Pharmacokinetics test 2

What pharmakinetic terms are associated with a one compartment system

1. Clearance 2. Volume 3. First order absorption rate constant(Ka) 4. fractional systemic bioavailability(F)

Secondary parameters of 1 compartment model

1. K(elimination rate constant) 2. half life 3. absorption half life(t1/2,a)

three requirements for two formulations to be considered bioequivalent

1. fractional bioavilability must be the same, so Frelative=1 2. Cmax must be the same 3. Tmax must be the same Sum: rate and extent of absorption must be the same

What assumptions does the one compartment model make

1. instantaneous drug distribution 2. system is open(all drug that enters also leaves) 3. Linear system 4. Stationary system; just means that parameters do not change with time 5. Clearance is a first order process

What are 1. permeability limited tissues and 2. perfusion limited tissues

1. membrane limits access to cell 2. flow of blood limits access to cell

What does a large volume of distribution value tell us? A low value?

A high value means a drug is more easily able to diffuse into tissues and is likely lipophilic or at a neutral charge.This also tells us that the drug has a high affinity for tissue binding proteins. A low value tells us the drug has a hard time passing through membranes and is more likely to stay in plasma. A low value also tells us that the drug has a higher affinity for plasma binding proteins.

3. In order to calculate the dose required to produce a specific area under the concentration-time curve (AUC) extrapolated through infinite time following administration of an intravenous bolus dose, what information is required?

A. An estimate of the clearance of the drug

What does increasing F also increase

AUC and Cmax, a change in F will not affect tmax or half life

what is the difference between absolute and relative bioavailability

Absolute: actual fraction of dose that is absorbed, determined by comparing AUC of IV administration to AUC of non-parenteral administration. Relative: fraction of a dose that is absorbed from one formulation compared to a second formulation administered by same route -most often used to compare generic formulation to innovator

Some types of therapeutic response are determined most significantly by the concentration at the end of the dosage interval. For such drugs, what information is required to calculate an intravenous bolus dose that will produce the desired concentration at a specific time t after the dose is administered?

Any two of the following three pieces of information would be required: the systemic clearance of the drug, the apparent volume of distribution of the drug, and the half-life of the drug

In order to calculate the dose required to produce a target initial concentration after an intravenous bolus dose, what information is required?

Apparent volume of distribution

2. In order to calculate the dose required to produce a target concentration at a specific time t following administration of an intravenous bolus dose, what information is required?

C. An estimate of both the apparent volume of distribution and the clearance of the drug

For extavasal administration, AUC=

(X0*F)/Cl

Some types of therapeutic response are determined most significantly by total systemic exposure. For such drugs, what information is required to calculate an intravenous bolus dose that will produce the desired AUC?

. The systemic clearance of the drug is sufficient

What factors affect AUC

Cl and F

What will changing F also change?

Cmax and AUC

A change in F will cause a proportional increase in____ but none in______

Cmax and AUC, but not in tmax or t1/2

What will changing ka also change?

Cmax, and tmax

What are the secondary parameters of the one compartment model?

Elimination rate constant K(influenced by both Cl and V) and Half life

T/F: Rate of absorption will affect AUC

False

T/F: Half life will increase if volume of distribution decreases.

False half-life will decrease if V decreases, as the drug can be removed quicker from a smaller space.

What happens to K and half life when volume increases

K decreases and half life increases

What happens to K and half life when clearance increases?

K increases and half life decreases

What happens to K and half life when volume decreases

K increases and half life decreases

Whats the difference between simple compartment models and multiple compartment models?

Simple models assume the drug is distributed throughout the body instantaneously while multiple models take notice of the degrees of permeability of different compartments throughout the body.

bioavailability

Symbolized by F and is a value between 0 and 1 which constitutes the fraction of the dose absorbed into systemic circulation

What does "well stirred" refer to?

That the drug is distributed throughout the entirety of the body instantaneously. This is simply an assumption in the 1 compartment model.

Some types of therapeutic response are determined most significantly by the concentration immediately after the dose is administered. For such drugs, what information is required to calculate an intravenous bolus dose that will produce the desired concentration at t = 0?

