Pharmacokinetics of benzodiazepine antagonist Ro 15–1788 in cirrhotic patients with moderate or severe liver dysfunction
✍ Scribed by Gilles Pomier-Layrargues; J.-François Giguère; Joël Lavoie; Bernard Willems; Roger F. Butterworth
- Publisher
- John Wiley and Sons
- Year
- 1989
- Tongue
- English
- Weight
- 437 KB
- Volume
- 10
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
Ro 15-1788, a benzodiazepine antagonist, has been advocated as a new treatment for hepatic encephalopathy. This drug is extensively metabolized by the liver in normal subjects. In the present study, we examined Ro 15-1 788 disposition in eight healthy controls (Group I), eight cirrhotic patients with moderately impaired liver function (Pugh score lo, Group 111). The subjects of each group were age and sex matched. After an intravenous infusion of 2 mg Ro 15-1788 over 5 min, blood samples were taken at fixed intervals up to 7 hr after the infusion. Plasma levels of the drug were determined by capillary gas chromatography. In controls, Ro 15-1788 had a high plasma clearance [16.3 f 2.6 ml per min per kg (mean f S.D.)], a short half-life (45.7 f 8.5 rnin), a large volume of distribution (0.62 2 0.09 liter per kg) and a low plasma protein binding (45 f 6%). Plasma clearance was reduced markedly in both groups of cirrhotic patients (-57 and -74%, respectively); the volume of distribution was unchanged in Group I1 and moderately increased in Group I11 (+37%). The elimination half-life was markedly prolonged in Groups I1 and I11 (+66 and +210%, respectively). Plasma clearance and Pugh score were highly correlated in cirrhotic patients (r = 0.830, p < 0.001). The plasma protein binding of Ro 15-1788 was lower in cirrhotics, resulting in a significant increase in the free fraction of the drug (+16% in Group 11; +44% in Group 111). These findings emphasize the need for adjustment of Ro 15-1788 dosage in cirrhotic patients, particularly in those with severe liver failure.
According t o a recent hypothesis, hepatic encephalopathy (HE) might be related t o disturbances in cerebral function induced by an endogenous benzodiazepine ligand (1). This hypothesis was based on evidence showing an increased density of brain benzodiazepine receptors in experimental models of HE (2, 3) as well as amelioration of HE using benzodiazepine antagonists in animal