Toxicokinetics of 2',3'-didehydro-3'-deoxythymidine, stavudine (D4T).
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, and T1/2 and species body weight. The multiples of exposure observed at the various no-effect doses in the drug safety evaluation studies (10x - 1102x) affirm that adequate doses of D4T were administered to laboratory animals to discern potential human risk.
Kaul
S
S
Metabolism and Pharmacokinetics and Drug Safety Evaluation, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
Dandekar
K A
KA
Schilling
B E
BE
Barbhaiya
R H
RH
D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001682:Biological Availability; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006207:Half-Life; D007275:Injections, Intravenous; D007774:Lactation / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D018119:Stavudine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D018119:Stavudine