Simultaneous measurement of intracellular triphosphate metabolites of zidovudine, lamivudine and abacavir (carbovir) in human peripheral blood mononuclear cells by combined anion exchange solid phase extraction and LC–MS/MS

All nucleoside reverse transcriptase inhibitors (NRTI) must first be metabolized to their triphosphate forms in order to be active against HIV. Zidovudine (ZDV), abacavir (ABC) and lamivudine (3TC) have proven to be an efficacious combination. In order simultaneously to measure intracellular levels...

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Published in:	Journal of chromatography. B, Analytical technologies in the biomedical and life sciences Vol. 850; no. 1; pp. 310 - 317
Main Authors:	Robbins, Brian L., Poston, Philip A., Neal, Erin F., Slaughter, Clive, Rodman, John H.
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier B.V 01-05-2007 Elsevier Science
Subjects:	Analysis Analytical, structural and metabolic biochemistry Antiviral drug metabolism Biological and medical sciences Carbovir triphosphate Chromatography, High Pressure Liquid - methods Dideoxynucleosides - blood Fundamental and applied biological sciences. Psychology General pharmacology HIV Infections - blood Human immunodeficiency virus Humans Lamivudine - blood Lamivudine triphosphate Medical sciences Pharmacology. Drug treatments Phosphates - blood Reference Standards Reverse Transcriptase Inhibitors - blood Tandem Mass Spectrometry - methods Zidovudine - blood Zidovudine triphosphate Zidovudine triphosphate Carbovir triphosphate Human immunodeficiency virus Lamivudine triphosphate Antiviral drug metabolism Solid phase extraction Purine nucleoside Antiretroviral agent RNA-directed DNA polymerase Metabolite Human immunodeficiency virus; Zidovudine triphosphate; Carbovir triphosphate; Lamivudine triphosphate; Antiviral drug metabolism Anion exchange Mononuclear cell Reverse transcriptase inhibitor Nucleoside analog Antiviral Nucleoside Pyrimidine nucleoside Human Enzyme Transferases Enzyme inhibitor Retroviridae Lamivudine Liquid chromatography Triphosphates Metabolism Lentivirus Virus Nucleotidyltransferases Blood cell Dideoxynucleoside Guanine derivatives Abacavir Simultaneous measurement Intracellular Pharmacokinetics Zidovudine
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Summary:	All nucleoside reverse transcriptase inhibitors (NRTI) must first be metabolized to their triphosphate forms in order to be active against HIV. Zidovudine (ZDV), abacavir (ABC) and lamivudine (3TC) have proven to be an efficacious combination. In order simultaneously to measure intracellular levels of the triphosphates (-TP) of ZDV, ABC (carbovir, CBV) and 3TC, either together or individually, we have developed a cartridge-LC–MS/MS method. The quantitation range was 2.5–250 pg/μl for 3TC-TP, 0.1–10.0 pg/μl for ZDV-TP and 0.05–5.00 pg/μl for CBV-TP. This corresponds to 0.1–11.0 pmol 3TC-TP per million cells, 4–375 fmol ZDV-TP per million cells and 2–200 fmol CBV-TP per million cells, extracted from 10 million cells. Patient samples demonstrated measured levels in the middle regions of our standard curves both at pre-dose and 4 h post-dose times.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1570-0232 1873-376X
DOI:	10.1016/j.jchromb.2006.12.015