Clinical pharmacokinetics of 3′‐azido‐3′‐deoxythymidine (zidovudine) and catabolites with formation of a toxic catabolite, 3′‐amino‐3′‐deoxythymidine

M. Patrick Stagg, Erika M. Cretton, Lauren Kidd, Robert B. Diasio, Jean‐Pierre ‐P Sommadossi

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Abstract

This study investigated pharmacokinetics and metabolism of 3′‐azido‐3′‐deoxythymidine (zidovudine) in patients after a 1‐hour intravenous infusion of 2.5 mg/kg zidovudine with a radiolabeled tracer amount of [5‐3H] ‐zidovudine. In addition to unchanged drug and its 5′‐O‐glucuronide (zidovudine glucuronide), two novel catabolites of zidovudine were detected as 3′‐amino‐3′‐deoxythymidine (AMT), and its 5′‐O‐glucuronide (GAMT). The AMT apparent plasma elimination half‐life (2.70 ± 0.7 hours) was longer than that of zidovudine (1.20 ± 0.30 hours) and zidovudine glucuronide (1.60 ± 0.5 hours). The zidovudine/AMT plasma peak concentration and area under the concentration‐time curve ratios were approximately 8 and 5, respectively. Urinary recovery of radioactivity was essentially complete within 24 hours. AMT glucuronide was not detected in urine or plasma, and only low levels of this catabolite were detected in bile. In contrast, AMT was not detected in bile. The substantial levels of AMT in the plasma of patients after zidovudine administration suggests that this catabolite may affect the pharmacodynamic properties of zidovudine in relation to its activity against human immunodeficiency virus replication and cytotoxicity to host cells. Clinical Pharmacology and Therapeutics (1992) 51, 668–676; doi:

Original languageEnglish (US)
Pages (from-to)668-676
Number of pages9
JournalClinical Pharmacology & Therapeutics
Volume51
Issue number6
DOIs
StatePublished - Jun 1992

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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