These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: Mechanistic aspects of the inhibition of microsomal drug oxidation by primaquine.
    Author: Murray M, Farrell GC.
    Journal: Biochem Pharmacol; 1986 Jul 01; 35(13):2149-55. PubMed ID: 3729971.
    Abstract:
    The kinetics of inhibition of microsomal drug oxidation (as aminopyrine N-demethylase activity) by the antimalarial agent primaquine were found to be concentration-dependent. Lower concentrations of primaquine (0-40 microM) elicited slope-hyperbolic, intercept-hyperbolic noncompetitive (mixed) inhibition with an inhibitor equilibrium-dissociation constant (Ki) of 21 microM. On the other hand, primaquine concentrations greater than 40 microM elicited essentially simple competitive inhibition as judged from Lineweaver-Burk and Dixon analysis with appropriate replots (Ki = 23 microM). The coincident Ki values suggest that the same enzyme-inhibitor complex is involved in inhibition over all concentrations of primaquine tested. The apparent change in kinetics was accounted for in terms of a four-step interaction scheme involving a ternary enzyme-substrate-inhibitor complex that catalyses substrate oxidation at a slower rate than the binary enzyme-substrate complex. Competitive inhibition reflects the likelihood that the ternary complex does not form at all, presumably due to reduced accessibility of the active site to substrate. A good correlation was found between the Ki values for the inhibition of aminopyrine N-demethylase activity (21 or 23 microM) and the modulation of aminopyrine binding (26 microM) by primaquine. These findings suggest that the inhibition of aminopyrine N-demethylase activity by primaquine is mediated via an interaction with the oxidised form of cytochrome P-450. In addition, the apparent change in inhibition kinetics suggests a concentration-dependent change in the capacity of primaquine to modulate substrate binding to cytochrome P-450 as well as the formation of a P-450-aminopyrine-primaquine ternary complex.
    [Abstract] [Full Text] [Related] [New Search]