ADME (Pharmacokinetics) Lecture Sep 17 Flashcards
The factor we look at most when discussin pharmacokinetics is the concentration of free drug in the plasma. WHat affect this?
The absorption of the drug across the cell membranes into the blood
The biotransformation (metabolism) of the drug
THe excretion fo the drug
What are the 5 major mechanisms of transport? Which two are not really involved in pharmacokinetics/
Passive diffusion
filtration
endocytosis
facilitated diffusion
active transport
Filtrations and endocytosis are not involved in drug transport
Describe passive diffusion
Passive diffusion refers to a situation where compunds move across membranes by passively diffusion trhoguh the membrane from one side to the other. The energy for this is provided by the concentration gradient - no additional energy is required.
At any point in time the drug is diffusing across in both directions - this is the flux. But if the system is not in equilibrium across the membrane, the net flow will be down the gradient.
What are the three hallmarks of passive diffusion that make it different from facilitate transport?
- Does NOT require energy input
- It does NOT saturate/approach some maximum rat eo fflux when the chemical concentration gradient is large - it just gets faster
- It is NOT inhibited by structurally similar compounds - every compound moves independently
In the Fick Equation describing passive diffusion, what variables is flux directly proportional to? What is flux indirectly proportional to?
Flux is directly propotional to: concentration gradient, diffusion consant (diffusibility of the molecule int he membrane), membrane: water partition coefficiency (measure of a compound ssolubility in the membrane -lipid solubility), and surface area
It is inversely proportional to membrane thickness (and indirectly inversely proportional to molecule size through the diffusion constant)
What effect does ionization have on membrane permeability?
What forms of weak acids will be able to cross the membrane?
What form of weak bases will be able to cross?
Ions cannot cross the membrane because they have a charge and are not lipid soluble.
Weak acids will be ions in the deprotenated form, so protenated weak acids will be neutral and can cross.
Weak bases are ions in the protonated form, so the deprotenated form is the nuetral form that is able to cross the membrane
WHat is the concept of ion trapping?
Where do weak bases get trapped?
Where do weak acids get trapped?
Differentials in pH across a membrane can result in ion trapping because the ions won’t be able to cross the membrane.
Weak bases are protonated in acidic (low pH) solutions, so bases will be trapped on acidic sides of membranes
Weak acids are deprotonated in basic (high pH) solutions, so acids will be trapped on basic sides of membranes.
Are the majority of drugs weak acids or weak bases?
70% are weak bases, like diphenhydramine (95% of which is ionized at physiological pH)
What is facilitated diffusion?
This is the movement of ions down the electrochemical gradient . THere is a carrier molecule involved, which moves a substrate from one side of the membrane to the other. No direct energy input is required.
Describe active transport
Acrive transport moves ions against the electrochemical gradient.
This requires energy!!
THe energy can come from two places: primary = ATP hydrolysis
or secondary = coupled to another compound’s gradient (symport)
In what two major ways do facilitated diffusion and active transport differ from passive diffusion?
Facilitate diffusion and active transport can be selective and inhibited by similar chemicals
They can also saturate at high substrate concentrations
What are the two carrier mediated mechanisms?
- ATP-binding cassette superfamily (ABC)
- Solute carrier family (SLC)
How do the ATP-binding cassette superfamily transporters work?
They are active transporters that use the primary mechanism of ATP hydrolysis to provide the energy for active transport.
They move substances out of cells or into cell organelles.
Describe the solute carrier transporters.
The SLC superfamily transporters particilate in facilitated diffusion and active transport through the secondary mechanism.
These move substances into and out of cells.
An important job here is reuptake of neurotransmitters like serotonin an ddopamine.
Why do both ABC and SLC transports contribute for many drug toxicities, drug-drug itneractions and inherited susceptibilities?
They are both selective and inhibited by closely related compounds.
How ar emost drugs absorbed in the body?
Which routes of administration will result in better absorption?
