PROTECTIVE EFFECT OF DILTIAZEM AGAINST ACETAMINOPHEN HEPATOTOXICITY IN MICE

There is evidence that an increase in cytosolic Ca++ concentration is a terminal event in the progression to cell death in toxic liver injur y. We have compared the hepatoprotective effects of N-acetylcysteine ( 1 g/kg) and the calcium channel blocking agent, diltiazem (24 mg/kg), when given at 30 min, 3 h and 6 h after single intraperitoneal overdos es of acetaminophen (500 mg/kg) in mice. Overall beneficial effects on mortality, liver necrosis score, and plasma alanine aminotransferase (ALT) activity were found in diltiazem-treated mice 24 h after acetami nophen overdose. However, the most marked effects were obtained when d iltiazem was given 6 h after acetaminophen. N-acetylcysteine was more effective than diltiazem at 30 min and 3 h, although it was less effec tive at 6 h. Mean plasma concentrations of the mercapturate metabolite (hepatic oxidative metabolism) were not significantly different among animals receiving acetaminophen alone or in combination with diltiaze m, which suggests that the hepatoprotective effects of diltiazem are n ot exerted by inhibition of drug metabolic enzymes.