Kinetics Exam 1
2 Mechs for Oral Absorption
Passive Diffusion Active Transport Mechs
What are the 2 primary mechanisms for drug entry into the cell?
Passive diffusion and active transport
LADME are all examples of what?
Pharmacokinetics- what the body does to the drug
AA
Products in conventional dosage forms NOT presenting bioequivalence problems
What induces P-gp?
Rifampin and st johns wart INCREASES action
How is bioequivalence tested?
24-36 healthy adult volunteers give single dose of med plasma harvested and analyzed for drug content determine and compare Cmax, Tmax, and AUC from the original and test product
__ half lives is what Doc H said he considers the drug to be gone
5 bc the remaining ~5% is statistically insignificant
Given 100 molecules of drug and after 4.32 half lives, 95 molecules of that drug is eliminated. How much drug is left in the blood?
5 molecules, 5% left
Drug transport includes:
absorption, distribution of the drug into potentially any tissue, transport into the liver cells for metabolism, and transport into the urine
Drugs that are weak bases ionize more in ___ environments
acidic
P-gp is a multi drug resistance transporter protein and it has been implicated because:
because of multidrug resistance in tumor cells
If the tissue affinity increases then the volume of distribution will:
decrease
AB1 equivalence
denotes equivalence to only 1 of those brands
AB2 equivalence
denotes equivalence to the other BRAND
liquids are emptied _____ than digested solids small particles are emptied _____ than large particles
faster, faster
M-M PK When the Km is greater than the concentration of the drug we are looking at then the equation is:
first order (concentration dependent)
When the concentration influences the rate, it is:
first-order
Ways that the body can eliminate drug:
hepatic renal bilary/fecal saliva sweat breath breast milk others
Tissues receiving ____ blood blow equilibrate rapidly with drug in plasma
high
A faster rate of absorption leads to ____
higher Tax; shorter Cmax
Cmax
maximal plasma drug concentration
Vmax:
maximum elimination rate conc/time dependent on enzyme conc (more enzyme, the faster we can go) CONSTANT
PK/PD
merging of pharmacokinetics and pharmacodynamics changes in EFFECT as a function of time
High tissue affinity = _____ drug accumulation
more
HIGHER K values denote ______________________ and ____________________________ .
more lipophilicity and less % renal excretion
When we combine info from PK and from PD, we are able to generate:
optimal dosing regimens
Which compounds move poorly into the lipid bilayer? polar or non polar?
polar compounds
What type of molecules are likely to be permeability-limiting?
polar molecules diffusing across relatively impermeable membranes (BBB)
What is the partition coefficient used to predict?
prediction of the ease of membrane transport
What are used to increase lipid solubility?
prodrugs
Most important concern when testing for bioequivalence:
producing the same therapeutic outcome as the product assessed in the clinical trial (the original product, bioequivalence tests are done in place of clinical trials)
AB
products that actual or potential bioequivalence problems have been resolved with adequate evidence of bioequivalence
Distribution
once a drug is in the bloodstream, it will distribute to anywhere in the body (which leads to side effects) crossing into tissues, however, depends on several other factors
Linear AUC is ____ the dose (conc)
proportional to- doubled dose? doubled auc.
Potassium citrate ________ urinary pH so oxalate salts are less likely to form (reducing chance of kidney stones)
raises
Clearance:
rate of elimination divided by plasma concentration = Vmax / Km + C
Drug Elimination M-M Composition of excrete products is affected by:
size of dose route of administration dosage form
In bioequivalence testing, the question is not whether the 2 products are different. The question is are they ______ ______
sufficiently similar
absolute bioavailability (F):
the systematic availability of a drug after extravascular administration (oral, rectal, transdermal..) measured by comparing the AUCs after extravascular and IV administration
Half-life
the time it takes for a given plasma drug concentration to be reduced by half
Most drugs are either ___ acids or ____ bases
weak, weak
Pharmacodynamics
what the drug does to the body causes desired and undesired effects comparing a concentration to an effect
When the concentration has NO influence on the rate, it is:
zero-order
Bioavailability is often described as a ____ of the dose
% (the measurement of the amount of drug that reaches the site of action)
Diffusion (permeability) rate limited drug distribution Diffusion is ______ of blood flow
(virtually) independent
Pharmacodynamic Graph description
*Changes in effect as a function of concentration (or dose)* "Exposure-response"
Pharmacokinetics Graph description
*changes of concentration as a function of time* "Input-exposure"
If the Cmax and the AUC of the test product are within the range of ___-___ of the original produce, then the test product is deemed to be bioequivalent.
0.8-1.25
Over ____ bound is considered "extensively" bound
0.9 0r 90%
Body membranes vary in thickness, what are the 3 types?
1. Several layers of cells 2. Single layer of cells 3. Less than one cell thick - membrane of the cell itself
What factors of a drugs formulation impact the rate of dissolution?
