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Br J Clin Pharmacol ; 75(6): 1497-505, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23116553

RESUMO

AIMS: Aldo-ketoreductases have been implicated in the metabolism of doxorubicin. We sought to assess the influence of AKR1C3 genetic variants on doxorubicin metabolism. METHODS: We sequenced AKR1C3 exon 5 and genotyped seven functional single nucleotide polymorphisms in CBR3, ABCB1 and SLC22A16 involved in doxorubicin pharmacology in 151 Asian breast cancer patients treated with doxorubicin-containing chemotherapy, and correlated these genotypes with doxorubicin pharmacokinetics and pharmacodynamics. RESULTS: Two previously reported AKR1C3 intronic variants, IVS4-212 C>G and IVS4+218 G>A, were detected. The AKR1C3 IVS4-212 GG genotype was associated with significantly lower cycle 1 day 15 leucocyte (mean leucocytes 2.49 ± 1.57 × 10(9) vs. 3.85 ± 3.42 × 10(9) l(-1) , P = 0.007) and neutrophil counts (mean neutrophils 0.70 ± 1.01 × 10(9) vs. 1.56 ± 2.80 × 10(9) l(-1) , P = 0.008) and significant improvement of progression-free survival [PFS, mean PFS 49.0 (95% confidence interval 42.2-55.8) vs. 31.0 (95% confidence interval 20.7-41.2) months, P = 0.017] and overall survival [OS; mean OS 64.4 (95% confidence interval 58.3-70.5) vs. 46.3 (95% confidence interval 35.1-57.5) months, P = 0.006] compared with those carrying at least one C allele. There was no significant association between AKR1C3 IVS4-212 C>G and doxorubicin pharmacokinetics. Of the other seven single nucleotide polymorphisms genotyped, CBR3 G11A correlated with doxorubicinol area under the concentration-time curve and OS, ABCB1 G2677T/A correlated with doxorubicin clearance and platelet toxicity, while ABCB1 IVS26+59 T>G correlated with OS. The AKR1C3 IVS4-212 C

Assuntos
3-Hidroxiesteroide Desidrogenases/genética , Antibióticos Antineoplásicos/farmacocinética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Doxorrubicina/farmacocinética , Hidroxiprostaglandina Desidrogenases/genética , Polimorfismo de Nucleotídeo Único , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Oxirredutases do Álcool/genética , Membro C3 da Família 1 de alfa-Ceto Redutase , Povo Asiático/genética , Neoplasias da Mama/tratamento farmacológico , Intervalo Livre de Doença , Éxons/genética , Feminino , Genótipo , Técnicas de Genotipagem , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Proteínas de Transporte de Cátions Orgânicos/genética , Farmacogenética
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