HEMODYNAMIC AND PHARMACOKINETIC STUDY OF TERTATOLOL IN PATIENTS WITH ALCOHOLIC CIRRHOSIS AND PORTAL-HYPERTENSION

Tertatolol, a recently developed beta1-beta2-blocker has two advantages: it does not induce withdrawal syndrome after abrupt cessation, and it preserves renal function. It has been suggested that the kinetics of tertatolol in patients with hepatic dysfunction are altered. Therefore, the hemodynamic effects and pharmacokinetics following the acute administration of tertatolol were studied in cirrhotic patients with-portal hypertension. Systemic, splanchnic and renal hemodynamics were evaluated before and 30 min after the simultaneous administration of 2.5 mg tertatolol p.o. and 1.25 mg deuterated tertatolol i.v. in 10 cirrhotic patients with esophageal varices. The pharmacokinetics of tertatolol were evaluated over a 4-day period. Tertatolol significantly decreased heart rate (-22 +/- 10%), cardiac output (-26 +/- 8%), and hepatic blood flow (-27 +/- 23%). The hepatic venous pressure gradient decreased from 15.7 +/- 5.0 to 12.9 +/- 4.0 mmHg (-17 +/- 13%, P < 0.01). Three out of 10 patients were non-responders to tertatolol. Renal blood flow (-9 +/- 28%) and intrinsic hepatic clearance of indocyanin green (-9 +/- 25%) were not significantly modified. The duration of effective beta-blockade was far less than 12 h. Tertatolol was rapidly absorbed with a C(max) of 70 +/- 51 mug/l at a peak time of 0.75 +/- 0.26 h. In comparison with healthy volunteers referred to in literature sources, plasma clearance was reduced to 49 +/- 28 ml/min, bioavailability was increased to 72 +/- 20%, and the volume of distribution was increased to 50 +/- 34 1, probably due, in part, to a weaker protein binding -85% - effect. No correlation was found between the severity of cirrhosis and pharmacokinetic data or hemodynamic measurements, however these results should be interpreted with caution. In conclusion, the magnitude of the effects of tertatolol on splanchnic hemodynamics was comparable to that of propranolol. Although pharmacokinetics were altered, our results do not support the previous suggestion of halving the recommended dose in cirrhosis. Tertatolol could be useful for the treatment of portal hypertension. Additional studies, e.g. after repeated dosing, are needed before recommending tertatolol for clinical use.