1. content/percent of each inactive ingredient 2. purity of each inactive ingredient 3. manufacturing process- mixers, presses, storage 4. with or without food?
Bioequivalence requirements can be waived under certain circumstances 1. 2. 3. 4. 5.
1. drug product is solution for IV injection at the same con as the reference drug 2. drug product is a topical product for dermo use 3. drug is an oral dosage form that is not intended to be absorbed (antacids) 4. drug is inhaled as vapor or gas 5. other rare situations
Factors that delay gastric emptying time
1. large meals (fatty meals more so) 2. some meds 3. cold beverages
Pharmacokinetics
Deals with what the body does to the drug Liberation, Absorption, Distribution, Metabolism, Excretion
What influences the volume of distribution?
A major factor is plasma drug protein binding
Occasionally identical active ingredient exist in different products and that causes us to need equivalence terms for that (ex. zestril & prinivil are both lisinopril) What terms do we use to distinguish these?
AB1 and AB2
How to determine if the test product is deemed bioequivalent
AUC test / AUC ref
Metabolism
After drug is absorbed, eventually the body gets rid of all the drug molecules
P-glycoprotein (P-gp)
An efflux membrane transporter (efflux = out of cell) potent drug efflux pump
Diffusion (permeability) rate limited drug distribution
As the cell membrane resistance to drug transport increases for whatever reason, then the rate limitation moves from perfusion to permeability - problem now lies in the drug moving through the membrane - RLS: slow diffusion of the drug across the capillary membrane
FDA definitions of: Bioavailability- Bioequivalence-
Bioavailability- measurement of rate and amount of therapeutically active drug that reaches systematic circulation Bioequivalence- similar bioavailability between two products when compared to each other
Km:
Concentration at 1/2Vmax- so it depends on Vmax CONSTANT
Therapeutic Equivalents
Contain the same therapeutically active drugs but may differ in color, scoring, flavor, package
Disposition
Distribution and Elimination Often times means the entire process and fate of the drug AFTER absorption
Perfusion-limited drug distribution
Drug distribution into tissues is so rapid that blood flow to the organ is the rate limiting step (perfusion) The membrane presents essentially NO barrier to delay drug distribution
passive diffusion
Drug passes through a membrane in which the membrane does not participate in the diffusion Process does not reach saturation
BUT when Km is greater then conc and elimination is independent of concentration this is _____ order
FIRST.. which is backwards of everything else we have learned
B
Drug products that the FDA at this time considers NOT to be therapeutically equivalent to other pharmaceutically equivalent products Further investigation is needed
A reason that brand and generic can affect patients differently:
Equality of drug contents does not guarantee equality of response - some manufacturers use different excipients and different manufacturing processes compared to the branded product.
The "Orange Book"
FDA Approved Drug Products with Therapeutic Equivalence Evaluations
The concentration of most drugs in the body are well below their Km values, which makes the elimination of most drug ____ order
First
Sites of absorption in the body:
GIT, veins, lungs, skin, others
At high concentrations (C>Km), half life _____ when the dose increases which makes them _____
INCREASES; proportional Zero order
The apparent volume of distribution of the drug will ______ when the fraction unbound increases.
Increase
AP
Injectable (aqueous) solutions
AO
Injectable oil solutions
Biopharmaceutics are applicable to any dosage form EXCEPT:
Intravenous administered products
Clearance is first- order when:
Km is greater than the concentration (Independent of conc) Cl = VK which is Vmax Volume / Km
A fast rate takes ___ time to accomplish the task than a slow rate.
LESS
___ and ___ compass the science of Biopharmaceutics bc they characterize the rate and extent of drug dissolution and the rate and extent of absorption.
Liberation and Absorption
Active Transport
Lipid insoluble drugs and large molecules often absorbed by active transports REQUIRES ENERGY and usually a carrier enzyme Process may become saturated (zero order) at high concentrations of drug
_________ lipid solubility -> ease of membrane penetration
MORE
What causes nonlinear PK?
Many ADME processes are enzyme-mediated or protein mediated so there is a possibility of saturation (no where for the drug to go so our first order becomes zero order-conc independent) drug toxicity damages to the kidney cyp450 induction/inhibiton
Clearance
Measurement of drug elimination from the body without identifying the mechanism of elimination VOLUME term, not amount: it is the volume of fluid cleared per unit of time
partition coefficient
Measures concentration of a drug in octanol and in water *at equilibrium* aka log P value or log K value
*Volume of Distribution*
NOT a real volume It is a proportionality constant between the amount of drug given and concentration observed *volume of fluid needed to dissolve the entire drug dose to provide the concentration observed*
The decline of drug conc is ___ _______ due to saturation of whatever the elimination process is
NOTTTT exponential
AN
Solutions and powders for aerosolization
T or F: there is a Km value for every drug
TRUE
What is happening when a drug reaches Vmax?
