Lec 67: Drug Metabolism II

Question 1

What are the four basic mechanisms of drug passage across membranes?

Answer 1

Passive diffusion, Filtration, Active transport and Endocytosis

Question 2

What law governs passive diffusion?

Answer 2

Fick’s Law. Diffusion down a concentration gradient.

Question 3

What determines molecular passage in the filtration method of drug passage across biological membranes?

Answer 3

The pore size. Molecules move down a concentration gradient.

Question 4

What feature distinguishes Active transport most prominently against the other methods of drug transport across membranes?

Answer 4

It requires ATP and can go (and often does) against the concentration gradient.

Question 5

MDR1 is aka?

Answer 5

Multi Drug Resistance gene 1 and it makes P-glycoprotein. Which is a drug transporter.

Question 6

Endocytosis is…?

Answer 6

The entrance of extracellular substances into the cell by binding a receptor on the cell surface and being pulled into the cell within an individual lipid membrane derived from the cell surface. (Potential vector for virus entrance into cells).

Question 7

What are 3 key factors that influence diffusional drug passage across the cellular membrane?

Answer 7

Concentration gradient, Lipid Solubility and Ionization

Question 8

How does concentration gradient affect the diffusional drug passage across the cellular membrane?

Answer 8

Drugs that are able to pass through the membrane will move from an area of lower concentration to an area of higher concentration.

Question 9

How does lipid solubility affect the diffusional drug passage across the cellular membrane?

Answer 9

The chemical structure of a drug determines the solubility. If it is lipid soluble the drug will pass more easily through the membrane.

Question 10

How do we measure the lipid solubility of a drug?

Answer 10

With the “Lipid solubility coefficient” - A higher coefficient means that the molecule is more easily able to pass through the lipid membrane.

Question 11

Two barbituate drugs have lipid solubility coefficients of 3.3 - (thiopental) and 0.002 - (barbital), which passes more easily through lipid membranes?

Answer 11

Thiopental. (Which is why it is used to induce anesthesia, it acts faster because of its higher lipid solubility coefficient).

Question 12

How does drug ionization affect the ability to diffuse into cells?

Answer 12

Molecules which are charged will have a harder time passing through lipid membranes. Those which are uncharged are free from hydration shells and can often diffuse through the membrane. Hydration shells forming around charged ions block this passage.

Question 13

If a weak acid (pKa ~ 3.5) is put in an acidic environment (like the stomach pH 1.5) What do can you say about its ionization state and diffusion potential?

Answer 13

It will NOT be ionized and so will be able to diffuse into the stomach.

Question 14

What are the two drug transporter families we learned in lecture?

Answer 14

ABC (ATP Binding Cassette) and SLC (Solute Linked Carrier) super families.

Question 15

Name an important example of the ABC super family and describe its mechanism.

Answer 15

MDR1 - Makes P-glycoprotein, an ABC that pumps solutes across cell membranes. (In the brain it often pumps drugs out by ATP hydrolysis, in other organs it can pump in or out depending on what it is used for).

Question 16

What are two examples of SLC transporters and what do they transport?

Answer 16

SERT - The serotonin transporter. (On which Prozac acts) and DAT - The Dopamine transporter. (On which cocaine and methylphenidate (Ritalin) act).

Question 17

How do facilitative transporters work?

Answer 17

They use ion coupled secondary active transport to move solutes across the membrane.

Question 18

What are the four routes of enteral drug administration?

Answer 18

Buccal cavity, stomach, small intestine and rectum.

Question 19

What are the five routes of parenteral drug administration?

Answer 19

Intravenous (IV), inhalation, intramuscular (IM), subcutaneous (SC) and percutaneous.

Question 20

What is the advantage of buccal cavity (sublingual) drug administration?

Answer 20

The drug enters the systemic circulation first by being absorbed under the tongue (instead of in the stomach or intestines) which avoids the first pass metabolism of the liver.

Question 21

What are the advantages/disadvantages of stomach absorption of a drug?

Answer 21

The low pH affects drug stability. Can easily absorb acidic (and weak base) drugs that are not ionized. Drugs are subject to first pass metabolism to the liver and then to the systemic circulation.

Question 22

What are the advantages/disadvantages of intestinal absorption of drugs?

Answer 22

The pH of the intestines is around 6-7.4. Ease of absorption of most drugs. Subject to first pass metabolism.

Question 23

What are some advantages/disadvantages of rectal administration of drugs?

Answer 23

There is less irritation than the oral route. You may be able to avoid first pass metabolism depending on location within the rectum. This administration location is less well tolerated than the oral route.

Question 24

What are some advantages/disadvantages of intravenous drug administration?

Answer 24

Sends the drug directly into the drug stream. 100% absorption and no first pass metabolism.

Question 25

What are some advantages/disadvantages of drug administration by inhalation?

Answer 25

Requires the drug be volatile or gaseous drug, provides rapid absorption for anesthetics or asthma medications.

