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Arzneimittelforschung 2004; 54(11): 732-745
DOI: 10.1055/s-0031-1297030
Antibiotika · Chemotherapeutika · Virustatika · Zytostatika
Editio Cantor Verlag Aulendorf (Germany)

In vitro and in vivo Pharmacokinetic Features and Metabolism of the Novel Cytotoxic Nucleoside Analog 3’-Azidothymidine 5’- [p-Methoxyphenyl Methoxyalaninyl Phosphate] (Compound 003)

Fatih M. Uckun
Drug Discovery Program, Parker Hughes Institute, St. Paul, Minnesota, USA
,
Chun-Lin Chen
Drug Discovery Program, Parker Hughes Institute, St. Paul, Minnesota, USA
,
Xing-Ping Liu
Drug Discovery Program, Parker Hughes Institute, St. Paul, Minnesota, USA
,
Ilker Dibirdik
Drug Discovery Program, Parker Hughes Institute, St. Paul, Minnesota, USA
,
Taracad K. Venkatachalam
Drug Discovery Program, Parker Hughes Institute, St. Paul, Minnesota, USA
› Author Affiliations
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Publication History

Publication Date:
24 December 2011 (online)

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Summary

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.

Zusammenfassung

Pharmakokinetische Eigenschaften und Metabolismus in vitro und in vivo des neuen zytotoxischen Nukleosid-Analogs 3’-Azidothymidin-5’-[p-methoxyphenyl-methoxyalaninyl-phosphat] (Substanz 003)

Die pharmakokinetischen Eigenschaften und der Metabolismus des neuen zytotoxischen Nukleosid-Analogs Substanz 003 (3’-Azidothymidin-5’-[p-methoxyphenyl-methoxyalaninyl-phosphat], CAS 149560-32-7) wurde an humanen Krebszellen sowie an Mäusen untersucht. Nach intravenöser oder oraler Verabreichung an Mäuse wurde Substanz 003 schnell zu den Metaboliten ala-AZT-MP (CAS 209214-06-2) und Zidovudin (Azidothymidin, AZT, CAS 30516-87-1) umgewandelt. Die Resultate deuten darauf hin, daß Paraoxon-sensitive Carboxyesterasen bei der Konversion der Substanz 003 zu ala-AZT-MP eine wesentliche Rolle spielen. Die vorliegende Studie bildet die Basis für zukünftige prärklinische und klinische pharmakodynamische Studien mit Substanz 003.

Key words

CAS 149560-32-7 - Compound 003 - Nucleoside analog - Zidovudine derivative, metabolism, pharmacokinetics