Skip to 0 minutes and 15 secondsLet's take a look at the impact of protein binding on hepatic metabolism. We've looked at this already but now we're going to zero in on how it impacts hepatic metabolism. The effect of fraction unbound if it increases from point one to point two now this is specifically for a low E drug. If we increase the fraction unbound the unbound concentration will double even though initially the total concentration has not changed. And as we've already indicated that will cause the clearance to increase which causes the total concentration to drop in half. That's because the fraction unbound does affect the clearance of a low E drug.

Skip to 1 minute and 7 secondsSo everything we've said about the impact of protein binding prior to this lesson was actually referring specifically to low E drugs. It's just that we hadn't talked about low E versus high E drugs yet. So in our first situation, we start with fraction unbounded 10%, then increases to 20% which doubles the clearance and that produces a decrease in half of the total serum concentration as the fraction bound remains doubled at 20%. So at the point at which steady state has been reestablished the fret of the concentration of unbound drug is unchanged but the concentration of total drug has dropped in half.

Skip to 2 minutes and 1 secondAnd again we can demonstrate this with the actual graph serum concentrations both of total concentration of unbound concentration indicating that at point B when the fraction unbound first doubled; the unbound concentration doubled; the total concentration did not initially change but then over time when we go from point B to point C, the unbound concentration dropped back to what it was initially and the total concentration dropped in half. Let's contrast this to what happens with a high E drug for which the fraction unbound does not affect clearance with a high E drug if the fraction unbound increases from point one to point two. We see that the concentration of unbound drug doubles but the clearance doesn't change.

Skip to 2 minutes and 57 secondsSo at this point the serum concentration is not going to change. The concentration of unbound drug has doubled and the concentration of total drug is unchanged. It's essentially the opposite of what happens for a low E drug. If we look at this using the graph from the previous slide, we see that from point B to Point C the unbound concentration on the bottom graph does not decrease because the clearance is not increased. Likewise, the total concentration from point B to Point C does not decrease because the clearance is not increased.

Skip to 3 minutes and 43 secondsSo those elements of the curve essentially are eliminated and the concentration of unbound drug that initially doubled when the F when the fraction unbound doubled stays at that same level and the total concentration never changes. So, let's review what we've covered about hepatic metabolism. If there is a big difference between an IV and a PO dose the drug probably has a significant first pass effect, that's what causes the need for a high PO dose because much of the drug as its absorbed into the hepatic portal vein and goes through the liver much of the drug is extract. It's a high E drug and that those are the types of drugs that are subject to our first pass effect.

Skip to 4 minutes and 37 secondsFor a low E drug the fraction Unbound increases how will this Css the total concentration change the answer is it will decrease for low E drug fraction unbound increases clearance will increase For a low E drug fraction unbound increases how will the concentration unbound drug change and that is no change at steady state. It increases initially but then the the clearance increased causes to come back to what it was. For a low E drug if the intrinsic clearance decreases how will the total concentration change and the answer is it will increase because of the decrease in clearance because low e drugs are impacted by intrinsic clearance.

Skip to 5 minutes and 26 secondsFor a low E drug if the liver blood flow decreases how will Css changed the answer is there will be no change. Because low E drugs are not impacted significantly by changes in liver blood flow. Only high E drugs. For a high E drug if the fraction unbound increases how will the total concentration at state state change? The answer is no change. High E drugs are only impacted by changes in liver blood flow not fraction unbound or intrinsic clearance. For a high E drug, if the fraction unbound increases how will the unbound concentration change at steady state interest will increase Now there's no change in clearance.

Skip to 6 minutes and 12 secondsFor a high E drug when fraction unbound increases but the fact that the fraction unbound increases will increase the unbound concentration at steady state but there will be no change in the total drug concentration because clearance has not changed For a high EPO drug if the liver blood flow increases bioavailability will decrease for a high E drug if liver blood flow increases metabolism will increase and therefore if it's a high e drug that's given orally when the metabolism increases the bioavailability will decrease because less drug will make it through the liver.

Skip to 6 minutes and 54 secondsLet's take a closer look now at intrinsic clearance what do we mean by the intrinsic metabolic activity of an enzyme one of the factors we can consider is the maximum rate of enzyme activity on the drug or the enzymatic substrate and we call this V-max. If we increase V-max that's referred to as induction or inducing the enzyme if we decrease V-max that's known as inhibition or inhibiting the enzyme the affinity of the enzyme for its substrate is indicated by the value Km which is actually a dissociation constant. Km is equal to the total concentration at steady state when the metabolic rate is half of the V-max.

Skip to 7 minutes and 45 secondsSo as a measure of affinity, Km is actually a dissociation constant so as Km increases the affinity of the enzyme for the for the drug substrate is decreased. The equation for intrinsic clearance, therefore, this V Max divided by Km plus the unbound concentration of the fact that for most drugs, the unbound concentration is much less than the Km enables us to eliminate the unbound concentration from the equation and suggest that intrinsic clearance is simply equal to V Max divided by Km.

Skip to 8 minutes and 28 secondsWhat this means is that as the V-max of a drug increases or as the the enzyme is induced the intrinsic clearance will increase If the Km increases or the affinity for the drug decreases as the Km increases the intrinsic clearance will decrease.

# Hepatic Metabolism Review : How will Css change if fu changes?

Although we have learned the effect of fu increase before, this time we focus on how it impacts hepatic metabolism for a high E drug and a low E drug.

The hepatic metabolism review helps us consolidate knowledge. If you aren’t familiar with the concept, please review the previous video 4.7.

Besides, Prof. Brown gives a closer look at intrinsic clearance (CLint). Metabolic capacity depends on Vm and Km.

How will they affect CLint? Please leave your answer below and explain why.

##### Educator:

Prof. Daniel L. Brown