Disposition of [1'-14C]Stavudine after Oral Administration to Humans

Disposition of [1'-14C]Stavudine after Oral Administration to Humans

The disposition of stavudine, a potent and orally active nucleoside reverse transcriptase inhibitor, was investigated in six healthy human subjects. Before dosing humans with [1'-(14)C]stavudine, a tissue distribution study was performed in Long-Evans rats. Results from this study showed no acc...

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Bibliographic Details
Published in:Drug metabolism and disposition Vol. 38; no. 4; pp. 655 - 666
Main Authors: LIAN ZHOU, KAUL, Sanjeev, LIU-KREYCHE, Peggy, TRAN, Scott B, ESPINA, Robert R, WARRACK, Bethanne M, ROONGTA, Vikram A, LYER, Ramaswamy A
Format: Journal Article
Language:English
Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01-04-2010
Subjects:
Administration, Oral
Animals
Anti-HIV Agents - administration & dosage
Anti-HIV Agents - pharmacokinetics
Area Under Curve
Biological and medical sciences
Biotransformation
Chromatography, High Pressure Liquid
Feces - chemistry
Humans
Hydrolysis
In Vitro Techniques
Isotope Labeling
Magnetic Resonance Spectroscopy
Mass Spectrometry
Medical sciences
Microsomes, Liver - metabolism
Pharmacology. Drug treatments
Rats
Rats, Long-Evans
Ribose - metabolism
Stavudine - administration & dosage
Stavudine - pharmacokinetics
Tissue Distribution
Human
Antiretroviral agent
RNA-directed DNA polymerase
Enzyme
Transferases
Oral administration
Enzyme inhibitor
Stavudine
Nucleotidyltransferases
Dideoxynucleoside
Reverse transcriptase inhibitor
Nucleoside analog
Antiviral
Pharmacokinetics
Pyrimidine nucleoside
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Summary:The disposition of stavudine, a potent and orally active nucleoside reverse transcriptase inhibitor, was investigated in six healthy human subjects. Before dosing humans with [1'-(14)C]stavudine, a tissue distribution study was performed in Long-Evans rats. Results from this study showed no accumulation of radioactivity in any of the tissues studied, indicating that the position of the (14)C-label on the molecule was appropriate for the human study. After a single 80-mg (100 microCi) oral dose of [1'-(14)C]stavudine, approximately 95% of the radioactive dose was excreted in urine with an elimination half-life of 2.35 h. Fecal excretion was limited, accounting for only 3% of the dose. Unchanged stavudine was the major drug-related component in plasma (61% of area under the plasma concentration-time curve from time zero extrapolated to infinite time of the total plasma radioactivity) and urine (67% of dose). The remaining radioactivity was associated with minor metabolites, including mono- and bis-oxidized stavudine, glucuronide conjugates of stavudine and its oxidized metabolite, and an N-acetylcysteine (NAC) conjugate of the ribose (M4) after glycosidic cleavage. Formation of metabolite M4 was shown in human liver microsomes incubated with 2',3'-didehydrodideoxyribose, the sugar base of stavudine, in the presence of NAC. In addition, after similar microsomal incubations fortified with GSH, two GSH conjugates, 3'-GS-deoxyribose and 1'-keto-2',3'-dideoxy-3'-GS-ribose, were observed. This suggests that 2',3'-didehydrodideoxyribose underwent cytochrome P450-mediated oxidation leading to an epoxide intermediate, 2',3'-ribose epoxide, followed by GSH addition. In conclusion, absorption and elimination of stavudine were rapid and complete after oral dosing, with urinary excretion of unchanged drug as the predominant route of elimination in humans.
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ISSN:0090-9556
1521-009X
DOI:10.1124/dmd.109.030239