Pharmacokinetics - Lecture 2

Question 1

Calculation of non-ionized/ionized ratios for WA and WB drugs

Answer 1

Non-ionized/ionized (N/I) ratio

Administer drug (pKa) —> tissue with a certain pH environment

Each pH unit from the pKa —> changes the N/I ratio by 10 fold

Question 2

Weak Acid Characteristics

Answer 2

WA takes ionized form as pH increases (more basic)

WA takes non-ionized form as pH decreases (more acidic)

Question 3

Weak Base Characteristics

Answer 3

WB favors ionized form as pH decreases (more acidic)

WB favors non-ionized form as pH increases (more basic)

Question 4

What is pKa?

Answer 4

50% ionized, 50% non-ionized

Question 5

Weak Acids Favors Non-Ionic or Ionic

Answer 5

Stomach = non-ionic
Intestine = ionic
Plasma = ionic

Question 6

Weak Bases favors Non-ionic or Ionic

Answer 6

Stomach = ionic
Intestine = ionic
Plasma = ionic

Question 7

For each pH unit from the pKa, this changes the N/I ratio by…

Answer 7

10 fold

Question 8

Is WA easily absorbed from stomach to plasma?

Answer 8

Yes

Question 9

Is WB easily absorbed from stomach to plasma?

Answer 9

No! It stays in the stomach due to ability to move across the membrane (which is hard because WB favors ionic, but ionic can’t cross membrane easily)

Question 10

Types of Carrier-Mediated Transport

Answer 10

Facilitated diffusion

Active transport

Receptor-mediated endocytosis

Question 11

Carrier-Mediated Transport

Answer 11

Proteins that bind to drugs to transfer across

Question 12

How many genes are in the human genome? How many encode for transporters or related proteins

Answer 12

~2,000 genes or 6-9% of the genome

Question 13

What type of substrate specificity does carrier-mediated transport have?

Answer 13

Broad

Question 14

Facilitated Diffusion

Answer 14

Protein transporter (uniporter)
Energy independent
Bi-vectorial
SoLute Carrier transporters (SLC)

Question 15

Active Transport

Answer 15

Transport drug against concentration gradient
Energy dependent (ATP)
Saturable (finite #)
Broad specificity
Susceptible to competitive inhibition
Transport continues until drug or ATP is depleted or transporter inhibited

Question 16

Two types of active transport transporters

Answer 16

Primary

Secondary

Question 17

Primary active transporters

Answer 17

Associated with active transport
Energy machinery within transporter
ATP Binding Cassette (ABC) transporter family

Question 18

Secondary active transporters

Answer 18

Associated with active transport
Energy is provided NOT within the transporter
Ion-coupled transports
- symporter: same direction as substrate
- antiporter: opposite direction as substrate
SLC transporter family (same as facilitated diffusion fam)

Question 19

ABC Transporters in Drug Disposition

Answer 19

Primary active transporters that mediate vectorial transport out of cell

Question 20

Multi-Drug Resistance (MDR) proteins

Answer 20

Resistance to cancer chemo agents

Broad specificity - organic cations and neutral drugs

Question 21

Mult-Drug Resistance-associates Proteins (MRP)

Answer 21

Efflux transporter for organic anions, phase 2 metabolites

Drug metabolism and excretion

Question 22

SLC Transporters in Drug Disposition

Answer 22

Organic Anion Transporter (OAT) family

Organic Cation Transporter (OCT) family

Question 23

OAT Family

Answer 23

OAT 1 and OAT 3
Antiporters
Anions
Basolateral (blood side) of epithelial cells

Question 24

OCT Family

Answer 24

OCT2
Uniporter
Organic cations

Question 25

NT reuptake transporters

Answer 25

Transports excess NT back to nerve ending
NET - norepinephrine transport, Na+ symport
DET - dopamine transport, Na+ symport
SERT - serotonin transport, Na+ symport
- SSRIs
- antidepressants target SERT

Question 26

Receptor-Mediated Endocytosis

Answer 26

Membrane pinches off and drug filled vesicle is transported into the cell

Requires energy, active transporter

Used for transport of large polypeptide and proteins

Question 27

Why do most drugs target the GI tract?

Answer 27

Relatively safe
Passive diffusion of lipid soluble drugs
Not saturable
No energy required for absorption

Question 28

Drug Properties that affect absorption

Answer 28

Lipophilicity- higher, better absorbed; lower, poorly absorbed
N/I ratios <0.001 are poorly absorbed
Drugs ionized at all pHs are poorly absorbed

Question 29

Even highly ionized drugs (N/I <0.001) will eventually be absorbed to some extent. Why?

Answer 29

Relatively high SA
Highly vascularized
Absorption from small intestine&raquo_space;> stomach due to low SA and thick mucosa layer in stomach

Question 30

Buccal cavity and distal rectum drugs absorbed via…

Answer 30

Directly to systemic venous circulation

Question 31

Drugs absorbed via stomach, intestine, or proximal rectum…

Answer 31

Capillaries and portal vein to liver for first pass metabolism and remaining drug is transported to hepatic vein and systemic circulation

Question 32

Pre-absorption metabolism and significance

Answer 32

Mucosal delivered drugs are susceptible to degradation

Significance: affects bioavailability of drug that is to be absorbed

Question 33

Drug Distribution

Answer 33

Drug concentration at the site of action determines pharmacological effect

Question 34

Concentration and pharmacological effect of drug distribution is determined by:

Answer 34

Where the drug is distributed

When it attains therapeutic concentration

Factors that affect drug distribution