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Antimicrobial Agents and Chemotherapy, March 1998, p. 612-617, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Anti-Human Immunodeficiency Virus Activity and Cellular Metabolism of a Potential Prodrug of the Acyclic Nucleoside Phosphonate 9-R-(2-Phosphonomethoxypropyl)adenine (PMPA), Bis(isopropyloxymethylcarbonyl)PMPA

Brian L. Robbins,1 Ranga V. Srinivas,1 Choung Kim,2 Norbert Bischofberger,2 and Arnold Fridland1,3,*

Department of Infectious Diseases, St. Jude Children's Research Hospital,1 and Department of Pharmacology, University of Tennessee,3 Memphis, Tennessee, and Gilead Sciences, Foster City, California2

Received 8 September 1997/Returned for modification 19 November 1997/Accepted 19 December 1997

Bis(isopropyloxymethylcarbonyl) 9-R-(2-phosphonomethoxypropyl)adenine [bis(POC)PMPA] has been identified as a novel prodrug of PMPA. The anti-human immunodeficiency virus activity of bis(POC)PMPA was >100-fold greater than that of PMPA in both an established T-cell line and primary peripheral blood lymphocytes. This improved efficacy was shown to be due to a rapid intracellular uptake of the prodrug resulting in an increased intracellular accumulation of PMPA diphosphate (PMPApp), the pharmacologically active metabolite. PMPApp levels in bis(POC)PMPA-treated cells exceeded by >1,000-fold the levels seen in cells treated with unmodified PMPA in both resting and activated peripheral blood lymphocytes. Significant differences in the intracellular catabolism of PMPA metabolites were noted between the resting and activated lymphocytes. The half-life for the disappearance of PMPApp, derived from either bis(POC)PMPA or PMPA, was 12 to 15 h in the activated lymphocytes and 33 to 50 h in the resting lymphocytes. This long persistence of PMPApp, particularly in resting lymphocytes, may be unique to the nucleoside phosphonate analogs and indicates that effective levels of the active metabolite can be achieved and maintained with relatively infrequent administration of the parent drug.

* Corresponding author. Mailing address: Department of Infectious Diseases, SJCRH, 332 N. Lauderdale, Memphis, TN 38105. Phone: (901) 495-3459. Fax: (901) 495-3099. E-mail: arnold.fridland{at}stjude.org.

Antimicrobial Agents and Chemotherapy, March 1998, p. 612-617, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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