Document Detail

Pharmacogenetic characterization of sulfasalazine disposition based on NAT2 and ABCG2 (BCRP) gene polymorphisms in humans.
MedLine Citation:
PMID:  18167504     Owner:  NLM     Status:  MEDLINE    
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 microg 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.
Y Yamasaki; I Ieiri; H Kusuhara; T Sasaki; M Kimura; H Tabuchi; Y Ando; S Irie; Ja Ware; Y Nakai; S Higuchi; Y Sugiyama
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-01-02
Journal Detail:
Title:  Clinical pharmacology and therapeutics     Volume:  84     ISSN:  1532-6535     ISO Abbreviation:  Clin. Pharmacol. Ther.     Publication Date:  2008 Jul 
Date Detail:
Created Date:  2008-06-19     Completed Date:  2008-07-07     Revised Date:  2010-09-08    
Medline Journal Info:
Nlm Unique ID:  0372741     Medline TA:  Clin Pharmacol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  95-103     Citation Subset:  AIM; IM    
Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
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MeSH Terms
ATP-Binding Cassette Transporters / genetics*,  metabolism
Arylamine N-Acetyltransferase / genetics*,  metabolism
Neoplasm Proteins / genetics*,  metabolism
Polymorphism, Genetic / drug effects,  genetics*
Sulfasalazine / blood,  pharmacokinetics*
Reg. No./Substance:
0/ABCG2 protein, human; 0/ATP-Binding Cassette Transporters; 0/Neoplasm Proteins; 599-79-1/Sulfasalazine; EC N-Acetyltransferase; EC protein, human

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