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Title: Oral sulfasalazine as a clinical BCRP probe substrate: Pharmacokinetic effects of genetic variation (C421A) and pantoprazole coadministration
Authors: Adkison, K.K.
Vaidya, S.S.
Lee, D.Y.
Koo, S.H. 
Li, L.
Mehta, A.A.
Gross, A.S.
Polli, J.W.
Humphreys, J.E.
Lou, Y.
Lee, E.J.D.
Keywords: ABC transporters
Clinical pharmacokinetics
Drug interactions
Metabolite kinetics
Issue Date: Feb-2010
Citation: Adkison, K.K., Vaidya, S.S., Lee, D.Y., Koo, S.H., Li, L., Mehta, A.A., Gross, A.S., Polli, J.W., Humphreys, J.E., Lou, Y., Lee, E.J.D. (2010-02). Oral sulfasalazine as a clinical BCRP probe substrate: Pharmacokinetic effects of genetic variation (C421A) and pantoprazole coadministration. Journal of Pharmaceutical Sciences 99 (2) : 1046-1062. ScholarBank@NUS Repository.
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 500mg oral dose of enteric coated sulfasalazine alone, with 40mg pantoprazole, or with 40mg 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-∞) values were 32.1 (13.2, 78.1), 16.8 (7.15, 39.6) and 62.7 (33.4, 118) μg h/mL, and Cmax were 4.01 (1.62, 9.92), 1.70 (0.66, 4.40), and 6.86 (3.61, 13.0) μg/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 500mg sulfasalazine are not sufficiently sensitive to ABCG2 genetic variation or inhibitors to be useful as a clinical probe substrate of BCRP activity. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association.
Source Title: Journal of Pharmaceutical Sciences
ISSN: 00223549
Appears in Collections:Staff Publications

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