Most drugs are absorbed by passive diffusion.
IM is the best way to get absorption because it’s pretty much 100% immediatley.
Subcutaneous is next best.
Oral is the worst.
What are the advantages and disadvantages of oral adminsitration of a drug?
Advantages: easy administration, cheaper, more safe, good patient compliance
Disadvantages: can be destroyed in the GI and become ineffective, they will have to go through the 1st pass metabolism in the liver and may be broken down, the rate of absoprtion will be variable depending on a number of factors
What is bioavailability?
WHat is the term for this?
How is oral biovailability calculated?
Bioavailability is the fraction (f from 0 to 1) of the adminstered dose that enters the general circulation.
Oral bioavailability is measured by the AUCoral/AUCiv
where AUC refers to the area under the plasma concentration-time curve.
Lipinski made 5 rules and a drug needs at least 4 of them in order to have good bioavailability. WHat are they?
- can’t have over 5 H-bond donors (O or N with 1 or more H)
- Can’t have over 10 H-bond acceptors (total O or N)
- Molecule mass can’t be over 500
- the octanol:water partition coeficiency must be less than 5
This describes a realtively small, moderately lipophilic molecule
What are the three determinants of drug distribution throughout the body?
- Relative tissue perfusion rates (tissues that are profused more rapidly will have drug distribution faster)
- Plasma protein binding
- Partitioning between the plasma and the tissues
WHat organs will have high perfusion rates and thus faster drug equilibratin (distribution)?
What organs will have low rates?
High rates in the kidney lung, liver, and brain - these organs will get the drug fastest
Intermediate rates in muscle
Low rates in fat and bone - these may never even get the drug
How do proteins binding to drugs in the plasma affect drug distribution?
Examples?
Drugs that are bound by proteins in the plasma will not cross the membrane into tissues, so they are pharmacologically inert (but still can act as a reservoir for the drug).
Weak acid drugs are bound by albumin and made inert.
Weak base drugs are bound by alpha1 acid glycoprotein (AGP)
How does tissue:plasma partitioning affect drug distribution?
Three things are involved in plasma partitioning:
pH and ion trapping - If the pH in the tissue is very different from the pH in the plasma, some drugs will be trapped in the plasma as ions.
Tissue protein binding - Sometimes, there will be compounds that have fairly high affinity for the proteins in the tissue (like actin or myosin). This means there will be more drug in the tissue than there is in the plasma at equilibrium.
Lipid solubility - some compounds that are hydrophobic will distribut around the body in accordance to which tissues have the highest fat content
How is the blood-brain barrier specialized?
It has tight endothelium and glial cells that do not allow big molecules to pass. Lipophyllic molecules still can though.
This is an important consideration in treating CNS infections
What is the apparent volume of distribution?
How is it calculated?
The Vd is the volume in which the drug appears to be distributed at equilibrium
Vd = Total amount of drug in body/Total concentration in the plasma
It reflects the relative affinity of a drug for the whole body compared to the affinity for the plasma
It can also be normalized to body weight to allow for interpretation of its apparent value.
What would cause an increase in Vd?
How about a decrease in Vd?
Anything that causes a drug to distribute out of the plasma an dinto tissue increases the Vd
Anything that causes a drug to remain in the plasma will decrease the Vd.
WHat are the three ways a drug’s action can be terminated?
It can be stored - redistributed (as in adipose tissue for lipophyllic drugs)
It can be excreted (as an unchanged “parent compound”)
Biotransformation - metabolism that inactivates the drug
What are the two phases of distribution? WHich one is redistribution?
1: distributes to tissues with highe rperfusion rates
2. Distributes to tissues wiht lower perfusion rates and will be trapped there if the drug has higher affinity for the lower perfused areas - like adipose tissue
What are the three steps throuh the nephron that need to be taken into consideration when thinking about a drug’s excretion through the renal system?
