Factor(s) affects Low E and High E drugs

If the concentration is 20 milligrams per liter entering the liver the 15 milligrams per liter exiting the liver we can say that the extraction is 0.25 because 5 milligrams per liter were extracted. We can also say that the FH is 0.75 because 75% of the original 20 milligrams per liter made it through the liver and we would say that this drug is a low E drug. Again because the extraction was less than 0.3 Extraction was only 0.25. So the answer to this equation this question is E. A, B and C are all correct.

Let’s consider clearance of high E drugs. This means that the extraction is greater than 70 percent. Now we know that this equation is one that we don’t want to deal with And fortunately we can zero in on one element of this equation because drug metabolite drug is metabolized so readily that changes in fraction unbound or intrinsic clearance really don’t matter. What this means that the hepatic clearance depends primarily on liver blood flow, QH. And for that reason, it’s a flow limited process. What we can do is eliminate every aspect of that clearance equation that includes fraction unbound or intrinsic clearance and zero in on the fact that the hepatic clearance is pretty much equivalent to liver blood flow.

Likewise, for the clearance of low e drugs where the extraction is less than 0.3, the livers metabolizing capacity is limited regardless of blood flow. So the QH value doesn’t really matter for lowE drugs Hepatic clearance depends primarily on intrinsic clearance and the fraction unbound. So it’s a capacity limited process. And what we can do is eliminate from the equation anything that includes liver blood flow the QH factor and say that hepatic clearance is roughly equivalent to the fraction unbound times the intrinsic clearance.

So let’s take a look at the factors that affect low E drugs. We know that the steady-state concentration is equivalent to the rate of infusion or we could use drug over dose over tau in this as well but we’ll stick with considering that it’s an infusion divided by the hepatic clearance. Now since low E drugs are based on fraction unbound and intrinsic clearance we can say that hepatic clearance is basically equivalent to fraction unbound times intrinsic clearance. And actually substitute dose into the equation for hepatic clearance So the Css is going to be equal to the rate of infusion divided by fraction unbound times intrinsic clearance.

If we want to find the concentration of unbound drug, we were then multiplied by the fraction unbound and interestingly when you do that, fraction unbound cancels out in the equation. So, for a low E drug Css equals the rate of infusion divided by fraction unbound times intrinsic clearance but the unbound concentration is dependent only on the rate of infusion divided by the intrinsic clearance. So for low E drugs intrinsic clearance affects both the Css and the C unbound SS whereas a change in fraction unbound affects only the total steady-state concentration. Now contrast this to high E drugs, we start with our same rate of infusion over hepatic clearance equation.

Now we say that only QH manners will only liver blood flow matters for how high E drugs. Therefore we can say that the hepatic clearance is equivalent to liver blood flow and we can substitute a liver blood flow in the Css equation for unbound concentration. We multiply by the fraction unbound. There there’s no fraction unbound already in the equation so it no longer cancels out as it did for the low E drugs. so we can say that for a high E drug liver blood flow or QH affects both the total concentration of steady state and the unbound concentration at steady state and the change in fraction unbound only affects the unbound concentration at steady state.

For high E drugs if it’s an oral dose the liver blood flow will affect the bioavailability due to the first pass effect.

Here’s some examples of low E and high E drugs. Again you don’t have to memorize. These it’s just for example purposes.

For a low E drug if liver blood flow decreases, the hepatic clearance will not be significantly affect. Remember for a low E drug its fraction unbound and intrinsic clearance that matters not liver blood flow Css will not increase because liver blood flow does not affect the clearance of a low E drug. And likewise the unbound concentration is not going to change because liver blood flow does not affect a low E drug so the answer to this question is A.