Breast Cancer Resistance Protein (BCRP/ABCG2) is a Major Determinant of Sulfasalazine Absorption and Elimination in the Mouse

Sulfasalazine is used in the treatment of rheumatoid arthritis, ulcerative colitis and Crohn's disease. When administered orally, sulfasalazine is poorly absorbed with an estimated bioavailability of 3–12%. Recent studies in T‐cell and Caco‐2 cell lines have shown that sulfasalazine is a substrate for the ATP‐Binding Cassette (ABC) efflux pump ABCG2. ABCG2 is known to efflux many xenobiotics and may augment the potential efficacy and toxicity of ABCG2 substrates. To date, there has not been a systematic study on the mechanisms involved in the transport of sulfasalazine, in‐vivo. We investigated whether Bcrp (abcg2) is involved in the disposition of sulfasalazine. After oral administration of 20 mg/kg sulfasalazine, the area under the plasma concentration (AUC) time curve in Bcrp (abcg2) knockout (KO) mice increased approximately 200‐fold higher than in wild‐type (WT) mice. Sulfasalazine bioavailability in Bcrp KO mice was 97% compared to 3% in wild‐type mice. In addition, treatment of WT mice with a single oral dose of iressa (50 mg/kg), a known inhibitor of BCRP, resulted in a significant increase in the AUC and bioavailability. During mini‐pump infusion studies, steady‐state plasma concentrations of sulfasalazine in Bcrp (abcg2) KO mice were 14‐fold higher than in WT mice, suggesting that clearance of this compound is significantly decreased in the absence of Bcrp (abcg2). Moreover, liver and kidney homogenate concentrations were 6‐fold higher in these KO mice than WT mice. However, brain homogenate and plasma protein binding of sulfasalazine obtained at steady state were similar between both genotypes. We conclude that Bcrp (abcg2) is an important determinant for the oral bioavailability and the elimination of sulfasalazine.