School of Medical Sciences, Universiti Sains Malaysia
Abstract
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 Blood samples were withdrawn hourly up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 (Vd) 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 (Cpmax) 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 Vd was believed to be caused by increased drug-receptor
interactions and decreased tissue/protein binding of PRN in these
patients