Exam 1 Bioavailability and Clearance

Question 1

What is bioavailability?

Answer 1

the fraction of the administered dose that reaches systemic circulation (the heart) → not 100% because of the first pass effect

Question 2

How is bioavailability calculated?

Answer 2

bioavailability of drug from a dosage form can be calculated relative to administration of another dosage form → if the other dosage form is IV, then F is termed the (absolute) bioavailability (F = AUCev/doseev / AUCiv/doseiv) BUT if the reference dosage form is another dosage form, the value of F is termed the relative bioavailability

Question 3

What are some important things to note about bioavailability?

Answer 3

1. bioavailability has no units

2. absolute bioavailability varies between 0 and 1

Question 4

What is the meaning of the calculation of F (absolute bioavailability)?

Answer 4

the number of F is the % of drug that reaches systemic circulation → 1-F is the % of dose that is lost before the dose reaches systemic circulation

Question 5

What is AUC?

Answer 5

AUC reflects the total amount of drug the body is exposed to → larger AUC means that the body is exposed to a larger amount of drug and smaller AUC means that the body is exposed to a smaller amount of drug →→→ AUC is proportional to dose in linear kinetics

Question 6

When given bioavailability, what should we assume?

Answer 6

that we are referring to absolute bioavailability unless otherwise indicated (aka use the IV data as reference)

Question 7

Why does F usually indicate absolute bioavailability of oral dosage forms?

Answer 7

the oral route is the most popular route of extravascular drug administration

Question 8

What is oral bioavailability and what is its equation?

Answer 8

oral bioavailability is the fraction of oral dose that reaches systemic circulation (F = AUCpo/dosepo / AUCiv/doseiv)

Question 9

If drug X is 50% absorbed from the intestine and 30% of drug X is metabolized by the liver during single pass. Intestinal (gut) metabolism of drug X is insignificant. What is F?

Answer 9

F = FaFgFh (where Fa is fraction of drug absorbed, Fg is fraction of drug that survived gut metabolism, and Fh is fraction of drug that survived hepatic metabolism) → F = 0.5*(1-0.3)= 0.35 (fraction of dose that reached systemic circulation)

Question 10

With IV route, how much of the dose reaches systemic circulation?

Answer 10

100%

Question 11

What are the determinants of F (oral bioavailability)?

Answer 11

intestinal absorption, intestinal metabolism (insignificant for most drugs), and hepatic metabolism

Question 12

What is the effect of insignificant intestinal metabolism?

Answer 12

low bioavailability is usually due to poor intestinal absorption and/or high hepatic metabolism during the first pass through the liver

Question 13

What is the first pass effect?

Answer 13

significant loss of drug during the first pass through the liver after oral administration

Question 14

How does intestinal absorption affect F?

Answer 14

1. if a drug showed poor dissolution → increased intestinal retention time → increased extent of absorption → increased AUCpo of the drug → increased F of the drug
2. if a drug is well absorbed and had complete abosrption → rate of absorption increases → AUCpo of drug remains the same → F of drug remains the same

Question 15

How are AUCpo and F related?

Answer 15

changes in AUCpo lead to changes in F

Question 16

How does hepatic metabolism affect F?

Answer 16

1. expression of hepatic CYP enzymes can be induced by drugs like rifampin → enzyme inducers
2. CYP enzyme function can be impaired by drugs such as cimetidine → enzyme inhibitor

Question 17

What is an example of fraction metabolized and F change with an enzyme inducer?

Answer 17

before rifampin → fraction metabolized is 80% so F is 20%

after rifampin → fraction metabolized is 90% so F is 10%

Question 18

True/false: Drugs that are poorly absorbed from the intestine are expected to show low F values.

Answer 18

true → low F values is due to poor intestinal absorption and/or high hepatic metabolism during first pass through the liver

Question 19

True/false: Drugs that experience significant first pass effect are expected to have low F values.

Answer 19

true → low F is due to poor intestinal absorption and/or high hepatic metabolism during first pass through the liver

Question 20

What is clearance (CL)?

Answer 20

the proportionality constant relating the rate of drug elimination and the plasma concentration (CL = kel*Vd) → aka volume of drug containing plasma from which drug is completely cleared

Question 21

How are most drugs found?

Answer 21

they are found in plasma (protein bound or free) → certain drugs such as tacrolimus and cyclosporine bind to RBC significantly

Question 22

For drugs that do not bind to blood cells, what is Cb relative to Cp?

