The Pharmacokinetics of Single Dose vs Steady-State Doses of Propranolol in Cirrhotic Malay Patients.

Pharmacokinetics of propranolol (PRN) given orally were studied in twelve cirrhotic Malay patients [10 males, 2 females], aged 33-62 years [49.83±9.17], body weight 39-72 kg [58.0±8.46] and height 142-168 cm [158.8±7.89] following single 20 mg and steady-state 20 mg tds for 7 days dosing of PRN. Blood samples were withdrawn hourly up to 48 hours. PRN concentrations in the plasma were assayed by HPLC with oxprenolol as the internal standard. Pharmacokinetic parameters were analysed using a non-linear regression program MultiForte. Area under the curve (AUC) as performed using the linear trapezoidal rule. Student's t-test was used to test for statistical significance and AUC in Malay cirrhotic patients was found to be much bigger than that observed in Caucasians. Steady-state AUC was significantly increased following multiple dosing (961.31±7.47 vs 2954.19±1153.34 ng.hr/ml), however, the volume of distribution (V(d)) declined (543.89±292.91 vs 224.14±1003.12 L) significantly compared to that of a single dose. The apparent systemic clearance (CL) was significantly reduced at steady-state (436.04±209.4 vs 129.51±48.42 ml/min) in comparison to single dose therapy. The peak plasma concentration (Cp(max)) was greatly increased at steady-state (54.32±22.37 vs 136.10±38.63 ng/ml). Based on the AUC, PRN bioavailability was greater in cirrhotic Malay patients compared to Caucasians who took only 20 mg instead of 80 mg doses. The decline in drug clearance following steady-state was due to saturation of the metabolizing capacity of hepatic enzymes and a decreased portal blood flow. Reduced V(d) was believed to be caused by increased drug-receptor interactions and decreased tissue/protein binding of PRN in these patients.