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Review ArticleReview

Toxicokinetics of 2′,3′-Didehydro-3′-Deoxythymidine, Stavudine (D4T)

Sanjeev Kaul, Kishor A. Dandekar, Beth E. Schilling and Rashmi H. Barbhaiya
Drug Metabolism and Disposition January 1999, 27 (1) 1-12;
Sanjeev Kaul
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Kishor A. Dandekar
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Beth E. Schilling
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Rashmi H. Barbhaiya
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Abstract

The toxicokinetic profile of D4T was assessed by conducting in vivo and in vitro studies. In the various studies, the i.v. and oral doses ranged from 12.5 to 600 and 5 to 2000 mg/kg, respectively. D4T was rapidly absorbed with an absolute oral bioavailability ranging from 77 to 100% in various species. The steady-state volume of distribution of D4T ranged from 0.50 to 1.12 liters/kg; radioactivity was distributed in all tissues, with the highest concentrations in the organs of excretion, liver and kidneys. D4T was eliminated from the body with a half-life of 0.30 to 1.23 h. Urinary recovery of unchanged drug was species-dependent and ranged from approximately 37 to 86%. In the mass balance studies, the recovery of total radioactivity at 96 h in rats and monkeys was approximately 85% and 50%, respectively; fecal recovery was <1.5% and approximately 14% was recovered as 14CO2 in expired air in rats. The in vitro protein binding of D4T was negligible (<10%) and D4T did not induce cytochrome P-450 in rats or monkeys. D4T was metabolized to thymine and polar metabolites by the S9 and liver slices in vitro. Significant interspecies correlations were found for total body clearance, steady state of volume of distribution, andT1/2 and species body weight. The multiples of exposure observed at the various no-effect doses in the drug safety evaluation studies (10× – 1102×) affirm that adequate doses of D4T were administered to laboratory animals to discern potential human risk.

Footnotes

  • Send reprint requests to: Dr. Sanjeev Kaul, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000.

  • ↵1 Present address: Berlex Laboratories, 300 Fairfield Road, Wayne, NJ.

  • Abbreviations used are::
    LSS
    liquid scintillation spectrophotometry
    CYP450
    cytochrome P-450
    HPLC
    high-performance liquid chromatography
    AUC
    area under the concentration-time curve
    CL
    total body clearance
    CLR
    renal clearance
    CLNR
    nonrenal clearance
    Vss
    steady-state volume of distribution
    Cmax
    peak concentration
    Tmax
    time of peak concentration
    UR
    urinary recovery
    D4T
    stavudine
    DDC
    lamivudinr
    DDI
    didanosine
    ZDV
    zidovudine
    • Received January 30, 1998.
    • Accepted August 7, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (1)
Drug Metabolism and Disposition
Vol. 27, Issue 1
1 Jan 1999
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Review ArticleReview

Toxicokinetics of 2′,3′-Didehydro-3′-Deoxythymidine, Stavudine (D4T)

Sanjeev Kaul, Kishor A. Dandekar, Beth E. Schilling and Rashmi H. Barbhaiya
Drug Metabolism and Disposition January 1, 1999, 27 (1) 1-12;

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Review ArticleReview

Toxicokinetics of 2′,3′-Didehydro-3′-Deoxythymidine, Stavudine (D4T)

Sanjeev Kaul, Kishor A. Dandekar, Beth E. Schilling and Rashmi H. Barbhaiya
Drug Metabolism and Disposition January 1, 1999, 27 (1) 1-12;
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