividual variability in the pharmacokinetics of imatinib is associated with the ABCG2 421CϾA polymorphism in a cohort of patients with gastrointestinal stromal tumors. Login to comment 29 ABCG2 p.Gln141Lys Human embryonic kidney cells (HEK293) transfected with pcDNA3, wild-type ABCG2, or an ABCG2 Q141K clone were generated as described previously.8 Cells were maintained in N-[2-hydroxyethyl]piperazine-NЈ-[2-ethanesulfonic acid] (HEPES)-buffered RPMI-1640 medium (Gibco BRL, Paisley, United Kingdom) supplemented with 10% (vol/vol) fetal calf serum. Login to comment 82 ABCG2 p.Gln141Lys To investigate the potential effect of the ABCG2 421CϾA variant on the protein`s ability to transport imatinib, human embryonic kidney cells (HEK293) transfected with pcDNA3, wild-type ABCG2, or an ABCG2 Q141K clone were exposed to 14 C-labeled imatinib for 2 hours, and the intracellular concentration was determined. Login to comment 84 ABCG2 p.Gln141Lys The cells homozygous for the studied variant exhibited significantly greater drug accumulation than the cells expressing wild-type ABCG2 (P ϭ .028), suggesting impaired outward-directed transport of imatinib by the ABCG2 Q141K variant (Fig 1). Login to comment 102 ABCG2 p.Gln141Lys Top, Comparative intracellular accumulation of 14 C-labeled imatinib in human embryonic kidney cells (HEK293) transfected with wild-type ABCG2 (HEK293/R) and ABCG2 Q141K clone (HEK293/K-5). Login to comment 117 ABCG2 p.Gln141Lys The studied variant in ABCG2 is an SNP causing a nonsynonymous change in the protein sequence, in which a 421C-to-A transition in exon 5 leads to a glutamine-to-lysine amino acid substitution at codon 141 (Q141K). Login to comment 119 ABCG2 p.Gln141Lys Although our own current in vitro transport studies in HEK293 cells transfected with the homozygous Q141K variant show Table I. Login to comment 120 ABCG2 p.Gln141Lys Genotype and allele frequencies for studied variant genes Variant† Effect‡ Activity§ Genotype frequency [No. of patients (%)]࿣ Allele frequency¶ Wt Het Var p q Enzyme genotypes CYP2C9*2 (430CϾT) R144C (exon 3) Decreased 60 (85.7) 9 (12.9) 1 (1.43) 0.921 0.0786 CYP2C9*3 (1075AϾC) I359L (exon 7) Decreased 60 (85.7) 10 (14.3) 0 (0) 0.929 0.0714 CYP2C19*2 (681GϾA) Splice defect (exon 4) None 40 (57.1) 27 (38.6) 3 (4.29) 0.764 0.236 CYP2C19*3 (636GϾA) W212X (exon 5) None 70 (100) 0 (0) 0 (0) 1.000 0.000 CYP2D6*4 (1846GϾA) Splice defect (exon 4) None 42 (62.7) 24 (35.8) 1 (1.49) 0.806 0.194 CYP3A4*1B (-392AϾG) Promoter Normal/ increased 64 (91.4) 6 (8.57) 0 (0) 0.957 0.0429 CYP3A5*3C (6986AϾG) Splice defect (intron 3) Severely decreased 0 (0) 13 (18.6) 57 (81.4) 0.0929 0.907 Transporter genotypes ABCB1 3435CϾT I1145I (exon 26) Reduced 21 (25.6) 41 (50.0) 20 (24.4) 0.506 0.494 ABCG2 421CϾA Q141K (exon 5) Reduced 66 (80.5) 16 (19.5) 0 (0) 0.902 0.0976 Wt, Homozygous wild-type patient; Het, heterozygous patient; Var, homozygous variant patient; p, frequency for wild-type allele; q, frequency for variant allele. Login to comment