Methylphenidate-induced hepatotoxicity in mice and its potentiation by beta-adrenergic agonist drugs

Methylphenidate hydrochloride, when administered as a single 75 to 100 mg/kg i.p. dose, was found to produce hepatic necrosis in male ICR mice. Peak hepatotoxicity, as measured by serum ALT elevations, occurred 16 hours post-treatment while maximal histopathological evidence of hepatotoxicity occurred 24-48 hours after the methylphenidate dose. Liver injury measured by either method was essentially nonexistent for dosages < or = 50 mg/kg in male mice, and was only minimally evident in female mice at the highest dosage testable. Co-treatment of mice with either alpha 1- or alpha 2-adrenergic agonist drugs had no meaningful effect on methylphenidate-induced hepatotoxicity. In contrast, the beta-adrenergic agonist drug isoproterenol produced a striking potentiation of the liver injury, and shifted the apparent threshold for toxicity approximately 5- to 10-fold. Co-administration of methylphenidate with the mixed alpha/beta-adrenergic agonist dobutamine or with the beta 2-selective agonists metaproterenol, ritodrine or terbutaline produced a similar potentiation of toxicity. Parallel tests with beta-adrenergic antagonists revealed that the potentiation by isoproterenol could be significantly diminished by a single dose of the non-selective beta-adrenoreceptor blocking drug nadolol or the beta 2-selective antagonist ICI-118,551, but not the beta 1-selective antagonist metoprolol. Collectively, these observations suggest that potentiation of methylphenidate hepatotoxicity occurs through stimulation of beta 2-adrenoreceptors. Mice co-treated with isoproterenol were found to have substantially higher serum and liver methylphenidate levels following the methylphenidate dose, and significant increases were also observed in the area-under-the-curve (AUC) for methylphenidate in both tissues of isoproterenol co-treated mice. The results of this study suggest that beta 2-adrenergic agonist drugs are capable of potentiating methylphenidate-induced hepatotoxicity in mice by increasing hepatic methylphenidate concentrations.