Question 26

What are some advantages/disadvantages of intramuscular drug administration?

Answer 26

Enters systemic circulation without first pass metabolism.

Question 27

What are some advantages/disadvantages of subcutaneous drug administration?

Answer 27

Slower absorption depending on blood flow?

Question 28

What are some advantages/disadvantages of percutaneous drug administration?

Answer 28

(Example steroid patches) useful for highly potent lipid soluble drugs.

Question 29

How can you describe the equilibrium between plasma bound drug in the body and free drug?

Answer 29

([Free drug]/[Kd][Free drug])

Question 30

Plasma protein binding - [total drug] = ?

Answer 30

[Free drug] + [Bound drug]

Question 31

How might lipophilic drugs interact with albumin?

Answer 31

They may become bound to it.

Question 32

(Mass of the Drug absorbed)/(plasma volume) = ?

Answer 32

Volume of Distribution

Question 33

Low volume of distribution indicates?

Answer 33

High plasma concentration

Question 34

High volume of distribution indicates?

Answer 34

Concentration of the drug in extravascular areas.

Question 35

Remember that bioavailability affects the amount of drug absorbed.

Answer 35

Also remember the implications for that in IV vs. Oral administration of the drug.

Question 36

Tissue accumulation of a drug can occur where in the body?

Answer 36

Really anywhere, but key locations are kidney, eye, lung, bone, and fat.

Question 37

What is the cause of drug accumulation in different organs?

Answer 37

It is caused by binding proteins unique to that organ or just accumulation of lipid soluble drugs in fat deposits.

Question 38

What happens to resevoirs of drugs (stored in organs) as blood concentration goes down?

Answer 38

The equilibrium will cause the drug to be released into the blood stream.

Question 39

Three factors affect the ability of drugs to enter the CNS, what are they?

Answer 39

There are relatively few pores in the blood brain barrier to allow entry, highly lipophilic drugs have a better chance of entry, ABC transporters (like MDR-1) pump many drugs that are able to enter, back out.

Question 40

Three special notes should be made of MDR-1 when it comes to CNS involvement.

Answer 40

Some drugs are especially good substrates for MDR-1 which means they should stay out of the CNS almost entirely.

1) Morphine which only has 10% of the CNS concentration compared to plasma concentration. (This is still enough for a therapeutic effect).
2) HIV proteases are pumped out quickly making the brain a safe haven for HIV
3) Some anti-cancer drugs are pumped out quickly, making using them to treat brain cancers difficult.

Question 41

What 5 factors influence placental passage of drugs to a growing conceptus?

Answer 41

1) Lipid solubility
2) Size and pH
3) Placental Transporters
4) Protein Binding
5) Placental metabolism of drugs

Question 42

How is placental passage of drugs affected by Lipid Solubility?

Answer 42

More soluble drugs are able to pass more easily and enter the fetal circulation.

Question 43

How is placental passage of drugs affected by size and pH of the drug?

Answer 43

Most smaller drugs (250-500) can pass easily depending on their charge and lipophilicity. (500-1000MW) drugs have a harder time and large polar drugs can’t pass through it at all (like Heparin).

Question 44

What should be remembered about fetal blood circulation of drugs? (Specifically blood pH related)

Answer 44

Fetal blood has a pH of about 7.3 making slightly basic drugs more ionized preventing them from leaving fetal circulation and therefore accumulating.

Question 45

How is placental passage of drugs affected by placental transporters?

Answer 45

P-glycoprotein transporter (MDR-1 gene’s product) will affect certain drugs the same way they do for the brain. Namely that they pump them out. This has implications for HIV treatment because the viral protease inhibitors won’t be able to remain in fetal circulation and the child will have an increased risk of catching parental HIV.

Question 46

How is placental passage of drugs affected by protein binding?

Answer 46

Greater protein binding (via albumin usually) leads to lower levels of fetal circulation but may not affect very lipophilic compounds.

Question 47

How is placental passage of drugs affected by the placental metabolism of drugs?

Answer 47

The placental barrier acts as a block and sometimes a site of metabolism for drugs that are trying to enter fetal circulation. This can have the effect of either increasing or decreasing drug toxicity.

Question 48

List 4 of the main methods of drug elimination.

Answer 48

Renal clearance, Fecal clearance, Expired clearance (breathing them out), Breast milk clearance (usually very small concentrations).

Question 49

How does ionization affect the renal clearance of a drug?

Answer 49

Urine pH is about 5.5, and plasma pH is about 7.5. That means that weak bases tend to move from the plasma to the urine in the kidney. (And acids will do the reverse).

Question 50

How is drug dosing affected in children and the elderly?

Answer 50

Dosing should be adjusted for children using the manufacturers specifications (usually based on age, weight, and surface area of the skin (if the drug is administered topically). For the elderly you should expect potentially decreased renal clearance and/or reduced respiratory capacity.