Effects of liver disease on the disposition of the opioid antagonist nalmefene.

OBJECTIVES: The pharmacokinetics of nalmefene and its glucuronide metabolite were investigated in 12 patients with liver disease (four patients with mild, five patients with moderate, and three patients with severe liver disease) and 12 age-, weight-, and gender-matched control subjects.

METHODS: Subjects received a single intravenous bolus 2.0 mg dose of nalmefene. Multiple blood and urine samples were collected for 48 hours. Within 1 week of nalmefene administration, antipyrine and galactose clearances were determined as general markers of hepatic metabolism and effective liver plasma flow, respectively. Plasma concentrations of nalmefene were determined by radioimmunoassay.

RESULTS: The antipyrine and galactose clearance values were 56% and 33% lower, respectively, in the patients with liver disease compared with the normal healthy control subjects. The systemic clearance of nalmefene was reduced by 32% (0.61 +/- 0.21 versus 0.90 +/- 0.27 L/hr/kg [mean +/- SD]) and the terminal elimination half-life was increased by 31% (10.5 +/- 1.9 versus 8.0 +/- 2.2 hours) in the patients with liver disease. This was primarily the result of a 31% reduction (0.181 +/- 0.067 versus 0.263 +/- 0.072 L/hr/kg) in nalmefene glucuronide formation clearance. There were no significant differences in nalmefene volumes of distribution or protein binding. There was a significant inverse relationship between nalmefene clearance and Pugh score (r = -0.57; p = 0.004), indicating decreasing nalmefene clearance with increasing severity of liver disease.

CONCLUSIONS: The clearance of nalmefene was significantly reduced in the presence of liver disease. However, because nalmefene will be primarily used in the acute care setting for reversal of opioid-induced effects, it is not likely that these alterations will necessitate a dosage modification.