Effects of clarithromycin and its metabolites on the mixed function oxidase system in hepatic microsomes of rats

Drug Metab Dispos. 1993 Mar-Apr;21(2):358-63.

Abstract

Clarithromycin and its metabolites have been examined for their abilities to induce specific form(s) of cytochrome P-450 and metabolite complex formation in rats. Pretreatment of rats with clarithromycin,N-demethyl clarithromycin, clarithromycin N-oxide, and decladinosyl clarithromycin resulted in 48-75% decreases in the amount of 2C11 and 100-600% increases in the amount of 3A1. Clarithromycin and N-demethyl clarithromycin, but not decladinosyl clarithromycin, produced a metabolite complex with cytochrome P-450 in vivo. Activities of testosterone 2 beta- and 6 beta-hydroxylases were increased by administration of clarithromycin and N-demethyl clarithromycin when these activities were measured in the presence of ferricyanide, but not significant induction was observed when measured in the absence of ferricyanide. Clarithromycin N-oxide treatment resulted in the increase in hydroxylation of testosterone not only at the 2 beta- and 6 beta-positions (430 and 190%, respectively), but also at 7 alpha-position (60%), regardless of the presence or absence of ferricyanide. In vitro experiments with hepatic microsomes of dexamethasone-pretreated rats indicated that the metabolites that were modified at the tertiary amino group more efficiently produced the metabolite complex with cytochrome P-450 compared with the parent compound. In contrast, decladinosyl and hydroxylated metabolites had similar or lower capacities for metabolite complex formation than did the parent compound. Clarithromycin and its N-modified metabolites were able to induce 3A1 and form a metabolite complex with cytochrome P-450 in vivo in varying extents. Decladinosyl clarithromycin has a weak inducibility of 3A1 and did not form a metabolite complex with cytochrome P-450 in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases*
  • Clarithromycin / metabolism
  • Clarithromycin / pharmacology*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Cytochrome P-450 Enzyme System / metabolism
  • Dexamethasone / pharmacology
  • Enzyme Induction / drug effects
  • Ferricyanides / pharmacology
  • In Vitro Techniques
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology*
  • Mixed Function Oxygenases / biosynthesis
  • Mixed Function Oxygenases / metabolism*
  • Oxidoreductases, N-Demethylating / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Steroid Hydroxylases / metabolism

Substances

  • Ferricyanides
  • hexacyanoferrate III
  • Dexamethasone
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Steroid Hydroxylases
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP3A
  • testosterone 7-alpha-hydroxylase, hamster
  • Oxidoreductases, N-Demethylating
  • Clarithromycin