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Pharmacogenetic Characterization of Sulfasalazine Disposition Based on NAT2 and ABCG2 (BCRP) Gene Polymorphisms in Humans
Author(s) -
Yamasaki Y,
Ieiri I,
Kusuhara H,
Sasaki T,
Kimura M,
Tabuchi H,
Ando Y,
Irie S,
Ware JA,
Nakai Y,
Higuchi S,
Sugiyama Y
Publication year - 2008
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/sj.clpt.6100459
Subject(s) - pharmacokinetics , abcg2 , pharmacology , pharmacogenetics , sulfasalazine , genotype , cyp2d6 , chemistry , medicine , transporter , atp binding cassette transporter , gene , biochemistry , disease , ulcerative colitis
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 AUC 0–48 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, AUC 0–48 of sulfapyridine (SP) tended to be lower in subjects with the ABCG2‐A allele as homozygosity. In NAT2 , AUC AcSP /AUC SP 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. Clinical Pharmacology & Therapeutics (2008); 84 , 1, 95–103 doi: 10.1038/sj.clpt.6100459