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Effect of DPC 333 [(2R)-2-{(3R)-3-Amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide], a Human Tumor Necrosis Factor -Converting Enzyme Inhibitor, on the Disposition of Methotrexate: A Transporter-Based Drug-Drug Interaction Case Study

Preclinical Candidate Optimization-Metabolism and Pharmacokinetics (G.L.) and Chemistry (J.D., C.P.D., T.M.), Bristol-Myers Squibb Company, Pennington, New Jersey; AstraZeneca Plc, Waltham, Massachusetts (C.E.G.); School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (H.X., K.L.R.B.); Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (H.H., L.-S.G); GlaxoSmithKline, King of Prussia, Pennsylvania (L.E.R.); Quest Pharmaceutical Services, Inc., Newark, Delaware (H.S.); and Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts (F.W.L.).

DPC 333 [(2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide] is a potent human tumor necrosis factor -converting enzyme inhibitor with potential therapeutic implications for rheumatoid arthritis. Methotrexate (MTX), a drug for the treatment of rheumatoid arthritis, is eliminated primarily unchanged via renal and biliary excretion in humans as well as in rats and dogs. The objective of the present study was to investigate the potential effect of DPC 333 on the disposition of MTX. In dogs, DPC 333 administered orally at 1.7 mg/kg 15 min before the intravenous administration of [¹⁴C]MTX (0.5 mg/kg) did not alter the plasma concentration-time profile of MTX; however, the total amount of radioactivity excreted in urine increased from 58.7% to 92.2% of the dose, and the renal clearance increased from 1.8 ml/min/kg to 2.9 ml/min/kg, suggesting a decrease in MTX disposition via biliary excretion. The biliary excretion of MTX was investigated in isolated perfused livers prepared from wild-type and TR^- [multidrug resistance-associated protein 2 (Mrp2)-deficient] Wistar rats in the absence and presence of DPC 333. Mrp2-mediated biliary excretion of MTX was confirmed with 95.8% and 5.1% of MTX recovered in the bile of wild-type and TR^- Wistar rats, respectively. DPC 333 at an initial perfusate concentration of 50 µM completely blocked the biliary excretion of MTX, but not the clearance from perfusate, in both wild-type and TR^- rats. These results suggest that the enhanced renal elimination of MTX may be due to the potent inhibition of biliary excretion and active renal reabsorption by DPC 333 and/or its metabolites.

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