Document Detail

Biphasic elimination of tenofovir diphosphate and nonlinear pharmacokinetics of zidovudine triphosphate in a microdosing study.
MedLine Citation:
PMID:  23187888     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Clinical Trial; Journal Article; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
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:
Created Date:  2012-11-28     Completed Date:  2013-02-04     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  100892005     Medline TA:  J Acquir Immune Defic Syndr     Country:  United States    
Other Details:
Languages:  eng     Pagination:  593-9     Citation Subset:  IM; X    
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MeSH Terms
Adenine / administration & dosage,  analogs & derivatives*,  blood,  pharmacokinetics
Anti-HIV Agents / administration & dosage*,  blood,  pharmacokinetics*
Biological Availability
CD4-Positive T-Lymphocytes / metabolism
Carbon Radioisotopes
Dideoxynucleotides / administration & dosage*,  blood,  pharmacokinetics*
Mass Spectrometry
Middle Aged
Organophosphonates / administration & dosage*,  blood,  pharmacokinetics*
Reverse Transcriptase Inhibitors / administration & dosage,  blood,  pharmacokinetics
Thymine Nucleotides / administration & dosage*,  blood,  pharmacokinetics*
Zidovudine / administration & dosage,  analogs & derivatives*,  blood,  pharmacokinetics
Grant Support
Reg. No./Substance:
0/Anti-HIV Agents; 0/Carbon Radioisotopes; 0/Dideoxynucleotides; 0/Organophosphonates; 0/Reverse Transcriptase Inhibitors; 0/Thymine Nucleotides; 0/tenofovir disoproxil; 4B9XT59T7S/Zidovudine; 92586-35-1/3'-azido-3'-deoxythymidine 5'-triphosphate; JAC85A2161/Adenine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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