00:01
Let's talk about a concept called first pass metabolism.
Let's take a look at how a drug enters into the body.
00:09
When an oral drug is ingested, it may start to be absorbed in the stomach, but most absorption occurs as it moves
from the stomach to the small intestine. Here, not all of the drug may be absorbed
across the gut wall; the fraction that is absorbed then enters the portal blood. This blood delivers the drug
to the liver prior to its entry into the systemic circulation. A drug can be metabolized in the gut wall
(e.g., by the CYP3A4 enzyme system) or in the portal blood,
but it is most commonly the liver that is responsible for the drug's metabolism before the drug reaches the systemic circulation.
00:49
The liver can also excrete the drug into the bile. Any of these sites – the stomach, the gut wall, the portal blood, or the liver –
can contribute to the reduction in the drug's bioavailability, a process known as first-pass elimination.
01:04
For example, the absolute bioavailability of diltiazem following oral administration is about 40%,
with a range that can vary significantly between individuals, from approximately 24% to 74%.
01:20
This wide range is attributable to interindividual variation in hepatic metabolism, which can be influenced
by factors such as genetic differences, liver function, concurrent medications, and other factors affecting liver enzyme activity.
01:38
Now, enterohepatic circulation
is a different concept because now
instead of having the drug being just simply eliminated
through the bile from the bowel,
it goes into the bile, and when it's in the bile,
it gets reabsorbed through the portal circulation
and goes back to the liver. So that circular motion
of the drug between liver and small bowel
refers to enterohepatic circulation.
Some drugs cycle between the intestine and liver.
02:06
So, clearance is the rate of elimination divided by
the plasma concentration.
02:11
It's going to be proportional to drug kinetics,
to blood flow, and to the condition of the organs
involved in clearing the drug through metabolism or excretion, which are mostly the liver and kidneys, respectively.
02:23
I want to also discuss something called flow limited
clearance. So, here we have a picture of the kidneys.
02:28
The kidneys are a classic example of flow limited clearance.
Remember that we have about 180 litres of blood
pumping through that kidney every single day.
If you cut that flow in half,
the ability of the kidney to clear drugs
is reduced by half, or at least the maximal amount.
02:47
So the kidney is a classic example of flow limited clearance.