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|Title:||Oral sulfasalazine as a clinical BCRP probe substrate: Pharmacokinetic effects of genetic variation (C421A) and pantoprazole coadministration|
|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|
|Appears in Collections:||Staff Publications|
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