Use of Accelerator Mass Spectrometry to Measure the Pharmacokinetics and Peripheral Blood Mononuclear Cell Concentrations of Zidovudine

• Published in: Journal of pharmaceutical sciences 2008-07, Vol.97 (7), p.2833-2843
• Main Authors: Vuong, Le T., Ruckle, Jon L., Blood, Arlin B., Reid, Michael J., Wasnich, Richard D., Synal, Hans-Arno, Dueker, Stephen R.
• Format: Article
• Language: English
• Subjects: absorption; accelerator mass spectrometry; Adult; AMS; AZT; Biological and medical sciences; cell loading; Dose-Response Relationship, Drug; Feces - chemistry; General pharmacology; human; Humans; isotope; kinetics; leukocytes; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Male; Mass Spectrometry - methods; Medical sciences; microdose; microdosing; Pharmaceutical technology. Pharmaceutical industry; pharmacokinetics; Pharmacology. Drug treatments; Reverse Transcriptase Inhibitors - blood; Reverse Transcriptase Inhibitors - pharmacokinetics; Reverse Transcriptase Inhibitors - urine; Saliva - chemistry; Tissue Distribution; ZDV; Zidovudine - blood; Zidovudine - pharmacokinetics; Zidovudine - urine
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.21160

The remarkable sensitivity of accelerator mass spectrometry (AMS) is finding many new applications in pharmacology. In this study AMS was used to measure [14C]-Zidovudine (ZDV) concentrations at the drug's site of action (peripheral blood mononuclear cells, PBMCs) following a dose of 520ng (less than one-millionth of the standard daily dose) to a healthy volunteer. In addition, the pharmacokinetics of this microdose were determined and compared to previously published parameters for therapeutic doses. Microdose ZDV pharmacokinetic parameters fell within reported 95% confidence intervals or standard deviations of most previously published values for therapeutic doses. Blood, urine, stool, saliva, and isolated PBMCs were collected periodically through 96h postdose and analyzed for ZDV and metabolite concentrations. The results showed that ZDV is rapidly absorbed and eliminated, has one major metabolite, and is sequestered in PBMCs. 14C mass balance assessments indicated a significant portion of ZDV remained after 96h with a much prolonged elimination half-life. Results of this study demonstrate the usefulness of microdosing and AMS as a tool for studying the pharmacokinetic characteristics, including PBMC concentrations, of ZDV and underscore the value of AMS as a tool with which to perform pharmacokinetic and mass balance studies using trace amounts of radiolabeled compound.