Bile Secretion in Anesthetized Rats

In contrast to other animals, rats do not possess a bile bladder. Therefore, cannulation of the bile duct in rats can be used as a suitable model to measure choleretic (increased bile production) or cholestatic (decreased bile production) side effect potential of drug candidates. If the test compound reduces bile production, it is recommended to investigate a putative hyperhpi-demic side effect potential of the drug candidate by its influence on total blood cholesterol and triglycerides in appropriate experimental methods. 

In addition this method of the bile fistula rat can be used for ADME profiling of drug candidates with respect to a hepatobiliary elimination potential (high first pass effect) (Herling et al. 2002). 

Bile secretion is studied in anesthetized bile fistula rats, which are anesthetized by an intraperitoneal injection of pentobarbital sodium (60 mg/kg), tracheotomized, and one jugular vein per rat is cannulated for intravenous administration (bolus injection or infusion of the drug candidate). Anesthesia is maintained for up to 7 hours by subcutaneous infusion of pentobarbital sodium (adjusted to the aesthetic depth of the individual animal about 24 mg/kg/h). Body temperature is monitored with a rectal probe thermometer, and temperature is maintained at 37 °C by means of a heated surgical plate. 

After laparotomy, the common bile duct is cannulated in the upper half with polyethylene tubing and bile is collected every 30 minutes up to 7 hours. The drug candidate is administered at an appropriate dose by bolus injections intravenously into the jugular vein one hour after finishing surgery or by intraperitoneal administration of a 1 % carboxymethylcellulose suspension, if not adequate soluble for an intravenous 

For ADME purposes the concentration of the parent test compound in the bile is measured by appropriate analytical methods and total compound excretion is calculated from the secreted volume and the measured concentration of the test compound in the bile of each sampling interval. 

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