- Filtration through the glomerulus (unbound drugs will be able to flow right through into the filtrate)
- Reabsorbtion (the kidney will reabsorb a lot of water, so the concentration of the drug in the filtrate will increase and the drug will want to be reabsorbed if it can - either passivly or through a transporter if it’s recognized by one)
- Secretion (some of the blood isn’t filtered thorugh the kidney, but active transporters that recognize anything in that blood will be able to actively pump it into the filtrate)
What is renal clearance?
What is the average renal clearance of a drug that is filtered through the glomerulus only?
What is the renal clearance of a drug that is filtered through the glomerulus and reabsorbed back through the tubule?
What is the renal clearacne of a drug that is filtered through th glomerulus and actively secreted?
Renal clearance (CLr) is the volume of the plasma that is cleared by the kidney in an hour
FOr a drug that is filtered only, the CLr will be equal to the glomerular filtration rate (usually 125 ml/min)
For a drug that is filtered and reabsorbed, the CLr will be less than the GFR (125)
FOr a drug that is filtered and secreted, CLr will be greater than the GFR (125)
How does biliary excretion work?
Describe enterohepatic circulation.
Often times the drug must be metabolized in order to enter biliary excretion.
Facilitated transport (solute carrier transporters) will move the drug into the hepatocyte from the blood.
Active transports will then pump the drug (often metabolized at this point) from the hepatocytes into the bile
The bile will then be stored in the gall bladder, which will pump it back into the GI system in response to a meal.
Enterohepatic circulation occurs when a conjugated drug is put back into the GI system through the bile, the microflora will use their enzymes to remove the sugar conjugates, and the drug will against be reabosrbed into the kidney and the cycle continues. This can lead to toxicity!
WHat does biotransformation usually do?
It uses enzymes to transform drugs.
Metabolites are generally more polar.
Matabolites may be active or inactive (sometimes the drug HAS to be metabolized in order to be active–a prodrug)
What are the two phases of biotransformation?
Phase 1:
Add or expose functional groups (OH, NH2, SH)
Oxidation is the most common
Metabolites generally more polar
Metabolites may be active or inactive
Phase 2:
Synthetic reactions
Glucaronidation is the most common reaction
Metabolite are generally more polar
THe metabolites are usually inactivated in the process.
What is the major organ of biotransformation?
WHat are some others?
The liver is the big one because it has most of the enzymes needed for the biotransofrmation enzymes. This also occurs because the liver is the organ almost alld rugs will go to before entering systemic circulation - it provides a perfect opporutnity to get rid of what the body doesn’t actually want.
Others include the GI tract, Kidney, lungs, skin, and plasma itself
Where is the cytochrome p450 system located in the cell?
Is it responsible for phase 1 or phase 2 of biotransformation?
They are localized to the SER
They are responsible for Phase I metabolism of many drugs
WHat does monamine oxidase do?
It converts norepinephrine to dihydroxymandelic acid.
It’s very important for terminating NT activity for norepeinephrine and serotonin - they degrade the amines.
This is a major drug target. Antidepressants are often MAO inhibitors so the serotonin isn’t degraded
What are 5 examples of phase II conjugation reactions? Which is the most comon?
- glucaronidation (MOST COMMON–in the SER)
- Acetylation
- Sulfate conjugation
- Methylation
- Glutathione conjugation
Acetylation and methylation are used to more mask an active site, whereas the other three are mostly used to make a drug really chunky and really polar
What are some inhibitors of biotransformation?
Drugs will competitively inhibit
Cimetidine, ketoconazole, grapefruit juice will inhibit the p450
Disfulriam will inhibit ALDH
Iproniazid will block MOA
What are some substances that will induce expression of P450?
Phenobarb
carcinogeni hydrocarbons
alcohol
rifamin
This will result in apparent drug tolerance because the body metabolizes drugs too fast
What are other factors that will alter biotransformation?
genetics (we all have different cyps)
diet
environment (manufacturing jobs)
age (lower)
pregnancy
