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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 [ MTX, a bicarboxylic acid (Fig. 1) structurally similar to folic acid, has been used for the treatment of rheumatoid arthritis at low doses (Weinblatt et al., 1985;Schnabel and Gross, 1994). MTX is minimally metabolized to 7-hydroxy MTX in vivo, whereas most MTX is eliminated as intact drug via renal and biliary excretion in humans (Henderson et al., 1965b;Lui et al., 1985;Nuernberg et al., 1990;Seideman et al., 1993;Chladek et al., 1998), and in the preclinical species including mice, rats, dogs, and monkeys (Henderson et al., 1965a;Steinberg et al., 1982;Masuda et al., 1997). In mice and rats, the routes of biliary and renal elimination contribute almost equally to the total body clearance of MTX, but in monkeys and humans, renal elimination is more extensive than biliary excretion (Henderson et al., 1965a,b;Steinberg et al., 1982;Williams and Huang, 1982;Nuernberg et al., 1990;Masuda et al., 1997). For example, after intravenous administration, the cumulative biliary excretion of MTX was 44 to 72% of the dose in bile duct-cannulated rats, but only 16% in rhesus monkeys with bile fistula; after intraperitoneal or intravenous administration, MTX recovery in feces was 45% of the dose in rats and 40% in mice, but only 13% in monkeys and 10% in humans. Biliary H.X. and K.L.R.B. were funded in part by Grant R01 GM41935 from the National Institutes of Health.Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

1. Using synthetic standards and/or spectral data, seven moricizine metabolites were structurally identified in human urine. Two novel metabolites were identified as phenothiazine-2-carbamic acid and ethyl [10-(3-aminopropionyl) phenothiazin-2-yl] carbamate. Two novel human moricizine metabolites, 2-amino-10-(3-morpholino-propionyl) phenothiazine, a previously identified dog metabolite, and 2-aminophenothiazine, a previously identified rat metabolite, were also identified. Three additional human metabolites, phenothiazine-2-carbamic acid ethyl ester sulphoxide (P2CAEES), moricizine sulphoxide, and ethyl ¿10-[N-(2'-hydroxyethyl)3-aminopropionyl] phenothiazin-2-yl¿ carbamate, all previously described in the literature, were observed. 2. Both 2-amino-10-(3-morpholinopropionyl) phenothiazine and ethyl [10-(3-aminopropionyl) phenothiazin-2-yl] carbamate, and possibly ethyl ¿10-[N-(2'-hydroxyethyl) 3-aminopropionyl]phenothiazin-2-yl¿ carbamate, possess the structural characteristics thought to be necessary for class 1 antiarrhythmic activity.

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