The apparent volume of distribution of the drug is sufficient

What does absolute bioavailability refer to?

The difference between the AUC from extravascular administration and the AUC from IV. F=AUC by mouth/AUC by IV

What does AUC tell us?

The drug exposure, or response of a system to a drug in regards to its clearance

bioequivalence

The similarity in concentration time profile produced by two different dosage forms

What is the apparent volume of distribution?

The size that the body would need to be if it was a single well stirred compartment. This parameter has units of volume. Basically, the volume which would account for the concentration of the drug in the body.

What is clearance?

The volume of blood from which drug is cleared per unit time. Clearance has units of volume per time

Explain the concept of "flip flop" kinetics. How does this work in relation to sustained release dosage forms

This occurs in sustained release dosage forms where the rate of absorption, ka, is smaller than the first order rate constant, K. In pharmacokinetics, flip-flop phenomenon happens when a drug is released at a sustained rate instead of immediate release, such as sustained-release formulation vs. immediate-release formulation (tablet, IV). In flip-flop kinetics, ka (absorption constant) is much slower than ke (elimination constant). Note: In most extravascular administration, absorption, or ka, is greater than elimination, k.

What does increasing volume do to Tmax, Cmax, and AUC

Tmax increase while Cmax decreases. This is because there is less drug in the serum concentration since it is diffusing into tissues with a larger V. AUC does not change

T/F: Clearance is independent of route of administration and dose

True

How can be obtain a value for half life?

Using clearance and volume of distribution

Necessary equations

Volume=initial dose/initial concentration Clearance=K*V Clearance=initial dose/ AUC

How do we identify flip flop kinetics?

When elimination isn't the slowest step in the process, but absorption is. This shows up on a graph as the initial slope being a long flat line while the next slope being a short steep line. Thus, the second slope is actually the absorption slope.

bioavailable dose

Xo*F

What factors influence the rate of absorption into blood when a dose is administered orally/any non parenteral route

bioavailability, dosage form, physiological parameters such as transporters. Absorption is usually first order, however there are some processes, such as absorption from transdermal patches and controlled release tablets, that are zero order.

Regardless of route of administration, a drug will always have the same

clearance and volume of distribution, this means that half life should also always be the same

What is the structure of the one compartment model with non parenteral administration?

dose input-->instantaneous distribution throughout the compartment-->dose elimination F*X0--ka-->V--Cl-->

'What is "instantaneous distribution of the drug" considered to be?

drug concentrations in the tissue equilibriate rapidly with concentrations in the blood.

Why does half life decrease with increasing clearance?

drug is removed faster

T/F: Clearance and volume of distribution are dependant on each other

false, they are independent. They also determine half life

What happens to K and half life when clearance decreases

half life increases and K decreases

What does increasing ka do to Cmax and tmax and half life

half life remains unchanged while Cmax increases and Tmax decreases Does not affect AUC

What will changing V also change?

half life, C max, and tmax

What will changing Cl also change?

half life, Cmax, Tmax and AUC

What types of drugs have a hard time passing through tissues?

hydrophilic and ionized

Describe the structure of he 1 compartment model: Dose input-->______-->dose elimination

instantaneous distribution throughout compartment. OR: Xo-->V--Cl-->

useful equation for K

k=[ln(C2/C1)]/(t2-t1)

Relevant equations

ka=.693/t1/2abs C[(ka*F*X0)/V(ka-K)]*[e^(-K*t)-e^(-ka*t)] Cl=Xa/AUC K=Cl/V

What is fick's law?

molecules will move from high concentrations to low concentrations to reach equilibrium.

bioavailability of a drug is affected by

physiochemical properties of a drug/formulation, labilit of a drug to pH/enzymes/etc, and membrane barriers

Change in dose causes a ____ in AUC

proportional change

Flip flop is related to the ____ step

rate controlling

Flip flop kinetics only applies to

sequential processes

What does Cmax tell us?

the rate of absorption is equal to the rate of elimination

What happens to Cmax, AUC, Tmax when clearance is increased

they decrease

What type of drug, unbound or bound, is able to stimulate receptors?

unbound