4723 Background: ATN is an oral selective endothelin A receptor antagonist in phase 3 clinical development for treatment of hormone-refractory prostate cancer. ATN is not a p-glycoprotein (Pgp) substrate, but inhibits Pgp with an IC50 ∼12 μM (>50-fold the mean plasma Cmax for 10 mg/d ATN, although maximal intestinal concentrations may be 80 μM). The antihistamine FEX is a sensitive probe Pgp substrate; in clinical trials, Pgp inhibitors erythromycin and ketoconazole increased FEX AUC >2-fold. METHODS To assess the effect of ATN on FEX PK, a phase 1 open label study was conducted in 12 healthy subjects (10 M and 2 F; mean±SD 27±9 yrs, 75±10 kg). Subjects received FEX 120 mg PO on Days 1 and 8, and ATN 10 mg PO QD from Day 3 through 9. Blood and urine samples for FEX assay were collected predose and over 48 h after each FEX dose. Plasma and urine concentrations of FEX were determined using validated LC/MS/MS methods. RESULTS FEX PK are summarized (mean±SD; N=11) in the following table. [Figure: see text] We observed no meaningful effect of MDR-1 genotype on FEX PK, nor on changes of FEX PK following dosing with ATN. FEX with ATN was generally well tolerated. One subject did not receive ATN on Days 7-8 and was excluded from PK analyses. Most AEs were mild; headache was the most common AE. CONCLUSIONS ATN increased FEX bioavailability but did not alter FEX elimination, indicating that 10 mg QD ATN does not affect systemic Pgp activity. Pgp inhibition in the gut appears to be a local effect of orally administered ATN and therefore PK interactions would only be expected between ATN and absorption-limited Pgp substrates. [Table: see text].