Ro 15–1788 Kinetics are Markedly Impaired in Cirrhotic Patients.

Abstract

It has been suggested that hepatic encephalopathy (HE) might be related to changes in the GABA-benzodiazepine receptor complex. A recent PET scan study reported an increased uptake of 11C RO 15–1788 (a specific ligand for brain benzodiazepine (Bz) receptors) in cirrhotic patients with HE, suggesting an increase in the density or affinity of Bz receptors. RO 15–1788, is extensively metabolized by the liver and marked changes in its kinetic parameters might best explain these findings. In the present study, we evaluated RO 15–1788 pharmacokinetics in 8 normal volunteers (group 1), 8 cirrhotic patients with moderately impaired liver function (Pugh score 10; group 3). The subjects of each group were age and sex-matched. After an i.v. injection of 2mg RO 15–1788, blood samples were taken at fixed intervals up to 7 hours after the injection. Ro 15–1788 plasma levels were determined using a specific gas chromatographic assay and plasma clearance and half-life were calculated. Mean age was 38.5 years old in group 1, 45.1 years old in group/ 2 and 44.7 years old in group 3. There were 7 males and 1 female in each group. Cirrhosis was related to chronic alcoholism in 13 patients, to chronic B virus infection in 1 and was cryptogenic in 2. Pharmacokinetic analyses demonstrated a marked decrease in Ro 15–1788 plasma clearance (-57%) and increase in half-life (+66%) in cirrhotic patients of group 2. RO 15–1788 elimination was further impaired in cirrhotic patients of group 3: mean decrease in plasma clearance: -74%; mean increase in half-life: + 210%. These data demonstrate that Bo 15–1788 pharmacokinetics are markedly altered in cirrhosis, changes being related to the degree of liver dysfunction. These findings might best explain the reported increase in RO 15–1788 brain uptake in cirrhotic patients with HE rather than changes in brain Bz receptors.