EFFECT OF LIVER-CIRRHOSIS ON THE SYSTEMIC AVAILABILITY OF NALTREXONE IN HUMANS

Background/Aims: Naltrexone is a competitive opiate antagonist with hi gh hepatic extraction, It is used for detoxification treatment for her oin addicts and has been proposed as a possible treatment of pruritus in cholestasis. Such patients are likely to have impaired liver functi on, underscoring the need to understand the pharmacokinetic behavior o f naltrexone in liver disease, These studies were undertaken to evalua te the effect of liver cirrhosis on the plasma time-course of naltrexo ne. Methods: A total of 18 patients were investigated: seven migraine patients with normal liver function regarded as controls and 11 patien ts with liver cirrhosis (six with decompensated disease and five with preserved liver function), A bolus of 100 mg of naltrexone was adminis tered orally in the morning, after an overnight fast. Blood samples we re taken in basal conditions and at fixed intervals, up to 24 h after administration, Serum levels of naltrexone and of its major active met abolite, 6 beta-naltrexol, were assayed by reversed-phase HPLC analysi s. Results: In control subjects, circulating concentrations of naltrex one were always much lower than those of 6 beta-naltrexol (area under the curve: naltrexone, 200+/-97 ng/mlx24 h; 6 beta-naltrexol, 2467+/-7 30 ng/m1x24 h, p<0.01). In severe cirrhosis serum levels of 6 beta-nal trexol increased more slowly, so that circulating levels of naltrexone during the first 2-4 h after drug intake were higher than those of 6 beta-naltrexol (6 beta-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 x 24 h) was significantly greater tha n in controls, whereas that for 6 beta-naltrexol (2021+/-955 ng/m1x24 h) was not significantly different, Patients with compensated cirrhosi s showed an intermediate pattern, No differences in elimination half-l ife of the two drugs were detected among the groups. Conclusions: Our data suggest the occurrence of important changes in the systemic avail ability of naltrexone and 6 beta-naltrexol in liver cirrhosis; such al terations are consistent with lesser reduction of naltrexone to 6 beta -naltrexol and appear to be related to the severity of liver disease, This must be considered when administering naltrexone in conditions of liver insufficiency.