Pharmacokinetic Interaction Between Verapamil and Methylxanthine Derivatives in Mice

The aim of this study was to assess the impact of a P-glycoprotein and CYP3A inhibitor, verapamil on the pharmacokinetics of two methylxanthines, pentoxifylline and lisofylline in male CD-1 mice. To differentiate the effects of verapamil, both methylxanthines were also given to male CF-1 mdr1a (-/-) and mdr1a (+/+) mice. CD-1 mice received a single dose (50 mg/kg) of pentoxifylline or lisofylline intravenously, whereas mutant animals were given the same dose of both compounds intravenously and orally. Blood and tissue samples were collected at different time points following drug administration and concentrations of pentoxifylline and lisofylline were measured by a chiral HPLC method. Verapamil significantly increased concentrations of both methylxanthines in murine serum and tissues. In contrast to lisofylline, pentoxifylline concentrations were also significantly higher in mutant mice 30 min following intravenous administration. Due to the fact that pentoxifylline is not a good P-glycoprotein substrate, a possible mechanism of this interaction might be that in the presence of verapamil, pentoxifylline elimination is inhibited by its metabolites that are normally eliminated through P-glycoprotein-mediated transport. This hypothesis was supported by the outcomes of pharmacokinetic analysis. In conclusion, the interaction between verapamil and pentoxifylline is, at least partially, P-glycoprotein-mediated, whereas alterations in lisofylline pharmacokinetics are caused by inhibition of drug metabolising enzymes.