The Application of Accelerator Mass Spectrometry to Absolute Bioavailability Studies in Humans: Simultaneous Administration of an Intravenous Microdose of 14C-Nelfinavir Mesylate Solution and Oral Nelfinavir to Healthy Volunteers

The absolute bioavailability of nelfinavir was determined in 6 healthy volunteers following simultaneous administration of 1250 mg oral nelfinavir and an intravenous infusion of 14C‐nelfinavir mesylate on day 1 and at steady state. Nelfinavir oral bioavailability decreased from 0.88 to 0.47 over the...

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Bibliographic Details
Published in:Journal of clinical pharmacology 2005-10, Vol.45 (10), p.1198-1205
Main Authors: Sarapa, Nenad, Hsyu, Poe-Hirr, Lappin, Graham, Garner, Ronald Colin
Format: Article
Language:English
Subjects:
Absolute bioavailability
Administration, Oral
Adolescent
Adult
AMS
Area Under Curve
Biological Availability
Carbon Radioisotopes
Diarrhea - chemically induced
HIV Protease Inhibitors - administration & dosage
HIV Protease Inhibitors - adverse effects
HIV Protease Inhibitors - pharmacokinetics
human microdosing
Humans
Infusions, Intravenous
Male
Mass Spectrometry - methods
Metabolic Clearance Rate
Middle Aged
nelfinavir
Nelfinavir - administration & dosage
Nelfinavir - blood
Nelfinavir - pharmacokinetics
Reproducibility of Results
Time Factors
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Summary:The absolute bioavailability of nelfinavir was determined in 6 healthy volunteers following simultaneous administration of 1250 mg oral nelfinavir and an intravenous infusion of 14C‐nelfinavir mesylate on day 1 and at steady state. Nelfinavir oral bioavailability decreased from 0.88 to 0.47 over the 11‐day study period. The moderate bioavailability of nelfinavir was due to significant first‐pass metabolism rather than low absorption, limiting the potential of formulation improvement to decrease pill burden. Human absolute bioavailability studies with accelerator mass spectrometry microdosing, in which an intravenous microdose is given along with a conventional oral dose of the same drug, can differentiate between gastrointestinal absorption and the first‐pass metabolism of new drug candidates. Accelerator mass spectrometry allowed a several thousand‐fold dose reduction of 14C‐nelfinavir relative to that required for liquid scintillation counting. Accelerator mass spectrometry microdosing reduces potential safety issues around dosing radioactivity to humans and prevents the need to formulate high intravenous doses.
ISSN:0091-2700
1552-4604
DOI:10.1177/0091270005280051