Pharmacokinetics I (Herbert Ho, MD) Flashcards
What are the two steps other than ADME that some sources include in pharmacokinetics?
- Liberation
2. Response
Why aren’t liberation and response included in pharmacokinetics?
Liberation is part of biopharmaceutics, while response is part of pharmacodynamics.
Enumerate the enteral routes of drug administration
- Oral
- Nasogastric tube
- Gastrostomy tube
Enumerate the parenteral routes of drug administration
- Intravenous (IV)
- Intramuscular (IM)
- Subcutaneous (SC)
- Intradermal (ID)
- Intra-arterial (IA)
- Topical (controversial)
If drug A is transformed into metabolite B, what is the mode of elimination?
Metabolism
Not excretion because the drug was changed
T/F: If Drug X is metabolised into an inactive metabolite and this inactive metabolite is excreted by the kidneys, the mode of elimination is both metabolism and excretion.
True
In enterohepatic recirculation, where is the compound (1) conjugated, (2) excreted, (3) deconjugated, and (4) reabsorbed?
(1) liver
(2) bile
(3) intestines
(4) into the circulation
T/F: Enterohepatic circulation decreases the half-life of a drug.
False
It actually increases it.
Bile acids are conjugated to what in the liver?
Taurine and glycine
T/F: 100% of bile salts are reabsorbed and used in cholesterol synthesis.
False
Only 95% are reabsorbed.
What may cause lower oestrogen circulating concentration leading to breakthrough pregnancy when taking oral contraceptive pills?
Antibiotic use, which leads to elimination of natural bacterial flora in the GIT
Enumerate the properties that make certain substances better absorbed
- Non-ionized
- Small
- Lipid-soluble
Enumerate the properties that make certain substances poorly absorbed
- Ionized
2. Large
Why are penicillin G and insulin poorly absorbed?
They are destroyed by stomach acid and/or digestive enzymes.
Why are tetracyclines poorly absorbed?
They are chelated to food components to form insoluble complexes.
Give examples of polar drugs that won’t cross cell membrane.
Aminoglycoside antibiotics such as streptomycin and gentamycin
What compounds undergo extensive metabolism, which is the reason for their poor absorption?
- Nitroglycerin
- Adrenaline
- Dopamine
Is distribution reversible or irreversible?
Reversible
Enumerate the factors affecting drug distribution
- Ionization
- Capillary permeability
- Blood flow
- Plasma protein binding
What is the only scenario where displacement of a drug from plasma protein binding will cause adverse effects?
When it has a very small volume of distribution or nowhere to go
Would the impact be greater if there’s a change in plasma protein binding (decrease of 1% bound protein) for a drug that’s 90% protein bound or 99% protein bound?
99% protein bound
This is because a 1% change equates to 2% free drug, which is a 100% increase in the amount of free drug.
What is the main organ of metabolism?
Liver
Where are the capillaries very leaky?
Liver and spleen
T/F: Drugs leave the capillaries regardless of whether they are poorly lipid soluble, charged or polar.
True
How do glucose and amino acids pass the blood brain barrier?
They have specific carrier-mediated transport systems.
What substances are tightly controlled in the brain?
Potassium, hydrogen and bicarbonate ions
In order to use dopamine and serotonin for treatment of nervous system disorders, what should you administer?
Precursors (L-DOPA and 5-hydroxytryptophan)
These are prodrugs.
What are the advantages of administering a prodrug?
- More stable
- More favorable PK
- Simpler dosage regimen
- May increase bioavailability
Describe: Acyclovir
- Used to treat chicken pox
2. Prodrug is only administered 2 times compared to 5 times for the active drug
How can radioactive iodine-labeled albumin help detect brain tumours?
Newly formed capillaries to tumours are leaky
Describe the hierarchy of organs in terms of the rate at which they receive the administered drug
Brain, liver, kidneys, and lungs > skeletal muscle > fat
Where is the drug concentration normally measured?
Blood
What is the formula for volume of distribution?
Vd = Dose/Cp
T/F: Correspondence of Vd with the volume of a certain body compartment may be purely coincidental
True
T/F: Gentamycin does not enter cells.
True
It is lipid-insoluble.
T/F: Ethanol Vd correspondence to total body water represents distribution in that compartment.
True
T/F: Warfarin is present in large amounts in the different tissues.
False
It is extensively bound to plasma proteins.
Give examples of drugs with physiologically impossible values.
Quinacrine - 300 L/kg
Amiodarone - 100 L/kg
What are the implications of low and high Vd with respect to intravascular concentration?
Low Vd - highly protein bound
High Vd - highly tissue bound
The smallest volume in which a drug may distribute is the (1).
Blood plasma volume
Define: Biotransformation
It is the chemical modification of drugs by enzymes to make them more polar.
Where can drug metabolising enzymes be found?
- Liver
- GIT wall
- Lungs
- Kidneys
- Skin
- Blood
- Brain
What are the two phases of metabolism or biotransformation?
- Functionalization
2. Conjugation
What are the processes involved in functionalization?
- Oxidation
- Reduction
- Hydrolytic reactions
What are the processes involved in conjugation?
- Glucoronidation
- Sulfation
- Acetylation
- Methylation
- Amino acid conjugation (glycine, taurine and glutathione)
T/F: Functionalization leads to inactivation, while conjugation does not.
False
It’s the other way around. Both, however, make the drug more polar.
T/F: Conjugation may precede functionalization.
True
T/F: Kidney can only eliminate polar substances.
True
What enzymes are largely responsible for phase 1 or functionalization reactions?
Liver Microsomal Cytochrome P450 Monooxygenases (CYPs)
What is the mechanism of action of CYPs?
They transfer electrons from NADPH to O2 and oxidise drugs (hydroxylation and dealkylation)
Where in the cell are phase 1 enzymes located?
