دورية أكاديمية
أعرض في EDS

Biphasic elimination of tenofovir diphosphate and nonlinear pharmacokinetics of zidovudine triphosphate in a microdosing study.

التفاصيل البيبلوغرافية
العنوان: Biphasic elimination of tenofovir diphosphate and nonlinear pharmacokinetics of zidovudine triphosphate in a microdosing study.
المؤلفون: Chen J; Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Flexner C, Liberman RG, Skipper PL, Louissaint NA, Tannenbaum SR, Hendrix CW, Fuchs EJ
المصدر: Journal of acquired immune deficiency syndromes (1999) [J Acquir Immune Defic Syndr] 2012 Dec 15; Vol. 61 (5), pp. 593-9.
نوع المنشور: Clinical Trial; Journal Article; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Lippincott Williams & Wilkins, Inc Country of Publication: United States NLM ID: 100892005 Publication Model: Print Cited Medium: Internet ISSN: 1944-7884 (Electronic) Linking ISSN: 15254135 NLM ISO Abbreviation: J Acquir Immune Defic Syndr Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Hagerstown, MD : Lippincott Williams & Wilkins, Inc., c1999-
مواضيع طبية MeSH: Adenine/*analogs & derivatives , Anti-HIV Agents/*administration & dosage , Anti-HIV Agents/*pharmacokinetics , Dideoxynucleotides/*administration & dosage , Dideoxynucleotides/*pharmacokinetics , Organophosphonates/*administration & dosage , Organophosphonates/*pharmacokinetics , Thymine Nucleotides/*administration & dosage , Thymine Nucleotides/*pharmacokinetics , Zidovudine/*analogs & derivatives, Adenine/administration & dosage ; Adenine/blood ; Adenine/pharmacokinetics ; Adult ; Anti-HIV Agents/blood ; Biological Availability ; CD4-Positive T-Lymphocytes/metabolism ; Carbon Radioisotopes ; Dideoxynucleotides/blood ; Female ; Humans ; Male ; Mass Spectrometry ; Middle Aged ; Organophosphonates/blood ; Phosphorylation ; Reverse Transcriptase Inhibitors/administration & dosage ; Reverse Transcriptase Inhibitors/blood ; Reverse Transcriptase Inhibitors/pharmacokinetics ; Tenofovir ; Thymine Nucleotides/blood ; Zidovudine/administration & dosage ; Zidovudine/blood ; Zidovudine/pharmacokinetics
مستخلص: 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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معلومات مُعتمدة: UL1 RR025005 United States RR NCRR NIH HHS; UL1-RR025005 United States RR NCRR NIH HHS
المشرفين على المادة: 0 (Anti-HIV Agents)
0 (Carbon Radioisotopes)
0 (Dideoxynucleotides)
0 (Organophosphonates)
0 (Reverse Transcriptase Inhibitors)
0 (Thymine Nucleotides)
4B9XT59T7S (Zidovudine)
6RGF96R053 (zidovudine triphosphate)
99YXE507IL (Tenofovir)
JAC85A2161 (Adenine)
تواريخ الأحداث: Date Created: 20121129 Date Completed: 20130204 Latest Revision: 20211021
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC3509498
DOI: 10.1097/QAI.0b013e3182717c98
PMID: 23187888
قاعدة البيانات: MEDLINE
الوصف
تدمد:1944-7884
DOI:10.1097/QAI.0b013e3182717c98