DISCUSSION
In this study, we investigated the pharmacokinetics of propranolol in
patients with liver cirrhosis, and in healthy individuals and patients
with chronic active hepatitis. We also identified the clinical factors
that affect pharmacokinetics of propranolol and suggested a model for
prediction of systemic exposure of propranolol. Generally, the
bioavailability of a drug with high hepatic extraction is influenced by
hepatic blood flow, protein binding, and intrinsic clearance; and the
elimination is determined mainly by hepatic blood flow.[7] As
propranolol is a typical drug with high hepatic extraction, the
reduction of hepatic blood flow by portal hypertension can have a
critical effect on the systemic exposure of propranolol by both
increasing bioavailability and reducing elimination.
A few small studies have evaluated the pharmacokinetics of propranolol
in normal subjects and patients with cirrhosis. A study with 6 normal
subjects and 6 cirrhotic patients showed that the AUC during a dosing
interval (AUCĪ) was 3.5 times higher in cirrhotic patients after the
administration of 80 mg of propranolol twice a day for 7 days.[12]
In another study involving 5 normal subjects and 15 cirrhotic patients,
AUCinf in cirrhotic patients was about 5 times higher
than in normal subject after the single administration of 40 mg of
propranolol.[13] In this study, the mean Cmax and
AUClast in patients with liver cirrhosis were higher by
1.2 folds and 1.4 folds compared to normal subjects, however, there was
no statistically significant difference. The increase of systemic
exposure in cirrhotic patients were obviously low comparing to previous
studies. This small increase can be because most patients with cirrhosis
were in Child-Pugh class A. In this study, the pharmacokinetics of
propranolol were also evaluated in the patients with CAH. The patients
with CAH exhibited the lowest systemic exposure of propranolol among
three groups. While the protein binding and intrinsic clearance were
comparable to those in normal subjects, the hepatic blood flow increased
due to inflammation in these patients, which presumably increased
hepatic elimination.
The Cmax and AUClast of propranolol were
predicted by sex, weight, total bilirubin level, platelet count
(AUClast only) and H/L ratio using the regression model.
Weight can naturally influence drug systemic exposure and total
bilirubin level and platelet count are considered to represent the liver
function being related to intrinsic hepatic clearance and plasma protein
binding. Interestingly, sex was a prediction factor for both
Cmax and AUClast. Several studies
reported that the sex difference in pharmacokinetics of
propranolol.[14-16] These studies have commonly reported that the
clearance of propranolol in male was higher. The authors suggested that
circulating gonadal hormones might influence propranolol metabolism. Our
finding is consistent with these previous reports.
A total of 78 subjects including 36 of cirrhotic patients, 18 of CAH
patients and 24 of normal subjects were completed this study. Not only
the number of subjects was large compared to previous studies, but this
study evaluated H/L ratio representing portal hypertension. To the best
of our knowledge, it is the first study that the measurement of portal
hypertension was used for the prediction of pharmacokinetics. The extent
of portal hypertension was found to significantly influence the systemic
exposure of propranolol. The developed prediction model is expected to
be applied to the pharmacokinetic prediction of drugs which is mainly
eliminated by metabolism and have high hepatic extraction.
Despite these positive aspects of the present study, there were some
limitations that should be addressed. The important one is the
limitation of disease status of patients with cirrhosis. Most patients
with cirrhosis were in Child-Pugh class A except for 2 patients who were
in class B. For this limitation, it is not certain that our proposed
model can be applied to patients with advanced chronic liver disease. In
addition, our prediction model can only be applied to a drug of high
hepatic extraction, because the influencing factors on the
pharmacokinetics of low hepatic extraction drugs are different from
those of high hepatic extraction drugs.