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Hepatic Blood Flow & First-Pass Effect

Hepatic Blood Flow & First-Pass Effect
This chart provides information on drugs that are metabolized by the cytochrome p450 system. Specifically for specific enzyme systems, the CYP1A2, CYP2C9, CYP2D6, and CYP3A4, these are four common enzyme systems that have been known to metabolize drugs. What I’ve listed in this chart are substrates that are metabolized also metabolic inducers within that enzyme system and metabolic inhibitors of enzymes in that system. It’s not intended that you memorize these simply to give you an idea of some of the commonly hepatic metabolized drugs, as well as inducers and inhibitors. Now, let’s consider what happens in terms of drug metabolism by the liver. The schematic and the upper right of this slide shows blood entering the liver, and hepatocytes that actually metabolize the drug.
What we find is that the drug from an oral dose the drug will be absorbed directly into the portal vein. Now you can see in this example, 80% of the drug shown on the left schematic. 80% was absorbed through the gut into the portal vein, 100 milligrams were administered 80 milligrams made it into the portal vein. And now those 80 milligrams go directly to the liver before reaching the systemic circulation. So the drug enters in the hepatic portal vein, and is then transported through sinusoids across hepatocytes where the drug can encounter hepatic metabolic enzymes. And this is where the drug is actually extracted by the liver.
Now, we can see that the FG represents the bioavailability of the drug, in terms of absorption from the gut into the portal vein. FH represents the amount of drug that makes it through the liver. In this case, 25% of the drug that entered the liver, made it through the liver, which means it’s 75% of the drug was extracted by the liver. As the drug passes through these sinusoids and is metabolized by the hepatocytes, and then the drug continues on in the central hepatic vein and reaches the systemic circulation. So, in this example we see that 20% of the drug actually made it through the liver was absorbed and made it through the liver.
Now, 0.8 was the FG that was absorbed into the hepatic portal vein, and then 25% made it through the liver. So, the FG of 0.8 multiplied by the FH of 0.25, means that the F, the bioavailability of this drug was 20%. Now the first pass effect is can be very significant when you have an oral drug, which has a high extraction entering the portal vein. If the extraction by the liver is very high, that much of that drug will be eliminated by the liver even before it get reaches the systemic circulation. This is referred to as the first pass effect. First pass through the liver directly from the portal vein, much of the drug is extract.
When we talk about hepatic extraction, we’re representing a decimal fraction from zero to one. It’s the fraction extracted during that first pass through the liver. So we simply measure the concentration of drug in the hepatic portal vein entering the liver, the concentration of drug as it’s exiting the liver. And so the extraction, the hepatic extraction or EH is the concentration entering the liver minus the concentration leaving the liver, divided by the concentration that was entering the liver. A drug is said to be high extraction if the extraction is greater than 70 percent. And it’s said to be a low E drug if the extraction is less than 30 percent.
The equation that represents hepatic extraction is the fraction of unbounded drug times the intrinsic clearance, divided by the liver blood flow QH, plus the fraction unbound times the intrinsic clearance. So there are three factors that are critical in terms of hepatic extraction. One is the fraction unbound that we’ve talked about in previous lessons. The intrinsic clearance is an intrinsic measure of enzyme activity, the specific enzyme for a given drug. And QH is the liver blood flow. Generally 1.5 liters per minute, which would be 90 liters per hour. Hepatic clearance is the liver blood flow times the extraction.
And since extraction is equal to fraction unbound times the intrinsic clearance, divided by liver blood flow plus fraction unbound times intrinsic clearance, we can say that hepatic clearance is equal to liver blood flow times fraction unbound times intrinsic clearance of the enzyme, divided by the liver blood flow plus the fraction unbound times the intrinsic clearance. Now this is an extremely ugly equation, that we wouldn’t want to be using routinely. Fortunately, we don’t have to. There are way, there are models that have been developed that allow us to abbreviate this equation significantly. Basically, what we need to focus on is that hepatic clearance depends on three factors.
The intrinsic clearance of the enzyme system involved the fraction unbound of the drug and liver blood flow. Let’s see if you can answer this question.

Prof. Brown introduces drugs that are metabolized by Cytochrome p450. Most of them are common drugs.

He also uses clear diagrams to demonstrate the concept of first-pass effect and bioavailability (F).

We can know the definition of hepatic extraction (EH) and clearance (CL).

What is the relationship between hepatic extraction (EH) and clearance (CL)? Please leave your answer below and explain why.


Prof. Daniel L. Brown

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Clinical Pharmacokinetics: Dosing and Monitoring

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