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 K_m = 32 nmol and V_max = 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 µg 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.

• Dioncophylline A
• naphthylisoquinoline alkaloids
• malaria
• biotransformation