Answer 22

Cb is less than Cp

Question 23

What happens if all drug molecules are distributed in the plasma?

Answer 23

drug amount in plasma = drug amount in blood

Cp0.5 = Cb1 since we assume plasma makes up 50% of total blood volume → Cb/Cp = 0.5

Question 24

What is the blood/plasma ratio (Cb/Cp) of a drug that does not bind to blood cells (aka no distribution into blood cells)?

Answer 24

0.5-0.6 (since the drug does not bind to blood cells)

Question 25

What is the blood/plasma concentration ratio (Cb/Cp) of a drug that distributes into RBCs significantly?

Answer 25

greater than 15 → these drugs bind to blood cells significantly (examples include tacrolimus and cyclosporine)

Question 26

True/false: When a drug is distributed mainly in the plasma, Vd estimated from blood concentration is larger than that from plasma concentration.

Answer 26

true → kel will remain the same as if the drug did bind to RBCs so want to use the equation Vd = dose/C0 in which C0 would be Cb0/Cp0 (small number since it does not bind to RBCs) so if C0 is a small number then Vd would be a large number →→ if drug is bound to RBCs, then Vd would be smaller from blood concentration than from plasma concentration

Question 27

What is CLb?

Answer 27

clearance from the measured blood concentration which is normally higher than CL for a drug that mainly distributes in the plasma

Question 28

What is the relationship between CLb and CL for a drug that distributes in the plasma?

Answer 28

CLb > CL

Question 29

What is the difference between systemic (plasma) clearance (CL) and blood clearance (CLb)?

Answer 29

1. CL is the proportionality constant relating the rate of drug elimination and the drug concentration in plasma (dA/dt = -CL*Cp) 2. CLb is the the proportionality constant relating the rate of drug elimination and the drug concentration in blood (dA/dt - -CLb*Cb) both have the same rate of elimination though (same kel!)

Question 30

How is CLb calculated?

Answer 30

1. can be estimated from CL and blood/plasma drug concentration ratio (Cb/Cp) 2. rate of drug elimination from blood = rate of drug elimination from plasma → CLb = CL*(Cp/Cb) = CL/(Cb/Cp)

Question 31

For drugs that are mainly distributed into plasma, what is the relationship between CLb and CL?

Answer 31

If CLb = CL/ (Cb/Cp) and Cb/Cp=0.5 then CLb = 2CL →→ CLb is two times greater than CL!!

Question 32

How does AUC different for a drug that is mainly distributed in plasma?

Answer 32

CLb = doseiv/AUCiv so if CLb = 2CL then AUCblood = 1/2 AUCplasma

Question 33

What is the equation relating CL, CLoral, and F?

Answer 33

CLoral = CL/F

Question 34

The equation CLoral = doseoral/AUCoral = CL/F reflects what?

Answer 34

reflects both the rate of drug elimination and the extent of absorption or significant first pass metabolism

Question 35

What causes a high CL/F value (aka high CLoral value)?

Answer 35

CL/F is larger for drugs that are eliminated faster and/or show decreased F (poor oral absorption or significant first pass effect)

Question 36

What are the major organs of drug elimination?

Answer 36

liver and kidney

Question 37

What is the equation for elimination (aka systemic clearance)?

Answer 37

``` elimination = hepatic metabolism + renal excretion CL = CLH + CLR ```

Question 38

What are important things to know about renal excretion?

Answer 38

1. most drugs are eliminated by metabolism to polar metabolites and the metabolites are excreted into the urine 2. some drugs are eliminated unchanged in the urine → can be measured by collecting and analyzing urine concentration data

Question 39

What can we assume if 20% of IV administered dose is found in the urine unchanged?

Answer 39

1. assume that hepatic metabolism and renal excretion are major elimination pathways → urinary excretion accounts for 20% of total drug elimination 2. fe is the fraction excreted unchanged into the urine (fe = 0.2)

Question 40

What is the equation for the fraction of drug excreted unchanged in urine (fe)?

Answer 40

fe = total drug excreted unchanged / dose = CLR / CL | CLR = CL*fe AND CLH = CL - CLR

Question 41

After oral administration of 1 g drug, you obtain plasma drug concentration v time. Using the data, you can estimate CL.

Answer 41

false → need IV data to estimate clearance!

Question 42

Based on the information below (Cb/Cp = 0.5, F = 0.1, and fe = 0), which one of the following CL is estimated to show the largest value?

Answer 42

CLpo (order from largest to smallest is CLpo > CLb > CL > CLH > CLR)