title: Biotransformation and pharmacokinetics of the antiplasmodial naphthylisoquinoline alkaloid dioncophylline A.
abstract: The biotransformation of the antiplasmodial naphthylisoquinoline alkaloid dioncophylline A by rat liver microsomes and its pharmacokinetics in male rats were studied. Incubation of dioncophylline A with rat liver microsomes resulted in the formation of the major metabolite 5'-O-demethyldioncophylline A, and a second minor metabolite, corresponding to the mass of an as yet unknown 4-hydroxydioncophylline A. Kinetic constants of the formation of 5'-O-demethyldioncophylline A were Km = 32 nmol and Vmax = 20 pmol min-1 mg-1). Administration of dioncophylline A at a dose of 6.67 mg kg-1 body weight to rats intravenously and orally (n = 4 per group) resulted in peak plasma levels of 0.84 and 0.11 microg ml-1, respectively. Levels of metabolites were below the limit of quantitation (LOQ). The following pharmacokinetic parameters of dioncophylline A were determined: oral bioavailability of 25%, plasma half-life of 2.5 h and partition volume of 8 l kg-1 body weight. Concentrations of dioncophylline A metabolites in all plasma and urine samples were below the limit of detection (LOD) and recovery of dioncophylline A in urine was very low, suggesting distribution into lipid rich tissues.
authors.affiliation: Department of Toxicology.
authors.forename: M
authors.initials: M
authors.lastname: Sieber
authors.forename: W
authors.initials: W
authors.lastname: Dekant
authors.forename: J H
authors.initials: JH
authors.lastname: Faber
authors.forename: G
authors.initials: G
authors.lastname: Bringmann
mesh_terms: D000284:Administration, Oral; D000470:Alkaloids / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000652:urine; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D007275:Injections, Intravenous; D007546:Isoquinolines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010963:Plasmodium falciparum / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000470:Alkaloids; D000962:Antimalarials; D007546:Isoquinolines; C104320:dioncophylline A