title: Depression of the N-demethylation of erythromycin, azithromycin, clarithromycin and clindamycin in murine Toxoplasma infection.
abstract: The N-demethylation of macrolides was studied in a murine model of infection. Mice were infected with a cystogenic strain of Toxoplasma gondii (20 or 40 cysts/mouse) and microsomes were prepared from liver homogenates and jejunum villus tip enterocytes on day 10 post-infection. The rate of N-demethylation of the anti-Toxoplasma macrolides azithromycin, clarithromycin and clindamycin was investigated and compared to that of the macrolide erythromycin, a marker of activity of the cytochrome P-450 3A (CYP3A) mono-oxygenases. In infected mice (20 cysts/mouse), the rate of N-demethylation fell in the liver and jejunum for erythromycin (-25% and -35%, respectively), azithromycin (-12% and -10%, respectively), clarithromycin (-23% and -21%, respectively) and clindamycin (-20% and -28%, respectively). The degree of hepatic depression was more marked in mice receiving a 40-cysts burden: for erythromycin (-54%), azithromycin (-29%), clarithromycin (-49%) and clindamycin (-47%).
authors.affiliation: Institut de Parasitologie, Faculté de Médecine, Université Louis Pasteur, Strasbourg, France.
authors.forename: M
authors.initials: M
authors.lastname: Berg-Candolfi
authors.forename: E
authors.initials: E
authors.lastname: Candolfi
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D017963:Azithromycin / Q000493:pharmacokinetics*; D017291:Clarithromycin / Q000493:pharmacokinetics*; D002981:Clindamycin / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004917:Erythromycin / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000378:metabolism; D007583:Jejunum; D007700:Kinetics; D051379:Mice; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D012016:Reference Values; D013997:Time Factors; D014124:Toxoplasmosis, Animal / Q000378:metabolism*
chemical_list: D002981:Clindamycin; D004917:Erythromycin; D017963:Azithromycin; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D017291:Clarithromycin