This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Naesens, L.
Right arrow Articles by De Clercq, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Naesens, L.
Right arrow Articles by De Clercq, E.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, July 1998, p. 1568-1573, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Antiretroviral Efficacy and Pharmacokinetics of Oral Bis(isopropyloxycarbonyloxymethyl)9-(2-Phosphonylmethoxypropyl)adenine in Mice

Lieve Naesens,1,* Norbert Bischofberger,2 Patrick Augustijns,3 Pieter Annaert,3 Guy Van den Mooter,3 Murty N. Arimilli,2 Choung U. Kim,2 and Erik De Clercq1

Rega Institute for Medical Research1 and Laboratory for Pharmacotechnology and Biopharmacy,3 Katholieke Universiteit Leuven, B-3000 Leuven, Belgium, and Gilead Sciences, Inc., Foster City, California 944042

Received 3 October 1997/Returned for modification 31 January 1998/Accepted 3 April 1998

To overcome the low oral bioavailability of the highly potent and selective antiretroviral agent (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA), a new lipophilic ester derivative, i.e., the bis(isopropyloxycarbonyloxymethyl)-ester [bis(POC)-PMPA], was prepared. The usefulness of bis(POC)-PMPA as an oral prodrug for PMPA was investigated in the intestinal mucosa Caco-2 cell monolayer model. The total transport of bis(POC)-PMPA was 2.7%, whereas it was less than 0.1% for PMPA. Bis(POC)-PMPA was considerably metabolized inside the epithelial cells, since the majority of the compound was recovered after transport in the form of the monoester metabolite [mono(POC)-PMPA]. In contrast, bis(POC)-PMPA was relatively resistant to degradation at the luminal side of the Caco-2 cells. Pharmacokinetic studies with mice showed that the oral bioavailability of bis(POC)-PMPA (calculated from the curves of the concentration of free PMPA in plasma) was 20%. Neither bis(POC)-PMPA nor mono(POC)-PMPA could be recovered in plasma, suggesting the efficient release of the active drug PMPA after oral administration of bis(POC)-PMPA. Severe combined immunodeficient (SCID) mice infected with Moloney murine sarcoma virus (MSV) and treated orally with bis(POC)-PMPA for 5 or 10 days (dosages, 50, 100, or 200 mg of PMPA equivalent per kg of body weight per day) showed a significant delay in MSV-induced tumor appearance and tumor-associated death. The antiviral efficacy of oral bis(POC)-PMPA was related to the dosage and treatment period and was not significantly different from that of subcutaneous PMPA given at an equivalent dose. The favorable pharmacokinetic profile, marked antiviral efficacy, and low toxicity make bis(POC)-PMPA an attractive oral prodrug of PMPA that should be further pursued in clinical studies with patients infected with human immunodeficiency virus or hepatitis B virus.

* Corresponding author. Mailing address: Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Phone: 32-16-337345. Fax: 32-16-337340. E-mail: lieve.naesens{at}rega.kuleuven.ac.be.

Antimicrobial Agents and Chemotherapy, July 1998, p. 1568-1573, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Wolf, K., Walter, H., Beerenwinkel, N., Keulen, W., Kaiser, R., Hoffmann, D., Lengauer, T., Selbig, J., Vandamme, A.-M., Korn, K., Schmidt, B. (2003). Tenofovir Resistance and Resensitization. Antimicrob. Agents Chemother. 47: 3478-3484 [Abstract] [Full Text]  
  • McColl, D. J., Miller, M. D. (2003). The use of tenofovir disoproxil fumarate for the treatment of nucleoside-resistant HIV-1. J Antimicrob Chemother 51: 219-223 [Full Text]  
  • van Gelder, J., Deferme, S., Naesens, L., De Clercq, E., van den Mooter, G., Kinget, R., Augustijns, P. (2002). Intestinal Absorption Enhancement of the Ester Prodrug Tenofovir Disoproxil Fumarate through Modulation of the Biochemical Barrier by Defined Ester Mixtures. Drug Metab. Dispos. 30: 924-930 [Abstract] [Full Text]  
  • Harrigan, P. R., Miller, M. D., McKenna, P., Brumme, Z. L., Larder, B. A. (2002). Phenotypic Susceptibilities to Tenofovir in a Large Panel of Clinically Derived Human Immunodeficiency Virus Type 1 Isolates. Antimicrob. Agents Chemother. 46: 1067-1072 [Abstract] [Full Text]  
  • Van Gelder, J., Deferme, S., Annaert, P., Naesens, L., De Clercq, E., Van den Mooter, G., Kinget, R., Augustijns, P. (2001). Increased Absorption of the Antiviral Ester Prodrug Tenofovir Disoproxil in Rat Ileum by Inhibiting Its Intestinal Metabolism. Drug Metab. Dispos. 28: 1394-1396 [Abstract] [Full Text]  
  • Shoshani, I., Laux, W. H. G., Perigaud, C., Gosselin, G., Johnson, R. A. (1999). Inhibition of Adenylyl Cyclase by Acyclic Nucleoside Phosphonate Antiviral Agents. J. Biol. Chem. 274: 34742-34744 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»