ADME (Pharmacokinetics) Lecture Sep 17

Question 1

The factor we look at most when discussin pharmacokinetics is the concentration of free drug in the plasma. WHat affect this?

Answer 1

The absorption of the drug across the cell membranes into the blood

The biotransformation (metabolism) of the drug

THe excretion fo the drug

Question 2

What are the 5 major mechanisms of transport? Which two are not really involved in pharmacokinetics/

Answer 2

Passive diffusion

filtration

endocytosis

facilitated diffusion

active transport

Filtrations and endocytosis are not involved in drug transport

Question 3

Describe passive diffusion

Answer 3

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.

Question 4

What are the three hallmarks of passive diffusion that make it different from facilitate transport?

Answer 4

1. Does NOT require energy input
2. It does NOT saturate/approach some maximum rat eo fflux when the chemical concentration gradient is large - it just gets faster
3. It is NOT inhibited by structurally similar compounds - every compound moves independently

Question 5

In the Fick Equation describing passive diffusion, what variables is flux directly proportional to? What is flux indirectly proportional to?

Answer 5

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)

Question 6

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?

Answer 6

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

Question 7

WHat is the concept of ion trapping?

Where do weak bases get trapped?

Where do weak acids get trapped?

Answer 7

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.

Question 8

Are the majority of drugs weak acids or weak bases?

Answer 8

70% are weak bases, like diphenhydramine (95% of which is ionized at physiological pH)

Question 9

What is facilitated diffusion?

Answer 9

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.

Question 10

Describe active transport

Answer 10

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)

Question 11

In what two major ways do facilitated diffusion and active transport differ from passive diffusion?

Answer 11

Facilitate diffusion and active transport can be selective and inhibited by similar chemicals

They can also saturate at high substrate concentrations

Question 12

What are the two carrier mediated mechanisms?

Answer 12

1. ATP-binding cassette superfamily (ABC)
2. Solute carrier family (SLC)

Question 13

How do the ATP-binding cassette superfamily transporters work?

Answer 13

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.

Question 14

Describe the solute carrier transporters.

Answer 14

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.

Question 15

Why do both ABC and SLC transports contribute for many drug toxicities, drug-drug itneractions and inherited susceptibilities?

Answer 15

They are both selective and inhibited by closely related compounds.

Question 16

How ar emost drugs absorbed in the body?

Which routes of administration will result in better absorption?

Answer 16

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.

Question 17

What are the advantages and disadvantages of oral adminsitration of a drug?

Answer 17

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

Question 18

What is bioavailability?

WHat is the term for this?

How is oral biovailability calculated?

Answer 18

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.

Question 19

Lipinski made 5 rules and a drug needs at least 4 of them in order to have good bioavailability. WHat are they?

Answer 19

1. can’t have over 5 H-bond donors (O or N with 1 or more H)
2. Can’t have over 10 H-bond acceptors (total O or N)
3. Molecule mass can’t be over 500
4. the octanol:water partition coeficiency must be less than 5

This describes a realtively small, moderately lipophilic molecule

Question 20

What are the three determinants of drug distribution throughout the body?

Answer 20

1. Relative tissue perfusion rates (tissues that are profused more rapidly will have drug distribution faster)
2. Plasma protein binding
3. Partitioning between the plasma and the tissues

Question 21

WHat organs will have high perfusion rates and thus faster drug equilibratin (distribution)?

What organs will have low rates?

Answer 21

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

Question 22

How do proteins binding to drugs in the plasma affect drug distribution?

Examples?

Answer 22

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)

Question 23

How does tissue:plasma partitioning affect drug distribution?

Answer 23

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

Question 24

How is the blood-brain barrier specialized?

Answer 24

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

Question 25

What is the apparent volume of distribution?

How is it calculated?

Answer 25

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.

Question 26

What would cause an increase in Vd?

How about a decrease in Vd?

Answer 26

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.

Question 27

WHat are the three ways a drug’s action can be terminated?

Answer 27

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

Question 28

What are the two phases of distribution? WHich one is redistribution?

Answer 28

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

Question 29

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?

Answer 29

1. Filtration through the glomerulus (unbound drugs will be able to flow right through into the filtrate)
2. 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)
3. 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)

Question 30

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?

Answer 30

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)

Question 31

How does biliary excretion work?

Describe enterohepatic circulation.

Answer 31

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!

Question 32

WHat does biotransformation usually do?

Answer 32

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)

Question 33

What are the two phases of biotransformation?

Answer 33

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.

Question 34

What is the major organ of biotransformation?

WHat are some others?

Answer 34

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

Question 35

Where is the cytochrome p450 system located in the cell?

Is it responsible for phase 1 or phase 2 of biotransformation?

Answer 35

They are localized to the SER

They are responsible for Phase I metabolism of many drugs

Question 36

WHat does monamine oxidase do?

Answer 36

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

Question 37

What are 5 examples of phase II conjugation reactions? Which is the most comon?

Answer 37

1. glucaronidation (MOST COMMON–in the SER)
2. Acetylation
3. Sulfate conjugation
4. Methylation
5. 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

Question 38

What are some inhibitors of biotransformation?

Answer 38

Drugs will competitively inhibit

Cimetidine, ketoconazole, grapefruit juice will inhibit the p450

Disfulriam will inhibit ALDH

Iproniazid will block MOA

Question 39

What are some substances that will induce expression of P450?

Answer 39

Phenobarb

carcinogeni hydrocarbons

alcohol

rifamin

This will result in apparent drug tolerance because the body metabolizes drugs too fast

Question 40

What are other factors that will alter biotransformation?

Answer 40

genetics (we all have different cyps)

diet

environment (manufacturing jobs)

age (lower)

pregnancy