Pharmacokinetic Principles: ADME

Question 1

AMDE:

Answer 1

Absorption, Metabolism, Distribution, Excretion

Question 2

ABSORPTION – Factors contributing to diffusion rate across a biological membrane:

Answer 2

• Passive diffusion
• Convective transport
• Carrier-mediated
  
  • Facilitated Diffusion or Active Transport (requires ATP)

Question 3

Passive diffusion rate or flux:

Answer 3

Fick’s Law of Diffusion

• depends on magnitude of concentration gradient across
the GI & vascular membranes (𝑪𝟏 − 𝑪𝟐) • membrane surface area

• membrane thickness

• partition coefficient of the drug

• drug diffusion coefficient

Question 4

Convective transport:

Answer 4

• driven by pressure gradient

* e.g. glomerular filtration

Question 5

Carrier-mediated (facilitated diffusion):

Answer 5

• lipid insoluble compounds too large to fit through
membrane pores

• transporter proteins facilitate diffusion down the concentration gradient

Question 6

Active transport:

Answer 6

Differs from passive diffusion

1. Can occur against a concentration gradient
2. transporters can become saturated
3. compounds with similar structures can compete for transporters

Question 7

pH-partition hypothesis of drug absorption:

Answer 7

1. The GI and other biological membranes act like lipid barriers
2. Neutral form of ionizable drugs are preferentially absorbed
3. Most drugs are absorbed by passive diffusion
4. Absorption rate and extent are related to partition coefficient
5. Weak acid and neutral drugs may be absorbed through stomach but basic drugs are not

Question 8

Ionization and pH at the site of absorption:

Answer 8

• % ionized depends upon pKa & pH @ absorption site

• Henderson-Hasselbalch:
𝒍𝒐𝒈 (𝐩𝐫𝐨𝐭𝐨𝐧𝐚𝐭𝐞𝐝) = 𝒑𝑲𝒂 − 𝒑𝑯 (unionized)/(ionized)

for acids:
(𝐮𝐧𝐢𝐨𝐧𝐢𝐳𝐞𝐝)/(𝐢𝐨𝐧𝐢𝐳𝐞𝐝)

for bases:
(ionized)/(unionized)

Question 9

Lipid Solubility & Partition Coefficient:

Answer 9

• Partition Coefficient describes the relative solubility of a molecule in lipid vs aqueous phase
• Most typically expressed as LogP

• Higher LogP = Higher absorption (passive membrane
diffusion)

• Regardless of lipophilicity drugs have to have some degree of aqueous solubility

Question 10

Biopharmaceutics Classification System:

Answer 10

Class I, Class II, Class III, Class IV

FDA classifies medications in terms of solubility and permeability

Question 11

Class I:

Answer 11

High Solubility High Permeability

Very well absorbed; fewer things can interact with them

Question 12

Class II:

Answer 12

Low Solubility High Permeability

Issues involved deal with alteration of intestinal pH

Question 13

Class III:

Answer 13

High Solubility Low Permeability

Problems with in terms a taking with food

Question 14

Class IV:

Answer 14

Low Solubility Low Permeability

Few orally administered drugs

Question 15

GI Transporters and Absorption (Influx):

Answer 15

• Influx Transporters:
  
  • peptide transporters
  • bile salt transporters
  • nucleoside transporters
  • OATP & OCTP
  • fatty acid transporters

Question 16

GI Transporters and Absorption (Efflux):

Answer 16

•Efflux Transporters
•P-glycoprotein (Pgp) – membrane bound
MDR protein
•MRP1; MRP2; MRP3;BCRP

Question 17

Distribution – what effects absorption?

Answer 17

• Blood Concentration and relative blood flow to the tissues
• Local pH & degree of drug ionization
• Drug partition coefficient
• Transporters at sites of distribution
• Nature of the tissue
  
  • adipose tissue
  • CNS
  • Bone

Plasma protein binding: both saturable and competitive
Protein-bound drug/free fraction at equilibrium
ONLY FREE DRUG CAN BE TRANSPORTED OR METABOLIZED

Question 18

What is Metabolism?

Answer 18

Process of enzymatic alteration of absorbed drug to an inactive or active metabolite (metabolic inactivation or activation)

Question 19

What is first-pass metabolism?

Answer 19

Drug concentration is greatly reduced before is reaches systemic circulation.

100% of GI absorbed drug is transported to the liver via the portal vein.

Question 20

What is first-pass elimination?

Answer 20

• Routes not subject to Hepatic First Pass
  
  • sublingual, transdermal, IV
• Hepatic first pass minimized by rectal administration (suppositories)

Question 21

What is Elimination?

Answer 21

• Occurs via metabolism and excretion
• Ideally metabolism yields metabolites more water-
soluble than parent
• Kidneys principle organ for excretion of water-soluble compounds

• Drugs with MW >300 and lipophilic (polar unionized with high MW as well) more likely to be eliminated via bile