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Microdose Study of 14 C‐Acetaminophen With Accelerator Mass Spectrometry to Examine Pharmacokinetics of Parent Drug and Metabolites in Healthy Subjects
Author(s) -
Tozuka Z,
Kusuhara H,
Nozawa K,
Hamabe Y,
Ikushima I,
Ikeda T,
Sugiyama Y
Publication year - 2010
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2010.206
Subject(s) - pharmacokinetics , microdose , probenecid , acetaminophen , glucuronidation , pharmacology , glucuronide , metabolite , chemistry , drug , bioavailability , urine , active metabolite , high performance liquid chromatography , chromatography , medicine , biochemistry , enzyme , microsome
A study of the pharmacokinetics of 14 C‐labeled acetaminophen (AAP) was performed in healthy Japanese subjects receiving an oral microdose of the drug. After separation by high‐performance liquid chromatography (HPLC), the levels of AAP and its metabolites in the pooled plasma specimens were quantified using accelerator mass spectrometry (AMS). The total body clearance (CL tot )/bioavailability (F) of AAP was within the variation in the reported values at therapeutic doses, indicating the linearity of AAP pharmacokinetics. AAP‐glucuronide (Glu) and AAP‐4‐ O ‐sulfate satisfied the criteria of safety testing of drug metabolites. AMS could detect AAP‐Cys, the active metabolite of AAP conjugated with cysteine, in the urine. Probenecid prolonged the systemic elimination of total radioactivity and caused a marked decrease in AAP‐Glu levels in plasma. Probenecid likely inhibited the glucuronidation of AAP and the renal elimination of AAP‐4‐ O ‐sulfate. Microdosing of 14 C‐labeled drug followed by AMS is a powerful tool that can be used in the early phase of drug development for pharmacokinetic analysis of drugs and their metabolites and for detecting the formation of active metabolites in humans. Clinical Pharmacology & Therapeutics (2010) 88 6, 824–830. doi: 10.1038/clpt.2010.206