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Research ArticleArticle

Pharmacokinetics and Disposition of the Oxytocin Receptor Antagonist L-368,899 in Rats and Dogs

Kathryn L. Thompson, Styliani H. Vincent, Randall R. Miller, Adria E. Colletti, Raul F. Alvaro, Michael A. Wallace, William P. Feeney and Shuet-Hing Lee Chiu
Drug Metabolism and Disposition October 1997, 25 (10) 1113-1118;
Kathryn L. Thompson
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Styliani H. Vincent
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Randall R. Miller
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Adria E. Colletti
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Raul F. Alvaro
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Michael A. Wallace
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William P. Feeney
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Shuet-Hing Lee Chiu
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Abstract

L-368,899 is a potent, orally-active oxytocin antagonist that completed phase I clinical trials for the prevention of preterm labor. The pharmacokinetics and disposition of L-368,899 were studied in rats (female and male) and dogs (female), the two species used in the toxicology studies. L-368,899 exhibited similar pharmacokinetics in rats and dogs. After iv dosing at 1, 2.5, and 10 mg/kg, the compound had a t1/2 of ∼2 hr and plasma clearance between 23 and 36 ml/min/kg at all doses and in both species. The exception was female rats at the 10 mg/kg dose where plasma clearance decreased to 18 ml/min/kg. TheVdss was between 2.0 and 2.6 liters/kg for rats and 3.4 to 4.9 liters/kg for dogs. After oral doing, L-368,899 was rapidly absorbed. Mean Cmax values were achieved at <1 hr at the low doses (25 mg/kg in rats and 5 mg/kg in dogs) and between 1 and 4 hr at the higher doses (100 mg/kg in rats and 33 mg/kg in dogs). In bile duct-cannulated female rats, ∼70% of a radioactive 28 mg/kg dose was recovered in bile and urine within 72 hr post dose. Plasma drug concentrations were higher in female than in male rats especially at the 25 mg/kg dose, where mean AUC values were 4.5-fold higher in the females. In both rats and dogs, plasma drug levels increased more than proportionally with increasing oral dose. In female rats, the mean AUC increased by ∼8-fold between 25 and 100 mg/kg, while in female dogs, the mean AUC at the 33 mg/kg dose was 12-fold higher than that at 5 mg/kg. Oral bioavailability was estimated at 14% and 18% for the 5 mg/kg dose in female and male rats, respectively, 41% for the 25 mg/kg dose in male rats and 17% and 41%, respectively, for the 5 and 33 mg/kg doses in dogs. Owing to nonlinear kinetics, bioavailability could not be calculated for the other oral doses. L-368,899 was metabolized extensively in both species after iv and oral dosing, with <10% of the dose excreted unchanged. The main route of elimination was via the feces, which contained >70% of the radioactive dose by 48 hr, primarily as metabolites. The gender and dose dependence of the pharmacokinetics of L-389,899 in rats were attributed to gender differences in metabolizing capacity and saturation of hepatic metabolism, respectively. This conclusion was based primarily on results from experiments comparing the rate of in vitro metabolism of L-368,899 in liver microsomes, which showed that the Vmaxand KM values for L-368,899 were 4-fold lower in female than in male rat liver microsomes.

Footnotes

  • Send reprint requests to: Mrs. Kathryn L. Thompson, Merck Research Laboratories, R80L-109, Rahway NJ 07065

  • ↵4 S. K. Painter, Merck Research Labs, unpublished results (1992).

  • ↵2 D. J. Pettibone, Merck Research Labs, unpublished results (1992).

  • ↵3 K. L. Thompson, S. H. Vincent, B. Arison, R. R. Miller, R. A. Stearns, B. V. Karanam, M. A. Wallace, D. C. Dean, and S.-H. L. Chiu: Metabolism of the oxytocin antagonist, L-368,899, in rats, dogs, monkeys and humans (Manuscript in preparation).

  • Abbreviations used are::
    L-368
    899, 1-(((7,7-Dimethyl-2(S)-(2(S)-amino-4-(methylsulfonyl)butyramido)bicyclo[2.2.1]-heptan-1(S)-yl)methyl)sulfonyl)-4-(2-methylphenyl)piperazine
    TFA
    trifluoroacetic acid
    LC-MS/MS
    liquid chromatography/tandem mass spectroscopy
    Clp
    plasma clearance,Vdss volume of ditsribution at steady state
    TAO
    5-methyl-4-[2-thiazolylazo]-1,3-benzenediol
    • Received December 24, 1996.
    • Accepted June 25, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 10
1 Oct 1997
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Research ArticleArticle

Pharmacokinetics and Disposition of the Oxytocin Receptor Antagonist L-368,899 in Rats and Dogs

Kathryn L. Thompson, Styliani H. Vincent, Randall R. Miller, Adria E. Colletti, Raul F. Alvaro, Michael A. Wallace, William P. Feeney and Shuet-Hing Lee Chiu
Drug Metabolism and Disposition October 1, 1997, 25 (10) 1113-1118;

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Research ArticleArticle

Pharmacokinetics and Disposition of the Oxytocin Receptor Antagonist L-368,899 in Rats and Dogs

Kathryn L. Thompson, Styliani H. Vincent, Randall R. Miller, Adria E. Colletti, Raul F. Alvaro, Michael A. Wallace, William P. Feeney and Shuet-Hing Lee Chiu
Drug Metabolism and Disposition October 1, 1997, 25 (10) 1113-1118;
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