Intrinsic Clearance - Biliary excretion

Summary

This script explores the liver's role in drug clearance through intrinsic clearance (CLi), which includes metabolism and biliary excretion. It highlights doxorubicin as a drug partially excreted in bile, and discusses cholestasis, a condition that impedes bile flow, potentially leading to drug accumulation. The script also covers enterohepatic circulation, where drugs like morphine and digoxin are reabsorbed after initial excretion. A strategy to mitigate adverse effects involves using cholestyramine to trap drugs in the intestine, preventing reabsorption and promoting elimination.

Takeaways

• 🧪 The liver's ability to clear drugs from the body is influenced by intrinsic clearance (CLi), which includes metabolism and biliary excretion.
• 💊 Doxorubicin, a cancer drug, is partially excreted in the bile unchanged and some of its metabolites are also active.
• 🔁 Cholestasis is a condition where bile flow from the liver to the duodenum is obstructed, potentially by gallstones, cancer, or certain drugs.
• 🚨 Elevated serum bilirubin concentration is a warning sign of impaired bile flow and may require dosage adjustment for drugs like doxorubicin.
• 🌡 Normal total bilirubin levels in adults are less than 1.2 milligrams per deciliter, and deviations may indicate the need for reduced medication dosages.
• 🔄 Enterohepatic circulation is the process where drugs excreted into the bile are reabsorbed into the bloodstream as they travel through the intestine.
• 💊 Morphine and digoxin are examples of drugs that may undergo enterohepatic circulation.
• 🛑 Cholestyramine can be used to mitigate adverse effects from drugs that undergo enterohepatic circulation by trapping them in the gut, preventing reabsorption.
• 🌀 Cholestyramine works by binding to bile acids and any trapped drugs, facilitating their passage out of the body in feces instead of reabsorption.
• 📚 The prescribing information for drugs like doxorubicin includes guidance on monitoring serum bilirubin levels to adjust dosages in cases of cholestasis.
• 🔍 Monitoring and understanding the liver's clearance mechanisms, such as intrinsic clearance and enterohepatic circulation, are crucial for safe and effective drug administration.

Q & A

What is the well-stirred model in the context of liver drug clearance?

The well-stirred model is a theoretical construct used to describe how the liver clears drugs from the body. It assumes that the liver and blood are well-mixed, allowing for a uniform concentration of the drug in the liver and blood.

What does CL sub i represent in the context of the liver's drug clearance?

CL sub i, or intrinsic clearance, represents the liver's ability to remove a drug through metabolism and biliary excretion, reflecting the efficiency of the liver in eliminating the drug.

How does the liver excrete waste products related to drug metabolism?

The liver excretes waste products in the bile, which then travels through the bile duct and is dumped into the duodenum as part of the digestive process.

What is an example of a drug that is partially excreted in the bile unchanged?

Doxorubicin, a drug used to treat some cancers, is an example of a drug that is partially excreted in the bile unchanged, with about 40% of it coming back out in the bile.

What is cholestasis and how can it affect drug clearance?

Cholestasis is a condition where bile is not properly moved from the liver to the duodenum, which can be caused by various factors such as gallstones, cancer, or certain drugs. This can lead to a buildup of drugs like doxorubicin in the body, affecting their clearance.

Why is it important to monitor a patient's serum bilirubin concentration when they are on doxorubicin?

Monitoring serum bilirubin concentration is important because elevated levels can indicate that substances are not moving efficiently from the liver to the duodenum, which may be a sign of cholestasis affecting drug clearance.

What is the normal total bilirubin concentration range for adults?

The normal total bilirubin concentration for adults is less than 1.2 milligrams per deciliter (mg/dL).

How might a clinician adjust the doxorubicin dose if a patient has elevated serum bilirubin levels?

If a patient has elevated serum bilirubin levels, indicating potential cholestasis, the clinician might reduce the doxorubicin dose to half or even a quarter of the normal dosage to compensate for the reduced clearance.

What is enterohepatic circulation and which drugs are known to undergo this process?

Enterohepatic circulation is a process where a drug excreted into the bile is reabsorbed as it travels down the intestine, effectively circulating between the liver and the intestine. Drugs such as morphine and digoxin are known to undergo enterohepatic circulation.

How can cholestyramine be used to help remove a drug from a patient's body experiencing adverse effects?

Cholestyramine can be given orally to bind to the drug being excreted in the bile, preventing its reabsorption and allowing it to pass out of the body through the feces, thus aiding in the removal of the drug from the patient's system.

What is the role of cholestyramine in the context of enterohepatic circulation?

Cholestyramine, when administered orally, is not absorbed by the gut but can bind to drugs in the bile as it re-enters the duodenum. This binding prevents the drug from being reabsorbed into the bloodstream, facilitating its elimination through feces.