Non-linear kinetics of 4-methylpyrazole in healthy human subjects

D. Jacobsen, S. K. Barron, C. Simon Sebastian, R. Blomstrand, K. E. McMartin

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

In order to evaluate the pharmacokinetic profile of the alcohol dehydrogenase inhibitor 4-methylpyrazole 4-MP, a placebo-controlled, double-blind, single-dose, randomized, sequential, ascending-dose "Phase-I study" was performed in healthy male volunteers at dose levels of 10 (n=4), 20 (n=4), 50 (n=4) and 100 mg·kg-1 (n=3). In the 10 and 20 mg·kg-1 group, the elimination of 4-MP from the plasma followed non-linear kinetics with mean rates of concentration decline of 3.66 and 5.05 μmol·1-1·h-1, respectively. In the two highest dose groups, the elimination also appeared to be non-linear although the patterns were not followed long enough to confirm this, The mean rates of concentration decline at the higher doses were significantly increased, up to 14.9 μmol·l-1·h-1 at 100 mg·kg-1. The average renal clearance of 4-MP was low, 0.016 ml·min-1·kg-1, and only 3% of the administered dose was excreted unchanged in the urine, indicating metabolism as the major route of elimination. Because of the apparently unusual kinetics following single dose treatment, thorough multiple dose studies need to be carried out to determine a safe dosage regimen for 4-MP.

Original languageEnglish (US)
Pages (from-to)599-604
Number of pages6
JournalEuropean Journal of Clinical Pharmacology
Volume37
Issue number6
DOIs
StatePublished - Nov 1989
Externally publishedYes

Keywords

  • 4-methylpyrazole
  • alcohol dehydrogenase inhibitor
  • healthy volunteers
  • pharmacokinetics
  • saturable kinetics
  • zero order elimination

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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