Influence of acetaminophen-induced hepatic necrosis on the pharmacokinetics of levonorgestrel.

The pharmacokinetics of levonorgestrel in control mice and in mice with induced hepatic necrosis were investigated. Hepatic necrosis was induced by fasting mice for 18 hr and then giving the acetaminophen in a dose of 750 mg/kg i.p. Measurement by radioimmunoassay of plasma levonorgestrel has been used to compare the pharmacokinetic parameters of the drug after oral and intravenous administration in both control and liver-affected animals. The pharmacokinetic parameters of levonorgestrel in control mice showed some similarity to those observed in human subjects, save the systemic bioavailability which was about 67% in mice compared to 100% in humans. The animals with induced hepatic necrosis compared with controls showed: 1 - Similar mean plasma levels; 2 - Increased metabolic clearance; 3 - Shortened elimination half-life; and 4 - No change in volume of distribution, half-life of distribution and systemic bioavailability. The reasons for any change have been discussed and interpreted.