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Research ArticleArticle

Orally Active Inhibitors Of Human Leukocyte Elastase. II. Disposition of L-694,458 in Rats and Rhesus Monkeys

Styliani H. Vincent, Susan K. Painter, Debra Luffer-Atlas, Bindhu V. Karanam, E. McGowan, Chris Cioffe, George Doss and Shuet-Hing L. Chiu
Drug Metabolism and Disposition August 1997, 25 (8) 932-939;
Styliani H. Vincent
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Susan K. Painter
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Debra Luffer-Atlas
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Bindhu V. Karanam
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E. McGowan
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Chris Cioffe
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George Doss
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Shuet-Hing L. Chiu
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Abstract

The disposition of L-694,458, a potent monocyclic β-lactam inhibitor of human leukocyte elastase, was studied in male Sprague-Dawley rats and rhesus monkeys. After iv dosing, L-694,458 exhibited similar pharmacokinetic parameters in rats and rhesus monkeys. The mean values for its plasma clearance, terminal half-life, and volume of distribution at steady state were 27 ml/min/kg, 1.8 hr, and 4.0 liters/kg in rats and 34 ml/min/kg, 2.3 hr, and 5 liters/kg in rhesus monkeys. The bioavailability of a 10 mg/kg oral dose was higher in rats (65%) than in rhesus monkeys (39%). In both species, concentrations of L-694,458 in plasma increased more than proportionally when the oral dose was increased from 10 mg/kg to 40 mg/kg. In monkeys a protracted plasma concentration-time profile was observed at 40 mg/kg, characterized by a delayed Tmax (8–24 hr) and a long terminal half-life (6 hr). [3H]L-694,458 was well absorbed after oral dosing to rats at 10 mg/kg, as indicated by the high recovery of radioactivity in bile (83%) and urine (6%) of bile duct-cannulated rats. Only ∼5% or less of the radioactivity in bile, urine, and feces was a result of intact L-694,458, indicating that the compound was being eliminated by metabolism, followed by excretion of the metabolites in feces, via bile. Demethylenation of the methylenedioxyphenyl group resulting in the catechol was the primary metabolic pathway in human and rhesus monkey liver microsomes. In rat liver microsomes, the major metabolite was the N-oxide of the methyl-substituted piperazine nitrogen. In rats dosed iv and orally with [3H]L-694,458, concentrations of radioactivity were highest in the lung (the primary target tissue), adrenals, and liver. L-694,458 was unstable in rat blood and plasma, degrading via a pathway believed to be catalyzed by B-esterases and to involve cleavage of the β-lactam ring and loss of the methylpiperazine phenoxy group. In vitro studies indicated that in human liver, L-694,458 was metabolized by CYP3A and 2C isozymes, and in both monkey and human liver microsomes the compound acted as an inhibitor of testosterone 6β-hydroxylation.

Footnotes

  • Send reprint requests to: Dr. Styliani H. Vincent, Merck Research Laboratories, RY 80L-109, P.O. Box 2000, Rahway, NJ 07065.

  • 2 L-694,458 has been licensed to DuPont Merck, and is also referred to as DMP 777.

  • Abbreviations used are::
    L-694
    458,N-[1(R)-(1,3-benzodioxol-5-yl)butyl]-3,3-diethyl-2(S)-[4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy]-4-oxo-1-azetidinecarboxamide
    Vdss
    volume of distribution at steady state
    TAO
    troleandomycin
    BNP
    bis-p-nitrophenyl phosphate
    PMSF
    phenylmethylsulfonyl fluoride
    HMQC
    heteronuclear multiple quantum coherence
    • Received November 1, 1996.
    • Accepted April 7, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 8
1 Aug 1997
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Research ArticleArticle

Orally Active Inhibitors Of Human Leukocyte Elastase. II. Disposition of L-694,458 in Rats and Rhesus Monkeys

Styliani H. Vincent, Susan K. Painter, Debra Luffer-Atlas, Bindhu V. Karanam, E. McGowan, Chris Cioffe, George Doss and Shuet-Hing L. Chiu
Drug Metabolism and Disposition August 1, 1997, 25 (8) 932-939;

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Research ArticleArticle

Orally Active Inhibitors Of Human Leukocyte Elastase. II. Disposition of L-694,458 in Rats and Rhesus Monkeys

Styliani H. Vincent, Susan K. Painter, Debra Luffer-Atlas, Bindhu V. Karanam, E. McGowan, Chris Cioffe, George Doss and Shuet-Hing L. Chiu
Drug Metabolism and Disposition August 1, 1997, 25 (8) 932-939;
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