The disposition of propranolol in blood has been investigated in 9 normal subjects and 7 patients with biopsy proven, well compensated cirrhosis using a protocol which allowed the estimation of the steady-state systemic availability of propranolol after oral administration. In addition, the systemic clearances of both antipyrine and indocyanine green (ICG) have been measured.The mean steady-state free (unbound) propranolol concentration in patients with cirrhosis was increased 3-fold in comparison with controls. This augmentation was due to an increase in systemic availability from 38 ± 3 % in controls to 54 ± 6%, a decrease in systemic clearance from 860 ± 90ml/min to 580 ± 140ml/min and an increase in free fraction of drug in blood from 0.06 ± 0.04 to 0.102 ± 0.65. The increase in the free fraction of drug also led to the volume of distribution increasing from 290 ± 17L to 380 ± 41L. As a consequence of both clearance and distribution changes, propranolol half-life increased from 4.0 ± 0.3h to 11.2 ± 3.2h.It is concluded that the reduced intrinsic clearance and/or portasystemic vascular shunts in cirrhosis, permits more of the absorbed drug to reach the circulation and that elimination of the drug from the systemic blood is also impaired. Furthermore, more of the drug in the systemic circulation is in the unbound form and potentially available to exert an increased pharmacological response.