Pharmacogenetic characterization of sulfasalazine disposition based on NAT2 and ABCG2 (BCRP) gene polymorphisms in humans

Y. Yamasaki, Ichiro Ieiri, H. Kusuhara, T. Sasaki, M. Kimura, H. Tabuchi, Y. Ando, S. Irie, J. A. Ware, Y. Nakai, S. Higuchi, Y. Sugiyama

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Abstract

The role of breast cancer resistance protein (BCRP), an efflux ABC transporter, in the pharmacokinetics of substrate drugs in humans is unknown. We investigated the impact of genetic polymorphisms of ABCG2 (421C>A) and NAT2 on the pharmacokinetics of sulfasalazine (SASP), a dual substrate, in 37 healthy volunteers, taking 2,000 mg of conventional SASP tablets. In ABCG2, SASP AUC0-48 of C/C, C/A, and A/A subjects was 171 ± 85, 330 ± 194, and 592 ± 275 μg h/ml, respectively, with significant differences among groups. In contrast, AUC0-48 of sulfapyridine (SP) tended to be lower in subjects with the ABCG2-A allele as homozygosity. In NAT2, AUCAcSP/AUCSP was significantly higher in rapid than in intermediate and slow acetylator (SA) genotypes. We successfully described the pharmacokinetics of SASP, SP, and N -acetylsulfapyridine (AcSP) simultaneously by nonlinear mixed-effects modeling (NONMEM) analysis with regard to both gene polymorphisms. The data indicate that SASP is a candidate probe of BCRP, particularly in its role in intestinal absorption.

Original languageEnglish
Pages (from-to)95-103
Number of pages9
JournalClinical Pharmacology and Therapeutics
Volume84
Issue number1
DOIs
Publication statusPublished - Jul 1 2008

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

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    Yamasaki, Y., Ieiri, I., Kusuhara, H., Sasaki, T., Kimura, M., Tabuchi, H., Ando, Y., Irie, S., Ware, J. A., Nakai, Y., Higuchi, S., & Sugiyama, Y. (2008). Pharmacogenetic characterization of sulfasalazine disposition based on NAT2 and ABCG2 (BCRP) gene polymorphisms in humans. Clinical Pharmacology and Therapeutics, 84(1), 95-103. https://doi.org/10.1038/sj.clpt.6100459