Effect of liver cirrhosis on the systemic availability of naltrexone in humans

Background/Aims: Naltrexone is a competitive opiate antagonist with high hepatic extraction. It is used for detoxification treatment for heroin addicts and has been proposed as a possible treatment of pruritus in cholestasis. Such patients are likely to have impaired liver function, underscoring the need to understand the pharmacokinetic behavior of naltrexone in liver disease. These studies were undertaken to evaluate the effect of liver cirrhosis on the plasma time-course of naltrexone. Methods: A total of 18 patients were investigated: seven migraine patients with normal liver function regarded as controls and 11 patients with liver cirrhosis (six with decompensated disease and five with preserved liver function). A bolus of 100 mg of naltrexone was administered orally in the morning, after an overnight fast. Blood samples were taken in basal conditions and at fixed intervals, up to 24 h after administration. Serum levels of naltrexone and of its major active metabolite, 6β-naltrexol, were assayed by reversed-phase HPLC analysis. Results: In control subjects, circulating concentrations of naltrexone were always much lower than those of 6β-naltrexol (area under the curve: naltrexone, 200±97 ng/ml×24 h; 6β-naltrexol, 2467±730 ng/ml×24 h, p<0.01). In severe cirrhosis serum levels of 6β-naltrexol increased more slowly, so that circulating levels of naltrexone during the first 2–4 h after drug intake were higher than those of 6β-naltrexol (6β-naltrexol/naltrexone ratio at 2 h: controls, 10.91±4.80; cirrhosis, 0.39±0.18, p<0.01). The area under the curve for naltrexone (1610±629 ng/ml×24 h) was significantly greater than in controls, whereas that for 6β-naltrexol (2021±955 ng/ml×24 h) was not significantly different. Patients with compensated cirrhosis showed an intermediate pattern. No differences in elimination half-life of the two drugs were detected among the groups. Conclusions: Our data suggest the occurrence of important changes in the systemic availability of naltrexone and 6β-naltrexol in liver cirrhosis; such alterations are consistent with lesser reduction of naltrexone to 6β-naltrexol and appear to be related to the severity of liver disease. This must be considered when administering naltrexone in conditions of liver insufficiency.