drug elimination Flashcards
drug elimination
is a defence mechanism that takes foreign substances out of the body and applied to any foreign substances, including medicines
Drug elimination is the irreversible loss of drug by excretion and metabolism and or metabolism
excretion
reversible loss is of the chemically unchanged drug
It occurs by taking this to urine. But sometimes we can have excreted drugs into bile, sweat, saliva, air, breast milk
metabolism
conversion of the drug into different chemical species or metabolite. also called biotransformation
mainly occurs in the liver
also in the lungs, GI wall, blood, skin, kidney
Metabolism (biotransformation) is a defence mechanism against undesirable foreign compounds, including drugs.
The liver is the major site of drug metabolism.
Most common routes are:
Oxidation, reduction, hydrolysis: Phase I reactions
Conjugation: Phase II reactions.
Metabolites can be:
Inactive,
Toxic,
Active, as the drug administered
Exploited therapeutically: Administration of prodrugs relies on metabolism to form the active compound (the metabolite) from the inactive prodrug
elimination of a drug will help predict
we can predict drug concentration following uptake of a medicine
We can predict how liver and renal disease may affect drug concentration.We have seen that lever. And again, these are the key organs involved in drug elimination.So if a patient has liver disease, renal dysfunction doesn’t mean that drug concentration will not decline as fast as he should
We also be able to predict interactions that affect drug elimination. So there are interactions of drugs with other drugs, with components in food, with components of natural and herbal products that may change the elimination of a drug. We will want to know whether these interactions change the elimination of a drug to the point that are clinically relevant.
we will be able to predict possibility in drug therapy due to the age because different age groups have different elimination capabilities for some drugs and also different population may have genetic differences in metabolizing enzymes, which may be, again, sometimes clinically relevant. The elimination process for each drug is described and quantify by its clearance.
Clearance (Cl) and volume of distribution (V) are the most important pharmacokinetics parameters for a drug because they determine:
the concentration that will be achieved after a dose, and so the effects and toxicity
how the concentration of a drug will evolve with time - length of effects and toxicity
the body exposure to the drug, and thus the effects and toxicity.
for an absorbed dose.
Clearance is defined as
The proportionality factor that relates the elimination rate of a drug with the drug concentration in blood (plasma).
Volume of fluid (blood, plasma) that is completely cleared of drug per unit time.
The units for clearance are volume/time (for example: mL/min, L/h)
Example: ClDrug = 15 mL /min
15 mL of plasma (blood) are cleared of drug every minute
steady state
the rate in which is how much drug is taking per unit of time equals the rate out, which is how much drug is eliminated from the body per unit time
Clearance, dosage regimen and steady state in a dose regimen
Rate in (dose / time) = Rate out (Cl x Css)
the liver
The liver receives blood from:
Hepatic artery (25%)
Hepatic portal vein from various GI segments (75 %)
Liver receives ≈ 1.5 L/min
Blood arriving from both systems fuse and enter the liver capillaries called “sinusoids”.
Blood leaves the liver via the hepatic vein that goes to the vena cava.
The liver secretes bile acids, which empty to the common bile duct, and finally go to the gallbladder.
Liver excretes and metabolizes drugs.
How does the liver eliminate drugs?
The liver is the organ with the largest metabolic capacity in the body
Hepatic elimination processes include metabolism + biliary excretion
Liver elimination works on endo- and exogenous substances.
Lipophilic chemicals are usually metabolized into more hydrophilic entities and then, excreted into urine or bile.
Drugs in blood may be:
Bound to plasma proteins,
Bound to blood cells
Free (unbound).
In principle, only free drug can enter the hepatocyte to be eliminated.
Biliary Excretion and Enterohepatic cycle
High Biliary Clearance:
Polar
MW > 350
Actively secreted
Examples:
Drugs: Pravastatine
Metabolites: Glucuronide conjugates of drugs
bilarlay excretion-bile duct- gallblader- intestine to feceaces or reacsopbed in to the blood
Enzymes and drug metabolism
To be metabolized by one specific enzyme, a drug must:
Have the right 3-D structure to interact with the “enzyme site” responsible for the reaction.
Have a certain affinity for this site
Enzyme-drug reactions are typically described by the Michaelis-Menten equation (see next slides).
Drugs metabolized by the same enzyme can be metabolized at different rates.
A drug can be metabolized by several enzymes. Understanding the “metabolic pathways” for a candidate is part of the drug discovery-development process
Enzymatic metabolism:the P450 family
is done by enzymes belonging to the cytochrome P450 family.
There are other enzymes also involved in drug metabolism
Some characteristics of drug metabolism:
Substrate specificity:
A drug is normally a good substrate for one (some) enzymes but not for others.
Kinetics: Enzymatic reactions follow Michaelis-Menten kinetics:
Vmax is the maximum elimination rate (mass/time)
KM is the Michaelis constant (mass/volume).
KM is the concentration of drug at which the rate of the process equals ½ Vmax
Drug metabolism is saturable:
At high concentrations of drug the rate of elimination becomes constant and equal to Vmax
For most drugs, saturation occurs at concentrations higher than those used for therapy.
