title: Intracellular studies of the nucleoside reverse transcriptase inhibitor active metabolites: a review.
abstract: Nucleoside reverse transcriptase inhibitors (NRTIs) plasma concentrations do not correlate with clinical efficacy or toxicity. These agents need to be phosphorylated to become active against HIV-infection. Thus, the characterization of the NRTIs intracellular metabolite pharmacological parameters will provide a better understanding that could lead to the development of more rational dose regimens in the HIV-infected population. Furthermore, intracellular measurements of NRTIs may provide a better marker with respect to clinical efficacy and toxicity than plasma concentrations. Thus, in this article we review the latest information regarding the intracellular pharmacological parameters of zidovudine (ZDV) and lamivudine (3TC) active metabolites in HIV-infected patients including the results from our recent clinical studies. We will start the discussion with ZDV and 3TC clinical efficacy, followed by systemic pharmacokinetics studies. We will then discuss the in vitro and in vivo intracellular studies with particular emphasis in the method development to measure these metabolites and we will conclude with the most current data from our clinical trials.
authors.affiliation: Department of Biochemistry, University of Puerto Rico School of Medicine, San Juan 00936-5067. j_rodriguez@rcmaxp.upr.clu.edu
authors.forename: J F
authors.initials: JF
authors.lastname: Rodriguez Orengo
authors.forename: J
authors.initials: J
authors.lastname: Santana
authors.forename: I
authors.initials: I
authors.lastname: Febo
authors.forename: C
authors.initials: C
authors.lastname: Diaz
authors.forename: J L
authors.initials: JL
authors.lastname: Rodriguez
authors.forename: R
authors.initials: R
authors.lastname: Garcia
authors.forename: E
authors.initials: E
authors.lastname: Font
authors.forename: O
authors.initials: O
authors.lastname: Rosario
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000963:Antimetabolites / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D002648:Child; D002851:Chromatography, High Pressure Liquid; D002986:Clinical Trials as Topic; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010710:Phosphates / Q000378:metabolism; D010766:Phosphorylation; D011122:Polyphosphates / Q000378:metabolism; D011863:Radioimmunoassay; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors; D015215:Zidovudine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; D000963:Antimetabolites; D010710:Phosphates; D011122:Polyphosphates; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; C005692:triphosphoric acid