Endoplasmic reticulum
Which enzyme makes drug interactions most probable?
CYP3A4
Describe the hierarchy of CYPs in terms of percentage of drugs metabolised
- CYP3A4
- CYP2D6
- CYP2C9 and CYP2C19
- CYP2E1, CYP2A6 and CYP1A2
Enumerate non-CYP biotransformation processes
- Hydrolysis
- Reduction
- Oxidation (flavinemonooxygenase, monoamine oxidase and alcohol & aldehyde dehydrogenase)
What processes lead to drug interactions?
Enyzme inhibition and activation.
What is the effect of inducers on elimination rate?
Increase
Why are inducers slower acting than inhibitors?
Transcription/translation and increased synthesis of heme must first take place.
Give examples of inducers
Rifampicin, barbiturates and St. Johns wort (herbal antidepressant)
Give examples of inhibitors
- Grapefruit juice
- Cimetidine
- Erythromycin
- Itraconazole
Give an example of a phase 2 enzyme
N-acetyltransferase 2 (NAT2)
Describe: N-acetyltransferase 2
- Slow metabolism of drugs such as isoniazid, procainamide and caffeine
- Slow acetylators have higher risk of bladder cancer
- Fast acetylators have higher risk of colorectal cancer
When taking a drug metabolised by C P450, what should be considered?
Interactions due to food items or herbal medicines
What is phase 3 metabolism?
Transport of drug from one compartment to another
Give examples of secondary or tertiary active transporters
- Organic cation transporter (OCT)
- Organic anion transporting polypeptide family (OATP)
- Organic anion transporter (OAT)
- Peptide transporter
- Sodium phosphate co-transporter
Give examples of primary active transporters
- P-glycoprotein
- Multidrug resistance associated protein 1 (MRP1)
- Canalicular multi specific organic anion transporter (cMOAT/MRP2/cMRP/MRP3)
NOTE: They are implicated in resistance of cancers due to pumping out of anticancer drugs.
Describe: P-glycoprotein
- ATP-requiring efflux pump
- Broad drug specificity (digoxin, quinidine, etc.)
- Located in cancer tissue among other sites
- Induced by: rifampicin and St. Johns wort
- Inhibited by: verapamil, quinidine, macrolides and antifungals
T/F: In a one compartment model, drug distribution is assumed to be instantaneous.
True
T/F: Most drugs support the two compartment model.
False
Most drugs support the one compartment model.
T/F: In pharmacology, linearity is in the semilog sense.
True
What is the equation for a one compartment model?
C = Coe^-kt
What is the equation for a two compartment model?
C = Ae^-bt + Be^-at
What is a first-order reaction?
Rates are linearly related to dose administered
What is the rate of change for first-order equations?
dA/dt = -kA
What is the value of e?
e = 2.718
What is the semi-log equation for a one compartment model?
ln(C) = ln(Co) - kt
Define: half-life
Amount of time required for a drug to be reduced to half its original concentration
Give the formula for half-life of 1st order reactions
t1/2 = 0.693/k
What are the important assumptions for a one compartment model with first-order input and first-order elimination?
- Dose is gradually absorbed
- Driving force is concentration gradient
- There is a single homogenous compartment
What is the formula for a one compartment model with first-order input and elimination?
Cp = [(F x dose x ka)/Vd(ka-k10)][e^-k10t - e^-kat]
What is another way of expressing the rate of elimination?
CL x Cp
What does it mean if a drug has low tmax?
It is absorbed quickly.
What is the relationship between distribution and elimination?
Distribution precedes elimination, but both happen all throughout.
Describe a “physiologically-based pharmacokinetic model”
It is derived from anatomy and physiology of the organism and not from drug data.
In a multi-compartment model, what is the total distribution space for drugs?
- Central compartment (organs with high blood flow)
2. Peripheral compartment (absorption > elimination; i.e. adipose tissues and muscles)
T/F: Drug distribution is instantaneous in a multi-compartment model.
False
Volume bound to proteins > volume in steady state > volume in central compartment
What do you call the clearance leaving the central component in a multi-compartmental model?
Central or metabolic clearance
In the log concentration vs. time plot, the number of kinks varies with the number of (1)
(1) compartments
What is the only assumption in the non-compartmental model?
First-order single exponential terminal phase is present. Terminal phase should resemble a 1C model.
When is the non-compartmental model useful?
When little is known about the drug.
T/F: Prior to the last 10 years, the method of choice was the 1C model.
False.
It was the non-compartmental model.
Define: Area Under the Curve (AUC)
It is a measure of exposure of our body to the drug.
What concept is used to compute for the area under the curve?
Trapezoidal concept
What is the formula for AUC from 0 to t?
Sigma (0-t) [0.5(Ct1 + Ct2)] x delta time
What is the formula for AUC from t to infinity?
AUC (t-infinity) = Clast/ke
Why is the logarithmic trapezoidal method more accurate when concentrations are decreasing?
Drug elimination is exponential.
What is the formula for AUC based on the logarithmic trapezoidal method?
AUC (t1 - t2) = [(Ct1 - Ct2)] x delta time/ln (Ct1/Ct2)
T/F: For submissions to the FDA, using the linear trapezoid method will suffice.
True
When is drug concentration assumed to be negligible?
After 4 - 7 half-lives
What is the formula for clearance?
Cl = Vd x ke
Cl = 0.693Vd/t1/2
Cl = rate of elimination/C
T/F: Clearance is the same as elimination.
False
Clearance is usually constant, while elimination rate is variable.
Describe the relationship of ka, Cmax and Tmax.
A higher ka would lead to higher Cmax and shorter Tmax
T/F: ka and Cpmax may be different for three graphs, but their AUCs may be equal.
True
