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Antimicrobial Agents and Chemotherapy, May 2002, p. 1357-1363, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1357-1363.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics of Amino Acid Phosphoramidate Monoesters of Zidovudine in Rats

Heng Song,1,{dagger} George W. Griesgraber,2 Carston R. Wagner,2* and Cheryl L. Zimmerman1*

Departments of Pharmaceutics,1 Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 554552

Received 2 July 2001/ Returned for modification 17 November 2001/ Accepted 25 January 2002

In vitro studies have demonstrated that water-soluble, nontoxic phosphoramidates of azidothymidine (zidovudine [AZT]) have significant and specific anti-human immunodeficiency virus and anticancer activity. Although polar, these compounds are internalized and processed to the corresponding nucleoside monophosphates. Eight methyl amide and methyl ester phosphoramidate monoesters composed of D- or L-phenylalanine or tryptophan and AZT were synthesized. The plasma stability and protein binding studies were carried out in vitro. Then in vivo pharmacokinetic evaluations of six of the compounds were conducted. Sprague-Dawley rats received each compound by intravenous bolus dose, and serial blood and urine samples were collected. AZT and phosphoramidate concentrations in plasma and urine were quantitated by high-performance liquid chromatography with UV or fluorescence detection. Pharmacokinetic parameters were calculated by standard noncompartmental means. The plasma half-lives of the phosphoramidates were 10- to 20-fold longer than the half-life of AZT. Although the renal clearances of the phosphoramidates were similar to AZT, their total body clearances were significantly greater than that of AZT. The 3- to 15-fold-larger volume of distribution (Vss) for the phosphoramidates relative to AZT appeared to be dependent on the stereochemistry of the amino acid, with the largest values being associated with the L-amino acids. The increased Vss indicates a much greater tissue distribution of the phosphoramidate prodrugs than of AZT. Amino acid phosphoramidate monoesters of AZT have improved pharmacokinetic properties over AZT and significant potential as in vivo pronucleotides.

* Corresponding author. Mailing address for Cheryl L. Zimmerman: College of Pharmacy, University of Minnesota, 9-149 Weaver-Densford Hall, 308 Harvard St., S.E., Minneapolis, MN 55455. Phone: (612) 625-4611. Fax: (612) 626-2125. E-mail: zimme005{at}tc.umn.edu. Mailing address for Carston R. Wagner: College of Pharmacy, University of Minnesota, 8-106 Weaver-Densford Hall, 308 Harvard St., Minneapolis, MN 55455. Phone: (612) 625-2614. Fax: (612) 624-0139. E-mail: wagne003{at}tc.umn.edu.

{dagger} Present address: Department of Clinical Pharmacology, Quintiles, Inc., Kansas City, MO 64134.

Antimicrobial Agents and Chemotherapy, May 2002, p. 1357-1363, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1357-1363.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.





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