Drug interactions:
Drug metabolism may be altered by diet, concomitant drugs and chemicals (food, natural products, tobacco). (See next slide for examples)
Enzyme-inhibition: direct inhibition or by competition
Enzyme-induction: A drug- or other chemical increases the activity of the enzyme (usually increased amount of enzyme):
Enzyme inducers: smoking, insecticides, rifampin, phenobarbital
Enzyme inhibitors: SSRIs inhibit the CYP2D6 system;
grape fruit inhibits CYP3A4
Variability: Levels and activity of enzymes may differ among individuals resulting in different values of clearance for a same drug. This variability can be clinically relevant in some cases.
genetic variations: fast metabolizer; slow metabolizer, ultra-fast metabolizer
age, physio-pathology (hepatic disease)
Michaelis-Menten kinetics
Model used for describing enzymatic reactions
Drug (D) form a complex (ED) with the enzyme (E).
ED undergoes through biotransformation under the Metabolite (M) is formed.
M leaves the enzymatic site and E can accept a another drug molecule.
dC/dt = rate of metabolism,
C = Drug concentrattion
Vmax maximum rate of metabolism
KM = Michaelis-Menten constant.
It measures the affinity of the drug for the enzyme.
When C = KM ; -dC/dt = 0.5*Vmax.
Extraction Ratio (E)
The value of an extraction ratio for a drug and eliminating organ can range from:
0 the drug is not eliminated as in this case: Centering = Cleaving
1 all the drug is eliminated as in this case: Cleaving = 0
EH = 0.25 25% of the drug entering the liver is eliminated.
The hepatic extraction ratio is a the measure of the liver efficiency in eliminating the drug from the systemic circulation over a single pass through the organ.
Link Clearance (Cl) - Extraction Ratio (E
The hepatic Clearance (ClH) measures the loss of drug across the liver and can be defined as:
The volume of blood entering the liver from which all the drug is removed per unit time.That is, an CLH = 45L/h for a drug indicates that the liver can extract all the drug present in 45L of blood in one hour
Or also as:
The ratio between the hepatic elimination rate and the incoming concentration.
Drugs with High Extraction Ratio
For some drugs the time required for:
(a) leaving blood cells
(b) dissociating from plasma proteins,
(c) diffusing hepatic membranes
(e) being metabolized by enzymes
(d) being transported to bile
is so short that most of the drug being delivered by the blood is removed by the liver.
The hepatic extraction ratio (EH) or liver capacity to extract irreversibly these drugs is high and approaches 1.
The Hepatic Clearance for these drugs gets close to the hepatic blood flow (~ 1.5 L/min = 90 L/h).
In practical terms, an extraction ratio between 0.7-1 is considered as high.
Partition out from blood cells, dissociation from plasma proteins, passage through membranes and into bile is very fast.
The elimination process depends primarily on the blood bringing more drug. Clearance is perfusion rate-limited.
Hepatic Clearance approaches hepatic Blood flow
QH ≈ 1.5 L/min or 90 L/h (E =1)
The hepatic clearance of drugs with high hepatic extraction ratio is:
very sensitive to changes in blood flow (example during surgery, some disease states)
relatively insensitive to changes in plasma binding, and enzymatic interactions
Drugs with high hepatic extraction ratio have usually low systemic absorption because of they are metabolized extensively by First Pass effect. For a drug with EH = 0.8, 80% of an oral dose will be lost by hepatic first pas effect
Low extraction Ratio
For other drugs, the value of the extraction ratio is smaller.
This can be due to a:
(a) slow dissociation from RBC,
(b) slow dissociation from plasma proteins,
(c) slow diffusion into the hepatocytes
(e) most frequent:slow enzymatic reaction
(d) slow transport into the bile.
practical terms, an extraction ratio 0.3 is considered as low.
One of these processes rate limits the hepatic elimination of the drug: Partition out from blood cells, dissociation from plasma proteins, passage through membranes and into bile is slow.
Most frequently: the drug is a poor substrate for the enzymes.
Because the poor efficiency of the liver in eliminating the drug: Centering ≈ Cleaving
ClH approximate ranges from 0 (EH=0) to 0.3x90L/h (EH=0.3) = 27 L/h
Hepatic Clearance is:
sensitive to changes plasma binding, enzymatic interactions
insensitive to changes in blood flow
Summary
Elimination, metabolism and excretion definitions
Cl concept and units. Links to drug therapy. Additivity of Cl: Total Cl = Hepatic Cl + Renal Cl
3. The liver as an eliminating organ. Biliary Clearance.
4. Concept of extraction ratio. For any eliminating organ: Clorgan = Qorgan x Eorgan
Relation between extraction ratio, clearance and elimination rate
Drugs with low and high extraction ratio. Impact on clearance and first pass effect.
Metabolism can be described with Michaelis-Menten Kinetics
- Some features of drug metabolism:
Specificity,
Saturation,
Drug interactions (competition, enzymatic induction, inhibition),
Variability.
