Exam 1: ADME Flashcards
What is biotransport?
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
Describe filtration
Open channels allow small molecules to move “bulk flow”
Describe facilitated diffusion
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
Describe active transport
Uses a carrier protein to move a drug against a concentration gradient
Uses a direct expenditure of ATP as the energy source
Describe pinocytosis
Used to move very large molecule in a solution inside the cell
Cell drinking
Describe passive diffusion
The most common method of biotransport of drugs Drugs must pass through 3 interfaces: Outer water-lipid interface Lipid membrane Inner water-lipid interface
What attributes of a drug favor its biotransport by passive diffusion?
Size: small
Lipid solubility: The more lipid soluble a drug is, the better the penetration through a membrane with passive diffusion
Unionized
What effect does protein binding of a drug have on its ability to passively diffuse?
If a drug is bound to a protein, it will not cross the membrane
Regarding drug binding, is bound, unbound (free), or both in an active state to interact with receptors?
Unbound drugs are in an active state to interact with receptors
What is the Brodie pH Partition Hypothesis?
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
What are the clinical implications of the Brodie pH Partition Hypothesis?
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
Contrast bioavailability (F) versus bioequivalence
Bioavailability is the fraction of drug absorbed
Bioequivalence is the extent of absorption and the rate of absorption
What is the “First pass effect?
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
What is enterohepatic recirculation and how does it affect bioavailability?
Drug already in the central circulation is removed by the liver, but then reenters the circulation
Falsely increases bioavailability
Explain diffusion (permeability) rate limited versus perfusion rate limited distribution
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)
What causes a drug to be restricted to the vascular space?
Cannot pass through endothelium
- –Drugs bound to blood constituents
- –Rare
What causes a drug to be restricted to the extracellular space?
Free portion of drug with moderate protein binding able to pass through endothelium
Limited lipid solubility (primarily water soluble)
Highly ionized
What causes a drug to cross most cell membranes and tissue barriers, but not cross the most restrictive barriers?
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
What causes a drug to cross all barriers?
Highly lipid soluble
Low protein binding
Non-ionized
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?
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
How effective is the blood‐placental barrier against penetration of most drugs?
The placental barrier is no barrier to most drugs
In general, how do lipid soluble drugs differ from water soluble drugs regarding ease of absorption and organ primarily involved in elimination?
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
Which domestic animal(s) is born with renal function near adult levels?
Foals and ruminants
GFR adult at 2 days, secretion adult at 2-4 days
Which domestic animal(s) is born with hepatic function near adult levels?
Foals have rapid hepatic metabolic development occurring within the first 3 days of life
What is biotransformation, what is the P450 enzyme system, and in what organ does biotransformation primarily occur?
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
Does biotransformation always inactivate a drug?
No, sometimes it causes bioactivation
Describe Phase 1 biotransformation
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
Describe Phase 2 biotransformation
Synthetic reaction
Adds an endogenous ligand
Usually makes more polar and usually water soluble
Usually ligand interacts with reactive group and metabolite is inactive
Cats are deficient in what enzyme system involved in biotransformation? State an example where this deficit makes cats more susceptible to drug toxicity
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
What is an enzyme inducer?
How rapid is its action?
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
What is an enzyme inhibitor? How rapid is its action?
Enzyme inhibitor decreases the activity of metabolic enzymes, thereby decreasing the rate of metabolism of other drugs
Immediate onset
What is an autoinducer?
Autoinducer is an enzyme inducer than increases the rate of metabolism of itself
