| Biphasic elimination of tenofovir diphosphate and nonlinear pharmacokinetics of zidovudine triphosphate in a microdosing study. | |
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MedLine Citation:
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PMID: 23187888 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVE: Phase 0 studies can provide initial pharmacokinetics (PKs) data in humans and help to facilitate early drug development, but their predictive value for standard dosing is controversial. To evaluate the prediction of microdosing for active intracellular drug metabolites, we compared the PK profile of 2 antiretroviral drugs, zidovudine (ZDV) and tenofovir (TFV), in microdose and standard dosing regimens. STUDY DESIGN: We administered a microdose (100 μg) of C-labeled drug (ZDV or tenofovir disoproxil fumarate) with or without a standard unlabelled dose (300 mg) to healthy volunteers. Both the parent drug in plasma and the active metabolite, ZDV-triphosphate (ZDV-TP) or TFV-diphosphate (TFV-DP) in peripheral blood mononuclear cells (PBMCs) and CD4 cells were measured by accelerator mass spectrometry. RESULTS: The intracellular ZDV-TP concentration increased less than proportionally over the dose range studied (100 μg-300 mg), whereas the intracellular TFV-DP PKs were linear over the same dose range. ZDV-TP concentrations were lower in CD4 cells versus total PBMCs, whereas TFV-DP concentrations were not different in CD4 cells and PBMCs. CONCLUSIONS: Our data were consistent with a rate-limiting step in the intracellular phosphorylation of ZDV but not TFV. Accelerator mass spectrometry shows promise for predicting the PK of active intracellular metabolites of nucleosides, but nonlinearity of PK may be seen with some drugs. |
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Authors:
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Jianmeng Chen; Charles Flexner; Rosa G Liberman; Paul L Skipper; Nicolette A Louissaint; Steven R Tannenbaum; Craig W Hendrix; Edward J Fuchs |
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Publication Detail:
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Type: Clinical Trial; Journal Article; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of acquired immune deficiency syndromes (1999) Volume: 61 ISSN: 1944-7884 ISO Abbreviation: J. Acquir. Immune Defic. Syndr. Publication Date: 2012 Dec |
Date Detail:
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Created Date: 2012-11-28 Completed Date: 2013-02-04 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 100892005 Medline TA: J Acquir Immune Defic Syndr Country: United States |
Other Details:
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Languages: eng Pagination: 593-9 Citation Subset: IM; X |
Affiliation:
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Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenine
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administration & dosage,
analogs & derivatives*,
blood,
pharmacokinetics Adult Anti-HIV Agents / administration & dosage*, blood, pharmacokinetics* Biological Availability CD4-Positive T-Lymphocytes / metabolism Carbon Radioisotopes Dideoxynucleotides / administration & dosage*, blood, pharmacokinetics* Female Humans Male Mass Spectrometry Middle Aged Organophosphonates / administration & dosage*, blood, pharmacokinetics* Phosphorylation Reverse Transcriptase Inhibitors / administration & dosage, blood, pharmacokinetics Thymine Nucleotides / administration & dosage*, blood, pharmacokinetics* Zidovudine / administration & dosage, analogs & derivatives*, blood, pharmacokinetics |
| Grant Support | |
ID/Acronym/Agency:
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UL1-RR025005/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Anti-HIV Agents; 0/Carbon Radioisotopes; 0/Dideoxynucleotides; 0/Organophosphonates; 0/Reverse Transcriptase Inhibitors; 0/Thymine Nucleotides; 0/tenofovir disoproxil; 30516-87-1/Zidovudine; 73-24-5/Adenine; 92586-35-1/3'-azido-3'-deoxythymidine 5'-triphosphate |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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