title: Oral sulfasalazine as a clinical BCRP probe substrate: pharmacokinetic effects of genetic variation (C421A) and pantoprazole coadministration.
abstract: This study evaluated the utility of oral sulfasalazine as a probe substrate for Breast Cancer Resistance Protein (BCRP; ABCG2) activity by assessing the impact of genetic variation or coadministration of an inhibitor (pantoprazole) on plasma and urine pharmacokinetics of sulfasalazine and metabolites. Thirty-six healthy male subjects prescreened for ABCG2 421CC (reference activity), CA, and AA (lower activity) genotypes (N = 12 each) received a single 500 mg oral dose of enteric coated sulfasalazine alone, with 40 mg pantoprazole, or with 40 mg famotidine (gastrointestinal pH control) in a 3-period, single fixed sequence, crossover design. No significant difference in sulfasalazine or metabolite pharmacokinetics in 421AA or CA compared to 421CC subjects was found; however, high inter-subject variability was observed. Geometric mean (95% CI) sulfasalazine plasma AUC((0-infinity)) values were 32.1 (13.2, 78.1), 16.8 (7.15, 39.6) and 62.7 (33.4, 118) microg h/mL, and C(max) were 4.01 (1.62, 9.92), 1.70 (0.66, 4.40), and 6.86 (3.61, 13.0) microg/mL for CC, CA, and AA subjects, respectively. Pantoprazole and famotidine did not affect sulfasalazine pharmacokinetics in any genotypic cohort. These results suggest that the pharmacokinetics of oral, enteric-coated 500 mg sulfasalazine are not sufficiently sensitive to ABCG2 genetic variation or inhibitors to be useful as a clinical probe substrate of BCRP activity.
authors: Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Research Triangle Park, USA.
authors: Kimberly K
authors: KK
authors: Adkison
authors: Soniya S
authors: SS
authors: Vaidya
authors: Daniel Y
authors: DY
authors: Lee
authors: Seok Hwee
authors: SH
authors: Koo
authors: Linghui
authors: L
authors: Li
authors: Amar A
authors: AA
authors: Mehta
authors: Annette S
authors: AS
authors: Gross
authors: Joseph W
authors: JW
authors: Polli
authors: Joan E
authors: JE
authors: Humphreys
authors: Yu
authors: Y
authors: Lou
authors: Edmund J D
authors: EJ
authors: Lee
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000493:pharmacokinetics*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D015738:Famotidine / Q000493:pharmacokinetics; D005753:Gastric Mucosa / Q000378:metabolism; D005838:Genotype; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D000077402:Pantoprazole; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D054328:Proton Pump Inhibitors / Q000493:pharmacokinetics; D013056:Spectrophotometry, Ultraviolet; D012460:Sulfasalazine / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D054328:Proton Pump Inhibitors; D012460:Sulfasalazine; D015738:Famotidine; D000077402:Pantoprazole; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human