Flashcards in ADME Deck (21):
What is meant when it is stated that drug follows “first‐order kinetic processes” and why this is a consideration when making dosage adjustments using TDM.
The body can handle a drug either as a zero order process, first order process, or a mixture of both. A first order process removes a constant proportion of the drug. A change in dose results in proportional change in plasma concentrations.
What is biotransport and explain the following mechanisms:
Biotransport is the movement of drugs across a biological membrane.
open channels allow small molecules to move, for example filtration of drugs at the glomerulus
b) Facilitated diffusion
A molecule crosses a membrane while bound to a carrier protein (the molecule hitches a ride). No energy required. Follows concentration gradient. CAN become saturated.
c) Active transport
Uses a carrier protein to move drug AGAINST a concentration gradient. Uses a direct expenditure of ATP as the energy source; uncommon route for drug transport
Cell Drinking, a type of endocytosis. It is used to move very large molecules in a solution inside the cell. E.g. uptake by renal tubule.
e) Passive diffusion
The most common method of drug biotransport; involves flow down a concentration
gradient, so does not require energy.
To passively diffuse, a drug must be water soluble enough to enter aq solutions but also
lipid soluble enough to transverse the lipid membrane (lipid solubility is most important).
What effect does protein binding of a drug have on its ability to passively diffuse?
Only free/unbound drugs can cross membranes
Regarding drug binding, is bound, unbound (free), or both in an active state to interact with receptors?
Unbound (free) drugs are in an active state to bind to receptors
What is the Brodie pH Partition Hypothesis and what are its clinical implications?
This uses the Henderson-Hasselback equation (where the pKA is the pH at which hald of a molecule is in its ionized form) in order to predict drug concentrations across a membrane. For example, a more acidic drug will stay on the more basic side* of the membrane “out”, and a more basic drug will stay on the more acidic side* of the membrane “in” [*intracellular pH is 6.8 and blood pH is 7.2-7.4]
Clinically, this is important because with all other things being equal, basic drugs penetrate intracellularly better than acidic drugs, and ion trapping can be used to enhance renal elimination of a drug or toxin.
Contrast bioavailability (F) versus bioequivalence.
Bioavailability is the extent of absorption. The fraction of drug absorbed. Calculated based on Area under curve and normalized for dose.
Bioequivalence refers to not only bioavailability but also the rate of absorption.
What is the “First pass” effect?
Every drug that is ingested orally must pass through the portal circulation and the liver. When a majority of the the drug is eliminated by the liver it is called “first pass effect”.
What is enterohepatic recirculation and how does it affect bioavailability?
It is when the drug is already in the central circulation and is removed by the liver, but is then reabsorbed by the GI tract and put back into central circulation. This falsely increases the value of F(fraction of drug absorbed).
Explain diffusion (permeability) rate limited versus perfusion rate limited distribution.
Distribution is diffusion (permeability) rate limited when:
The drug is ionized and polar (water soluble), such that physiological barriers restrict the diffusion of such drugs into the cell.
Distribution is perfusion rate limited when:
The drug is highly lipophilic
The drug easily diffuses through highly permeable membrane such as those of capillaries and muscles.
Describe the characteristics that would cause a drug to have these distribution patterns:
-Restricted to the vascular space
-Restricted to the extracellular space
- Crosses most cell membranes and tissue barriers. (Moves into WBCs. Overcomes blood‐ placenta, blood‐milk, blood‐prostate, barriers.) Does not however cross the most restrictive barriers such as the blood‐brain, blood‐aqueous humor, or blood‐testis barrier
-Crosses all barriers (blood‐brain, blood‐aqueous humor, and blood‐testis barriers)
a. Restricted to the vascular space
Can not pass through the endothelium
Drugs bound to blood constituents
b. Restricted to the extracellular space
Free portion of drug with moderate protein binding is able to pass through the endothelium
Limited lipid solubility (primarily water soluble)
c. Crosses most cell membranes and tissue barriers. (Moves into WBCs. Overcomes blood‐ placenta, blood‐milk, blood‐prostate, barriers.) Does not however cross the most restrictive barriers such as the blood‐brain, blood‐aqueous humor, or blood‐testis barrier.
Free portion of drugs with moderate protein binding
Moderate lipid solubility
Many drugs in this group are ion trapped as tissue pH is slightly acidic versus plasma
d. Crosses all barriers (blood‐brain, blood‐aqueous humor, and blood‐testis barriers)
Highly lipid soluble, low protein binding, non- ionized
How effective is the blood‐placental barrier against penetration of most drugs?
The placenta does not have an effect on drug distribution. The blood-placenta barrier is almost not a barrier, nearly all drugs penetrate it. There are exceptions like heparin (because it is so highly ionized in plasma that it doesn’t cross the placenta). If you need an anti-coagulant in the dam without causing damage to fetus you could give heparin.
In general, how do lipid soluble drugs differ from water soluble drugs regarding:
a. Ease of absorption
b. Organ primarily involved in elimination (kidney or liver)
a. Ease of absorption - lipid soluble drugs diffuse much more rapidly than water soluble (please add here if you find anything else!)
b. Organ primarily involved in elimination (kidney or liver)
Lipid soluble drugs can not be excreted in the urine or feces due to them being lipophilic and hydrophobic. Therefore, they cant be excreted by the kidney but rather the liver.
Which domestic animal(s) is born with renal function near adult levels?
Foals and Ruminants
Does biotransformation always inactivate a drug?
No, bioactivation can also occur as stated previously, but It is rare
Compare and contrast Phase 1 versus Phase 2 biotransformation processes.
Phase 1 adds or uncovers a reactive group and makes the molecule more chemically reactive. Metabolite can be same, less, or more active and will more likely to undergo Phase 2 metabolism. Phase 2 adds an endogenous ligand and makes it more polar and water soluble. Metabolite is inactive.
What is an “enzyme inducer” versus an “enzyme inhibitor” and how rapidly are their actions seen? What is an autoinducer?
Enzyme inhibitor: decreases the activity of metabolic enzymes, thereby decreasing the rate of metabolism of other drugs. Immediate onset.
Enzyme inducer: Increases the amount of enzymes available for metabolism, thereby increasing the rate of metabolism of itself (autoinduction) or other drugs (induction). Requires several weeks.
What attributes of a drug favor its biotransport by passive diffusion?
Drugs must be water soluble enough to enter aqueous solutions but lipid soluble enough to traverse lipid membrane
-Small, unionized, unbound
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
i.e. 80% pup to 60% dog
and 74% calf and 58% adult
This causes a larger volume for drugs that distribute primarily to extracellular space
They also have low albumin, which means lower protein binding and hence greater distribution but perhaps greater excretion (unbound drug)
Which domestic animal(s) is born with hepatic function near adult levels?
Foals, they develop in 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 molecule. It happens in the tissues, it is moderately active in the kidney, skin, intestine, and adrenal gland, but the most active tissue is the liver. It is enzyme mediated, which means that the enzyme is a protein, chemical catalyst that lowers the activation energy for the reaction.
The P450 enzyme system is an enzyme family with broad substarte specificities. Most significant of all drug oxidation reactions. Very important in detoxication of many compounds.