The pharmacokinetics of exaprolol and propranolol in rats with interrupted enterohepatic circulation

Abstract

The pharmacokinetics of two beta adrenoceptor blocking drugs, exaprolol and propranolol, in rats with interrupted enterohepatic circulation was studied. The tritium-labelled drugs were given intravenously to four groups of rats: control, bile-duct cannulated, bile-duct ligated, and pretreated with neomycin. Plasma levels and excretion were observed up to 96 h after administration. The pharmacokinetic parameters show an enhanced plasma elimination of both drugs at interrupted enterohepatic circulation compared to the control group. Significant changes were observed in the excretion pattern with bile-duct cannulated and bile-duct ligated rats, while the total radioactivity excreted in urine and faeces does not differ between control and neomycin pretreated rats.

Utilization of dried blood spots within drug discovery: modification of a standard DiLab® AccuSampler® to facilitate automatic dried blood spot sampling

“…Propranolol was chosen as the test substance as its pharmacokinetic profile is well understood and as such compound quantification across the 24 h time cross was more likely. 10 During this time each animal had free access to food and water at all times and the light, temperature and humidity were regulated. Upon completion of the study both animals were sacrificed by terminal anaesthesia and cervical dislocation.…”

Pharmacological effects are model specific in animal models of portal hypertension

“…In the CBDL model, there is a high risk of development of biliary cysts, which seemed not to be the case in the present study. Furthermore, the bile excretion is interrupted in the CBDL model, which might have an influence on pharmacokinetics of pharmacologic agents that are metabolized in the liver, which is the case for propranolol, and an enhanced plasma elimination of propranolol has previously been demonstrated in BDL rats [3]. Another difference is the development of severe biliary fibrosis in CBDL rats, and cirrhosis is seldom observed.…”

“…The most extensively studied rat models have been conducted using partial portal vein ligation, which is a presinusoidal portal hypertension model, and common bile duct ligation (CBDL) and carbon tetrachloride (CCL 4 )-induced cirrhosis, which both resemble sinusoidal portal hypertension. Because of difference in etiology and type of the experimental portal hypertension model, pharmacologic effects may differ between these models [3].In the present issue of the journal, Fizanne et al[4] investigated the hemodynamic effects of propranolol in CBDL and CCL 4 rats. Apart from having sinusoidal portal hypertension, rat models differ from cirrhosis in humans, who have postsinusoidal hypertension, with respect to developments of portosystemic collaterals, which are mainly an esophageal venous network in humans and splenorenal shunts in rats.…”

“…The most extensively studied rat models have been conducted using partial portal vein ligation, which is a presinusoidal portal hypertension model, and common bile duct ligation (CBDL) and carbon tetrachloride (CCL 4 )-induced cirrhosis, which both resemble sinusoidal portal hypertension. Because of difference in etiology and type of the experimental portal hypertension model, pharmacologic effects may differ between these models [3].…”