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Research ArticleArticle

Metabolism and Pharmacokinetics of 1-(2′-Trimethylacetoxyethyl)-2-ethyl-3-hydroxypyridin-4-one (CP117) in the rat

Ruksana Choudhury, Rafiu O. Epemolu, Bijaya L. Rai, Robert C. Hider and Surinder Singh
Drug Metabolism and Disposition March 1997, 25 (3) 332-339;
Ruksana Choudhury
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Rafiu O. Epemolu
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Bijaya L. Rai
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Robert C. Hider
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Surinder Singh
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Abstract

Metabolism and pharmacokinetics of 1-(2′-trimethylacetoxyethyl)-2-ethyl-3-hydroxypyridin-4-one (CP117) were studied in the rat. Urinary recovery studies were conducted in normal (oral and intravenous) and iron-overloaded rats (500 mg Fe/kg body weight; oral only). In normal rats, the majority of the dose recovered in the urine was as the hydrophilic metabolite, CP102, accounting for 69.7 ± 9.4% (oral) and 80.7 ± 7.9% (intravenous) of the administered dose. There was, however, a dramatic decrease in the amount of CP102 recovered (47.7 ± 5.9%) (p ≤ 0.05) in the iron-loaded group of animals. The amount of CP102 glucuronide conjugate recovered in the normal and iron-overloaded rats after oral administration of CP117 did not differ significantly with values of 6.5 ± 2.5% and 7.1 ± 2.5%, respectively. There was, however, a significant increase in CP102 glucuronide conjugate (13.7 ± 3.0%) (p ≤ 0.05) after intravenous administration of CP117. Urinary iron content was determined in the iron-overloaded and normal (oral) animals. Negligible levels of the CP117 iron complex and only 0.6 ± 0.2% was present as the corresponding CP102 complex in the urine of normal animals. Less than 0.1% of the administered dose was recovered as CP117-iron complex and only 1.3 ± 0.2% as CP102-iron complex in the iron-overloaded animals. Total recovery of the administered dose was significantly different between normal (po) and iron-overloaded groups of animals, decreasing from 76.4 ± 11.7% to 57.2 ± 9.6%, respectively (p ≤ 0.05). There was no significant difference between the two routes of administration in normal animals, with total recovery of the administered dose of CP117 being 96.1 ± 9.1% by the intravenous route.

Intravenous and oral pharmacokinetics of CP117 was studied in the rat at a fixed dose of 450 μmol/kg. The AUC of the drug was 43.2 ± 9.1 μmol/liter · hr and 4.1 ± 1.8 μmol/liter · hrvia the intravenous and oral routes, respectively, thus indicating that the systemic bioavailability of the drug is <10%. Pharmacokinetic parameters of the drug determined by the intravenous route indicate that CP117 has a plasma clearance of 10.9 ± 3.0 μmol/liter · hr, a mean residence time of 0.14 ± 0.05 hr, and volume of distribution at steady-state of 1.54 ± 0.52 liters · kg−1. The Cmax andtmax of CP117 were 12.1 ± 2.5 μmol/liter and 7.0 ± 2.7 min, respectively. The AUC of the main metabolite, CP102, decreased from 425.3 ± 8.5 μmol/liter · hr to 282 ± 31 μmol/liter · hr via the intravenous and oral routes, which is presumed to reflect differences in hepatic extraction and routes of elimination of the drug. Parallel absorption studies conducted using the in situ isolated rat gut loop model indicate that the majority of the administered dose was absorbed intact as the parent drug with mesenteric vein AUC values of 3.1 ± 1.7 mmol/liter · hr and 0.3 ± 0.04 mmol/liter · hr for CP117 and CP102, respectively.

Footnotes

  • Send reprint requests to: Dr. Surinder Singh, Department of Pharmacy, King’s College London, Manresa Road, Chelsea, London SW3 6LX, UK.

  • ↵2 Choudhury et al., unpublished observations.

  • ↵3 Singh et al., unpublished observations.

  • Abbreviations used are::
    DFO
    desferrioxamine
    HPO
    3-hydroxypyridin-4-one
    CP20
    1,2-dimethyl-3-hydroxypyridin-4-one
    CP94
    1,2-diethyl-3-hydroxypyridin-4-one
    CP102
    1-(2′-hydroxyethyl)-2-ethyl-3-hydroxypyridin-4-one
    GIT
    gastrointestinal tract
    CP117
    1-(2′-trimethylacetoxyethyl)-2-ethyl-3-hydroxypyridin-4-one
    CP41
    1-(3′-hydroxypropyl)-2-methyl-3-hydroxypyridin-4-one
    CP162
    1-(2′-trimethylacetoxyethyl)-2-methyl-3-hydroxypyridin-4-one
    PBS
    phosphate-buffered saline
    MeCN
    acetonitrile
    DMSO
    dimethylsulfoxide
    CP40
    1-(2′-trimethylacetoxyethyl)-2-methyl-3-(trimethylacetoxy)-pyridin-4-one
    DCM
    dichloromethane
    CV%
    coefficient of variation
    M%D
    mean percentage difference
    MQL
    minimum quantifiable level
    AUC
    area under the plasma concentration-time curve
    t1/2
    terminal half-life
    CL
    clearance
    CLR
    renal clearance
    AUMC
    area under the first-moment curve
    Vdss
    volume of distribution at steady-state
    MRT
    mean residence time
    MAT
    mean absorption time
    tmax
    time to peak
    Cmax
    peak plasma
    • Received July 31, 1996.
    • Accepted December 6, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Research ArticleArticle

Metabolism and Pharmacokinetics of 1-(2′-Trimethylacetoxyethyl)-2-ethyl-3-hydroxypyridin-4-one (CP117) in the rat

Ruksana Choudhury, Rafiu O. Epemolu, Bijaya L. Rai, Robert C. Hider and Surinder Singh
Drug Metabolism and Disposition March 1, 1997, 25 (3) 332-339;

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Research ArticleArticle

Metabolism and Pharmacokinetics of 1-(2′-Trimethylacetoxyethyl)-2-ethyl-3-hydroxypyridin-4-one (CP117) in the rat

Ruksana Choudhury, Rafiu O. Epemolu, Bijaya L. Rai, Robert C. Hider and Surinder Singh
Drug Metabolism and Disposition March 1, 1997, 25 (3) 332-339;
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