Exam 1: ADME

Question 1

What is biotransport?

Answer 1

Biotransport is the movement of substances through the cell membrane and the following are mechanisms of it:
Filtration, facilitated diffusion, active transport, pinocytosis, and passive diffusion

Question 2

Describe filtration

Answer 2

Open channels allow small molecules to move “bulk flow”

Question 3

Describe facilitated diffusion

Answer 3

A type of passive diffusion that utilizes a carrier protein for the solute to cross the membrane
Uses no energy, but still follows a concentration gradient
Can become saturated

Question 4

Describe active transport

Answer 4

Uses a carrier protein to move a drug against a concentration gradient
Uses a direct expenditure of ATP as the energy source

Question 5

Describe pinocytosis

Answer 5

Used to move very large molecule in a solution inside the cell
Cell drinking

Question 6

Describe passive diffusion

Answer 6

The most common method of biotransport of drugs
Drugs must pass through 3 interfaces:
Outer water-lipid interface
Lipid membrane
Inner water-lipid interface

Question 7

What attributes of a drug favor its biotransport by passive diffusion?

Answer 7

Size: small
Lipid solubility: The more lipid soluble a drug is, the better the penetration through a membrane with passive diffusion
Unionized

Question 8

What effect does protein binding of a drug have on its ability to passively diffuse?

Answer 8

If a drug is bound to a protein, it will not cross the membrane

Question 9

Regarding drug binding, is bound, unbound (free), or both in an active state to interact with receptors?

Answer 9

Unbound drugs are in an active state to interact with receptors

Question 10

What is the Brodie pH Partition Hypothesis?

Answer 10

Predicts drug concentrations across a membrane
Acidic drugs concentrate on the more basic side of a membrane
Basic drugs concentrate on the more acidic side of a membrane

Question 11

What are the clinical implications of the Brodie pH Partition Hypothesis?

Answer 11

All other things being equal, basic drugs penetrate intracellularly better than acidic drugs
“Ion trapping” can be used to enhance renal elimination of a drug or toxin

Question 12

Contrast bioavailability (F) versus bioequivalence

Answer 12

Bioavailability is the fraction of drug absorbed

Bioequivalence is the extent of absorption and the rate of absorption

Question 13

What is the “First pass effect?

Answer 13

The removal of the drug by the liver before it enters the central circulation after oral dosing
Can be bypassed by rectal and buccal administration

Question 14

What is enterohepatic recirculation and how does it affect bioavailability?

Answer 14

Drug already in the central circulation is removed by the liver, but then reenters the circulation
Falsely increases bioavailability

Question 15

Explain diffusion (permeability) rate limited versus perfusion rate limited distribution

Answer 15

Diffusion Limited Distribution
Occurs when the drug is ionized and polar (water soluble), such that physiological barrier restricts the diffusion of such drugs into the cell

Perfusion Limited Distribution:
Occurs when the drug is highly lipophilic
The drug easily diffuses through the highly permeable membrane (capillaries and muscles)

Question 16

What causes a drug to be restricted to the vascular space?

Answer 16

Cannot pass through endothelium

• –Drugs bound to blood constituents
• –Rare

Question 17

What causes a drug to be restricted to the extracellular space?

Answer 17

Free portion of drug with moderate protein binding able to pass through endothelium
Limited lipid solubility (primarily water soluble)
Highly ionized

Question 18

What causes a drug to cross most cell membranes and tissue barriers, but not cross the most restrictive barriers?

Answer 18

Free portion of drugs with moderate protein binding
Moderate lipid solubility
Unionized drug
—Many drugs in the group are ion trapped as tissue pH is slightly acidic versus plasma

Question 19

What causes a drug to cross all barriers?

Answer 19

Highly lipid soluble
Low protein binding
Non-ionized

Question 20

How do neonates differ from adults relative to percentage of body water and how might this affect the dose of a water‐soluble drug given to a neonate?

Answer 20

Neonates have a larger percent body water
80% pup… 60% dog
74% calf… 58% adult
Large volume of distribution for drugs that distribute primarily to extracellular space

Question 21

How effective is the blood‐placental barrier against penetration of most drugs?

Answer 21

The placental barrier is no barrier to most drugs

Question 22

In general, how do lipid soluble drugs differ from water soluble drugs regarding ease of absorption and organ primarily involved in elimination?

Answer 22

Ease of absorption:
-Lipophilic drugs are readily absorbed/stored
-Hydrophilic drugs are readily excreted
Organ primarily involved in elimination (kidney or liver):
-Water soluble drugs are excreted by the kidney and the liver
-Lipid soluble drugs are not readily excreted

Question 23

Which domestic animal(s) is born with renal function near adult levels?

Answer 23

Foals and ruminants

GFR adult at 2 days, secretion adult at 2-4 days

Question 24

Which domestic animal(s) is born with hepatic function near adult levels?

Answer 24

Foals have rapid hepatic metabolic development occurring within the first 3 days of life

Question 25

What is biotransformation, what is the P450 enzyme system, and in what organ does biotransformation primarily occur?

Answer 25

Biotransformation is the chemical alteration of a molecule
-Enzyme mediated
The P450 enzyme system is an enzyme family with broad substrate specificities
-Most significant of all drug oxidation reactions
-Very important in detoxication of many compounds
-Also, can cause bioactivation
Most active tissue is the liver

Question 26

Does biotransformation always inactivate a drug?

Answer 26

No, sometimes it causes bioactivation

Question 27

Describe Phase 1 biotransformation

Answer 27

Nonsynthetic reaction
Adds or uncovers a reactive group
Makes the molecule more chemically reactive. Metabolite can be the same, less, or more active
More likely to undergo Phase 2 metabolism

Question 28

Describe Phase 2 biotransformation

Answer 28

Synthetic reaction
Adds an endogenous ligand
Usually makes more polar and usually water soluble
Usually ligand interacts with reactive group and metabolite is inactive

Question 29

Cats are deficient in what enzyme system involved in biotransformation? State an example where this deficit makes cats more susceptible to drug toxicity

Answer 29

Glucuronyl transferase
Acetaminophen cannot be given to cats. Cats quickly deplete this and acetaminophen is rerouted through a P450 system and creates a toxic metabolite. This is okay until you run out of glutathione. This will lead to cell death
–Acetyl cysteine can be given to replenish the glutathione

Question 30

What is an enzyme inducer?

How rapid is its action?

Answer 30

Enzyme inducer increases the amount of enzymes available for metabolism, thereby increasing the rate of metabolism of itself (autoinduction) or other drugs
Requires several weeks

Question 31

What is an enzyme inhibitor? How rapid is its action?

Answer 31

Enzyme inhibitor decreases the activity of metabolic enzymes, thereby decreasing the rate of metabolism of other drugs
Immediate onset

Question 32

What is an autoinducer?

Answer 32

Autoinducer is an enzyme inducer than increases the rate of metabolism of itself