In vitro and in vivo pharmacokinetic features and metabolism of the novel cytotoxic nucleoside analog 3'-azidothymidine 5'-[p-methoxyphenyl methoxyalaninyl phosphate] (Compound 003).

Abstract

The pharmacokinetic features and metabolism of the novel cytotoxic nucleoside analog Compound 003 (3'-azidothymidine 5'-[p-methoxyphenyl methoxyalaninyl phosphate], CAS 149560-32-7) were studied in both human cancer cells and mice. In mice, Compound 003 was rapidly converted into ala-AZT-MP (CAS 209214-06-2) and zidovudine (azidothymidine, AZT, CAS 30516-87-1). Maximum ala-AZT-MP concentrations were reached almost immediately (tmax < 5 min), while 50.4 min and 143.5 min were required to reach maximum AZT concentrations after intravenous and oral administration, respectively. The results indicate that paraoxon-sensitive carboxylesterases play an important role in the conversion of Compound 003 to ala-AZT-MP. This study provides the basis for future preclinical as well as clinical pharmacodynamic studies of Compound 003.

• Authors: Fatih M Uckun, Chun-Lin Chen, Xing-Ping Liu, Ilker Dibirdik, Taracad K Venkatachalam
• Journal: Arzneimittel-Forschung (Arzneimittelforschung) Vol. 54 Issue 11 Pg. 732-45 ( 2004) ISSN: 0004-4172 [Print] Germany
• PMID: 15612614 (Publication Type: Journal Article)

Chemical References

• 3'-azidothymidine 5'-(p-methoxyphenyl methoxyalaninyl phosphate)
• Antineoplastic Agents
• Dideoxynucleotides
• Zidovudine
• Esterases
• Paraoxon

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (administration & dosage, metabolism, pharmacokinetics)
• Body Fluids (metabolism)
• Cell Line, Tumor
• Chromatography, High Pressure Liquid
• Chromatography, Thin Layer
• Dideoxynucleotides
• Dose-Response Relationship, Drug
• Esterases (antagonists & inhibitors)
• Female
• Gastric Mucosa (metabolism)
• Injections, Intravenous
• Intestinal Mucosa (metabolism)
• Magnetic Resonance Spectroscopy
• Mass Spectrometry
• Mice
• Paraoxon (pharmacology)
• Pilot Projects
• Spectrophotometry, Ultraviolet
• Subcellular Fractions (metabolism)
• Zidovudine (administration & dosage, analogs & derivatives, metabolism, pharmacokinetics)