The concentration increased until it is saturated then doesn't get any higher which is when it reaches Vmax (no matter how much more you add)
When the pH of the environment = pKa of the drug:
The concentration of ionized drug = the concentration of unionized drug
Liberation
The drug must be released or "liberated" from the dosage form Can be v simple or super complicated process Highly evaluated by the FDA in BE studies
Absorption
The entry of the drug molecules into the body (into blood flow or tissues)
Biopharmaceutics
The study of how pharmaceutical formulation variables influence the performance of a drug product in the body (in vivo) BEGINS when the dosage form is given to the patient, ENDS once the drug is liberated and absorbed into systematic circulation
The goal of Metabolism
To make the molecule more water soluble and easier to eliminate in urine
Volume of Distribution
Useful in relating amount of drug in the body to the plasma drug concentration It is the volume of a compartment needed to dissolve the dose given -(considers tissue and plasma 1 compartment)
Which medication is more lipophilic? Colchicine, K = 1.19 Warfarin, K = 2.89
Warfarin
M-M PK When the Km is less than than the concentration of the drug we are looking at then the equation is:
Zero-order (conc independent)
Drugs that are weak acids ionize more in ____ environments
basic
AUC
area under the plasma drug concentration vs time curve a measurement of the total amount of unaltered drug that reaches systematic circulation
2 products are considered to be ________ is they will not produce different clinical effects or adverse events
bioequivalent
Drug accumulation depends on what 2 factors?
blood flow and the affinity of the drug for the tissue
facilitated diffusion
carrier mediated system no energy required may become saturated
Clearance equation
clearance = dose / AUC dose = AUC x clearance
Relative (apparent) Bioavailability
comparison of the bioavailability between a drug product and a recognized standard usually non-IV forms are compared (i.e oral vs rectal) Relative F fraction or %
Clearance is zero-order when:
concentration is greater than Km (dependent on conc) inversely proportional to concentration
The order of a reaction refers to the influence the _________ of a drug has on the _____ of the chemical rxn
concentration; rate
Half life is ______ when we have low conc of drug (Km > C) which makes half life _____ of concentration
constant; independent
The main PK parameter that is changed is the apparent ____
elimination rate constant
What inhibits P-gp?
erythromycin, verapamil, and ritonavir REDUCES action
Bioavailability
establishes the rate and extent of PARENT DRUG input into systematic circulation
How is bioavailability measured?
how much drug is absorbed in the circulation from liberation of the drug from the dosage form, then absorption, survival of the dreaded first-pass of the drug dose through the liver and now ready for distribution throughout the body. Generally a fraction or % of the administered dose
Drug Elimination M-M Half life ______ as dose increases and AUC is now proportional to _____
increases; the dose squared
Linear Half-life is _____ the dose (conc)
independent of
Linear clearance is _____ the dose (conc)
independent of
What are the tissues that have high blood flow?
kidneys liver muscle brain
Drug Elimination M-M As the dose increases, the drug response curve may show:
large increase in pharmacological effects with increasing dose
first-order kinetics
linearity- what we want bc it creates PREDICTABILITY
What type of drugs are likely to be perfusion-limited?
lipophilic drugs or small molecules
Diffusion (permeability) rate limited drug distribution Takes _____ for the tissue to reach equilibrium
longer
Lower Vmax -> _____ 1/2vmax -> _____ Km
lower, lower whatever happens to the max it happens to the km too
Clearance units
mL/ hr or mL/min
Diffusion (permeability) rate limited drug distribution Transfer is dependent on the:
nature of drug and membrane
Zero-order kinetics
nonlinearity eventually - some drugs don't follow the rules
The accumulation of drug occurs the side of the membrane where:
pH favors greater ionization
What dictates the degree of ionization at various pH values
pKa
Active transport is important in _______ and ______ SECRETION of drugs and metabolites
renal, biliary
Sink Condition
the ability of the dissolution media to dissolve at least 3 times the amount of drug that is in your dosage form (not from notes, just for better understanding)
Dissolution
the action or process of dissolving or being dissolved
If pH is increased on one side of the cell membrane this will change:
the amount of drug that is ionized (the magnitude depends on pKa)
P-gp helps to keep drugs out of ______ _____
the brain
What drives the absorption process?
the concentration gradient and absorption moves from side of high to low concentration FICKS 1ST LAW
Calculating Bioavailability is done how?
the most common method is the comparison of AUC "normalized" to dose
When studying biopharmaceutics, the parameters to consider are:
the rate of dissolution sink condition
At high doses or conc (c> Km), AUC is proportional to _____
the square of the dose ZERO order
Tmax
time to reach the maximal plasma drug concentration (the Cmax)
AT
topical solutions
What can p-gp do?
transport drugs back out of the gut wall and into the gut lumen -> reducing absorption primarily found in GIT
