Week 3 Flashcards
What is the principal site of drug metabolism?
In the liver is the main site
However, other body sites, such as the lungs, skin, kidney and GI tract also have metabolic enzymes
Where does drug biotransformation/ hepatic elimination occur?
In the liver:
→ there are metabolic enzymes that help to eliminate the drug
→ secretion into bile
What is the hepatic clearance formula
ClH=QhxERh
CLH is the hepatic clearance, i.e. the volume of blood that is cleared of drug per unit time on passage through the liver
QH is the liver blood flow
ERH is the hepatic extraction ratio, i.e. the fraction of drug that is removed from the blood on one pass through the liver
*For the liver, QH is the sum of two blood flows – the hepatic portal vein and hepatic arterial blood flow which are ~1050 and 300 mL/min, respectively.
→ The total hepatic blood flow is therefore ~1500 mL/min depending on the individual.
How do we know if a drug has a low or high hepatic extraction ratio?
Hepatic blood flow is ~1500 mL/min
High extraction ratio >0.7 and these high extraction ratio drugs have CLH values >1000 mL/min.
A low extraction ratio is < 0.3 and low extraction ratio drugs have CLH values < 500 mL/min.
An intermediate extraction ratio is between 0.3-0.7 and CLH values of 500-1000 mL/min.
What are the processes that influence hepatic clearance and extraction ratio?
Hepatic clearance of drugs occur in the liver within the hepatocytes (main cells)
Five main processes that can influence the ability of the liver to extract and eliminate the drugs from the blood (hepatic clearance→ the volume of blood plasma that is cleared of drug after it is removed per unit time)
The drug is identified within the blood plasma (1)
(2) if the drug is unbound then it can be bounded by binding to proteins → needs to be extracted via the blood plasma - renal elimination (the kidney)
(3) the unbound drug from (2) continues to be unbound in the hepatocyte (cell) in the liver → either goes to (4)- metabolite (via enzymes) or (5)- secreted via the bile
What are the factors that influence hepatic clearance and extraction ratio?
- Hepatic blood flow (QH) or perfusion: influences drug delivery to the liver hepatocytes. Disease and exercise can change perfusion.
- Whether or not the drug binds to plasma proteins or cells, focussing on Fu value- fraction unbound in blood- as only unbound drug is free to permeate the hepatocyte. Disease and competing drugs can influence drug binding to plasma proteins and cells.
- Membrane permeability of the drug or the intrinsic ability of the drug to cross plasma membranes. An increase in permeability can increase uptake into hepatocytes. This is not often a rate-limiting step.
- Intrinsic clearance (CLint) or the inherent ability of hepatocytes to eliminate drugs via metabolism or secretion into bile:
Drugs with a strong affinity for their metabolising enzymes, for which there are a large number of metabolising enzymes;
or drugs that have transporters that promote their secretion into bile; are more efficiently extracted by the liver and therefore have higher ER.
Disease and other drugs can affect intrinsic clearance.
Note: Any one of these five processes may be the slowest or rate-limiting step in the overall drug elimination within the liver (depending on the drug). Exception: membrane permeability
What determines the rating limiting step (s) on the overall hepatic elimination of a drug and Influences the changing of these factors on the overall hepatic elimination of a drug?
Depends whether the drug’s extraction ratio is low, intermediate or high
What is Rowland’s equation for hepatic clearance?
describes the relationship between intrinsic clearance, plasma protein binding and blood flow on hepatic extraction ratio and clearance
What happens when a drug has a high hepatic ER?
The hepatic clearance is dependent on blood flow, meaning blood flow will affect the hepatic clearance
For drugs with a high hepatic extraction ratio (i.e. ER > 0.7), hepatic blood clearance approaches hepatic blood flow (since CLH = QH . ERH). This is because a high extraction ratio approaches 1, meaning close to 100% of the drug is being excreted, so CLH= QH
Process:
The drug in the blood plasma will become unbound from plasma proteins or cells
The drug will then cross the hepatocyte membrane and is rapidly eliminated by metabolism or secretion into blood, bile or both
There is a high hepatocyte uptake and is an excellent substrate for elimination processes
The elimination becomes rate-limited by perfusion
What are the characteristics of drugs that have high hepatic ER?
Hepatic drug clearance are more affected by the changes to in liver blood flow and is less affected by the changes in plasma protein binding or intrinsic clearance (i.e. changes in hepatic metabolism or biliary excretion)
Reducing hepatic blood flow, reduces hepatic clearance (i.e. diseases such as congestive heart failure, hypotension, drugs)
Greatly affected by the “first pass” metabolism / effect when given orally because whenever the drug is administered orally, enters the liver, and suffers extensive biotransformation to such an extent that the bioavailability is drastically reduced and the active drug concentration upon reaching systemic circulation or its site of action is reduced
What happens when a drug has an intermediate hepatic ER?
Hepatic clearance would be affected by changes in the hepatic blood flow, binding to plasma proteins and changes in intrinsic clearance (all the factors)
What happens when a drug has a low hepatic ER?
Low hepatic ER is binding sensitive
Hepatic clearance is affected by changes in intrinsic clearance and is dependent on binding to plasma proteins and/ or cells in the blood
→ This is because only unbound drugs are available to be penetrated across the hepatocyte membrane, as the the drop in drug concentration on passage through the liver is small (i.e. the unbound concentration of drug in plasma leaving the liver is essentially the same as the unbound concentration that enters the liver).
Dependent on binding to plasma proteins:
Depends on whether the drug is fraction unbound in the blood starting from the beginning
→ Binding insensitive: occurs when <75-80% of the drug is protein bound to begin with. For these drugs, changes in the fraction bound do not result in massive changes in the unbound drug concentration and so =, does not greatly affect drug into the liver and the clearance
→ Binding sensitivity: occurs when >80% of the drug is protein bound to begin when. For these drugs, small changes in the fraction bound can lead to large changes in the free/unbound drug concentration (the available concentration to enter the liver), because if this would result in a great dip between the unbound concentration and the bound concentration affecting its permeability)
CLH of highly protein bound drugs can therefore be influenced by small changes in fraction unbound
What is it called when elimination is influenced by protein binding?
‘restrictive elimination’.
What is bile?
Produced by the hepatic cells that line the bile canaliculi via active secretion processes
helps with fat digestion and absorption through their digestion action
(emulsification) and micellar formation (enhances absorption of fat)
Bile consists of water, bile salts, bile pigments, electrolytes, phospholipid, cholesterol and other lipids.
Bile flows from the cannaliculi to the intrahepatic bile ducts, then enters the gallbladder where it is concentrated.
The common bile duct then empties bile into the duodenum (Figure 2).
How does the molecular weight of drugs impact where it is excreted?
Drugs with molecular weight > 500 Da are typically excreted in bile
Drugs with molecular weight between 300-500 Da are excreted in both urine and bile and each of these routes can compensate for the other
Drugs with molecular weight < 300 Da are typically excreted exclusively into the urine via the kidneys
