Antimicrob Agents Chemother. 1998 Mar;42(3):612-7.

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.

Robbins BL, Srinivas RV, Kim C, Bischofberger N, Fridland A.

Source

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Abstract

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.

PMID:: 9517941; [PubMed - indexed for MEDLINE]
PMCID: PMC105507

Free PMC Article

Images from this publication.See all images (3) Free text

Publication Types, MeSH Terms, Substances, Grant Support

Publication Types

MeSH Terms

Substances

Grant Support

LinkOut - more resources

Full Text Sources

Medical

HIV/AIDS Medicines - MedlinePlus Health Information

Supplemental Content

Related citations

Antiviral activities of 9-R-2-phosphonomethoxypropyl adenine (PMPA) and bis(isopropyloxymethylcarbonyl)PMPA against various drug-resistant human immunodeficiency virus strains. [Antimicrob Agents Chemother. 1998]
Antiviral activities of 9-R-2-phosphonomethoxypropyl adenine (PMPA) and bis(isopropyloxymethylcarbonyl)PMPA against various drug-resistant human immunodeficiency virus strains.
Srinivas RV, Fridland A. Antimicrob Agents Chemother. 1998 Jun; 42(6):1484-7.
Antiretroviral efficacy and pharmacokinetics of oral bis(isopropyloxycarbonyloxymethyl)-9-(2-phosphonylmethoxypropyl)adenine in mice. [Antimicrob Agents Chemother. 1998]
Antiretroviral efficacy and pharmacokinetics of oral bis(isopropyloxycarbonyloxymethyl)-9-(2-phosphonylmethoxypropyl)adenine in mice.
Naesens L, Bischofberger N, Augustijns P, Annaert P, Van den Mooter G, Arimilli MN, Kim CU, De Clercq E. Antimicrob Agents Chemother. 1998 Jul; 42(7):1568-73.
Metabolism of GS-7340, a novel phenyl monophosphoramidate intracellular prodrug of PMPA, in blood. [Nucleosides Nucleotides Nucleic Acids. 2001...]
Metabolism of GS-7340, a novel phenyl monophosphoramidate intracellular prodrug of PMPA, in blood.
Eisenberg EJ, He GX, Lee WA. Nucleosides Nucleotides Nucleic Acids. 2001 Apr-Jul; 20(4-7):1091-8.
Review Tenofovir disoproxil fumarate: a nucleotide reverse transcriptase inhibitor for the treatment of HIV infection. [Clin Ther. 2002]
Review Tenofovir disoproxil fumarate: a nucleotide reverse transcriptase inhibitor for the treatment of HIV infection.
Fung HB, Stone EA, Piacenti FJ. Clin Ther. 2002 Oct; 24(10):1515-48.
Review Novel approaches for designing 5'-O-ester prodrugs of 3'-azido-2', 3'-dideoxythymidine (AZT). [Curr Med Chem. 2000]
Review Novel approaches for designing 5'-O-ester prodrugs of 3'-azido-2', 3'-dideoxythymidine (AZT).
Parang K, Wiebe LI, Knaus EE. Curr Med Chem. 2000 Oct; 7(10):995-1039.

See reviews... See all...

Cited by 31 PubMed Central articles

A multi-compartment, single and multiple dose pharmacokinetic study of the vaginal candidate microbicide 1% tenofovir gel. [PLoS One. 2011]
A multi-compartment, single and multiple dose pharmacokinetic study of the vaginal candidate microbicide 1% tenofovir gel.
Schwartz JL, Rountree W, Kashuba AD, Brache V, Creinin MD, Poindexter A, Kearney BP. PLoS One. 2011; 6(10):e25974. Epub 2011 Oct 19.
New approaches in the management of chronic hepatitis B: role of tenofovir. [Infect Drug Resist. 2009]
New approaches in the management of chronic hepatitis B: role of tenofovir.
Reijnders JG, LA Janssen H. Infect Drug Resist. 2009; 2:13-26. Epub 2009 Apr 24.
Review Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection. [J Antimicrob Chemother. 2011]
Review Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection.
Anderson PL, Kiser JJ, Gardner EM, Rower JE, Meditz A, Grant RM. J Antimicrob Chemother. 2011 Feb; 66(2):240-50. Epub 2010 Nov 30.

See all...

Related information

Related Citations
Calculated set of PubMed citations closely related to the selected article(s) retrieved using a word weight algorithm. Related articles are displayed in ranked order from most to least relevant, with the “linked from” citation displayed first.
Compound
PubChem chemical compound records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records. Multiple substance records may contribute to the PubChem compound record.
Compound (MeSH Keyword)
PubChem chemical compound records that are classified under the same Medical Subject Headings (MeSH) controlled vocabulary as the current articles.
References for this PMC Article
Citation referenced in PubMed article. Only valid for PubMed citations that are also in PMC.
Substance
PubChem chemical substance records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records.
Substance (MeSH Keyword)
PubChem chemical substance (submitted) records that are classified under the same Medical Subject Headings (MeSH) controlled vocabulary as the current articles.
Free in PMC
Free full text articles in PMC
Cited in PMC
Full-text articles in the PubMed Central Database that cite the current articles.

Recent activity

Clear Turn Off Turn On

Anti-human immunodeficiency virus activity and cellular metabolism of a potentia...
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.
Antimicrob Agents Chemother. 1998 Mar ;42(3):612-7.

PubMed
Evidence of in vitro development of drug resistance to azidothymidine in T-lymph...
Evidence of in vitro development of drug resistance to azidothymidine in T-lymphocytic leukemia cell lines (Jurkat E6-1/AZT-100) and in pediatric patients with HIV-1 infection.
J Acquir Immune Defic Syndr. 1993 Dec ;6(12):1287-96.

PubMed
High-dose pentoxifylline in patients with AIDS: inhibition of tumor necrosis fac...
High-dose pentoxifylline in patients with AIDS: inhibition of tumor necrosis factor production. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group.
J Infect Dis. 1995 Jun ;171(6):1628-32.

PubMed
Alkalemia-associated morbidity and mortality in medical and surgical patients.
Alkalemia-associated morbidity and mortality in medical and surgical patients.
South Med J. 1987 Jun ;80(6):729-33.

PubMed
Stages of progression in drug involvement from adolescence to adulthood: further...
Stages of progression in drug involvement from adolescence to adulthood: further evidence for the gateway theory.
J Stud Alcohol. 1992 Sep ;53(5):447-57.

PubMed

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

PubMed

Display Settings:

Send to: