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.

Outlines

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💊 Liver Clearance and Drug Metabolism

This paragraph discusses the liver's role in drug clearance using the well-stirred model, focusing on intrinsic clearance (CLi). It explains how the liver metabolizes and excretes drugs through biliary pathways, with examples like doxorubicin, a chemotherapy drug partially excreted in bile. The paragraph also touches on cholestasis, a condition hindering bile flow, which can affect drug accumulation in the body. Monitoring serum bilirubin levels is crucial for assessing liver function and adjusting drug dosages accordingly. The concept of enterohepatic circulation, where drugs are reabsorbed after initial excretion, is introduced with drugs like morphine and digoxin as examples. The use of cholestyramine to enhance drug elimination by preventing reabsorption during enterohepatic circulation is also mentioned.

Keywords

💡Intrinsic Clearance (CL sub i)

Intrinsic clearance is a measure of the liver's ability to metabolize and excrete drugs. It is a key concept in understanding how the liver processes substances. In the script, intrinsic clearance is mentioned as a reflection of the liver's metabolic and biliary excretion capabilities, which is crucial for the well-stirred model of drug clearance discussed in the video.

💡Well-stirred Model

The well-stirred model is a theoretical framework used to describe how the liver clears drugs from the body. It assumes that the liver is a well-mixed compartment where the drug is uniformly distributed before being cleared. The script uses this model to explain the process of intrinsic clearance and how it affects drug elimination.

💡Biliary Excretion

Biliary excretion is the process by which the liver removes waste products and drugs through bile. It is a significant pathway for drug elimination, as highlighted in the script when discussing how the liver handles drugs like doxorubicin, which can be partially excreted unchanged in the bile.

💡Doxorubicin

Doxorubicin is a chemotherapy drug used to treat various cancers. In the script, it is used as an example of a drug that undergoes both metabolism and biliary excretion, with some of the drug being re-excreted into the bile unchanged, illustrating the concept of biliary excretion in drug clearance.

💡Cholestasis

Cholestasis is a condition where the flow of bile from the liver to the duodenum is obstructed, which can be caused by various factors such as gallstones, cancer, or certain drugs. The script mentions cholestasis as a condition that can affect drug clearance by impeding biliary excretion, impacting the accumulation of drugs like doxorubicin in the body.

💡Bilirubin

Bilirubin is a waste product that is processed by the liver and excreted in bile. Elevated levels of serum bilirubin can indicate cholestasis. In the script, monitoring bilirubin levels is suggested as a way to assess liver function and adjust drug dosages, such as doxorubicin, accordingly.

💡Enterohepatic Circulation

Enterohepatic circulation refers to the process where a drug is excreted into the bile, then reabsorbed from the intestine back into the bloodstream. The script describes this phenomenon with drugs like morphine and digoxin, emphasizing the complexity of drug clearance and the body's recycling of certain substances.

💡Morphine

Morphine is an opioid used for pain management. It is mentioned in the script as an example of a drug that undergoes enterohepatic circulation, highlighting the concept of reabsorption of drugs from the gastrointestinal tract back into the bloodstream.

💡Digoxin

Digoxin is a medication used to treat heart conditions. The script cites digoxin as another example of a drug involved in enterohepatic circulation, illustrating the recycling of the drug within the body and its impact on drug clearance dynamics.

💡Cholestyramine

Cholestyramine is a medication that can be used to bind bile acids and certain drugs in the gastrointestinal tract, preventing their reabsorption and promoting their elimination in feces. The script describes its use in cases of adverse drug effects, as a means to accelerate the removal of drugs like olsalazine from the body.

💡Olsalazine

Olsalazine is a drug used for rheumatoid arthritis that undergoes enterohepatic circulation. The script mentions it in the context of using cholestyramine to trap and eliminate olsalazine from the body, demonstrating the use of specific interventions to manage drug clearance in cases of adverse effects.

Highlights

Intrinsic clearance (CLi) reflects the liver's ability to remove drugs through metabolism and biliary excretion.

The liver excretes waste products in the bile, which travels through the bile duct and is dumped into the duodenum.

Some drugs, like doxorubicin, are partially excreted in the bile unchanged.

Doxorubicin metabolites can also be active, and about 40% of the drug comes back out in the bile unchanged.

Cholestasis is a condition where bile is not moved from the liver to the duodenum, potentially caused by gallstones, cancer, or certain drugs.

Doxorubicin can build up in the body if bile movement is impaired, necessitating monitoring of serum bilirubin concentration.

Elevated serum bilirubin concentration indicates impaired movement of substances from the liver to the duodenum.

Normal total bilirubin concentrations in adults are less than 1.2 milligrams per deciliter.

If a patient's total bilirubin is higher than normal, the doxorubicin dose may need to be reduced.

Enterohepatic circulation is the process where drugs reabsorbed in the intestine end up in the blood for a second time.

Drugs like morphine and digoxin are thought to undergo enterohepatic circulation.

Cholestyramine can be used to trap drugs in the bile, preventing reabsorption and aiding in drug elimination.

Cholestyramine is not absorbed from the gut and helps to bind and remove drugs from the body.

Leflunomide, used for rheumatoid arthritis, is an example of a drug that undergoes enterohepatic circulation.

Clinicians may administer cholestyramine to patients experiencing adverse effects from drugs to facilitate quicker elimination.

The trapped drug with cholestyramine passes out unabsorbed into the feces, aiding in drug clearance.

Transcripts

let's look at the more factors that

affect how quickly the liver can clear

drugs from the body using the

well-stirred model this time we're going

to look at intrinsic clearance and the

well-stirred equation intrinsic

clearance is represented by CL sub i

intrinsic clearance reflects how well

the liver removes the drug by metabolism

and by biliary excretion the liver

excretes waste products in the bile

which then travels through the bile duct

and is dumped into the duodenum there

are a few drugs that we know get at

least partially excreted in the bile

unchanged one such drug is doxorubicin

which is a drug used to treat some

cancers notice the doxorubicin given to

a patient gets metabolized with some of

the metabolites also being active about

40% of the doxorubicin comes back out in

the bile unchanged cholestasis is a

condition where bile is not being moved

from the liver to the duodenum might be

caused by a gallstone blocking the duct

cancer and even some drugs like birth

control pills

bactrim or erythromycin might cause

cholestasis when bile isn't moving

doxorubicin can build up in the body to

compensate for this possibility the

prescribing information for doxorubicin

tells us to watch the patient's serum

bilirubin concentration bilirubin is

also extreme

accumulates in the blood during

cholestasis if the patient has an

elevated serum bilirubin concentration

that should warn the clinician that

substances aren't moving from the liver

to the duodenum normal total bilirubin

concentrations and adults are less than

1.2 milligrams for death

later if a patient's total bilirubin is

higher than that we might need to cut

the doxorubicin dose in half or even to

a quarter of what we might normally give

what makes things even more interesting

is sometimes that drug that gets passed

by the liver into the duodenum via the

bile duct is not at the end of its

journey sometimes that drug gets

reabsorbed as it travels down the

intestine and ends up in the blood of

second time this is known as

enterohepatic circulation some common

drugs such as morphine and digoxin are

thought to undergo some a neuropathic

circulation an interesting trick with an

aromatic circulation to be done with

less solute Imai which is a drug used

for rheumatoid arthritis the flu demise

undergoes enterohepatic circulation if a

patient is having adverse effects from a

drug and the clinician wants to try to

get it out of the patient as quickly as

possible they sometimes give the patient

outlets tyramine

by mouth cholestyramine isn't absorbed

from the gut but as it passes through

the LeFleur demise that's being excreted

in bile back into the duodenum gets

trapped onto the cold starving

then as the trapped drug passes down the

intestine instead of getting reabsorbed

like it might normally do it passes out

on absorbed into the feces