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Pharmacokinetics > Exam 1 Bioavailability and Clearance > Flashcards

Exam 1 Bioavailability and Clearance Flashcards

1
Q

What is bioavailability?

A

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

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2
Q

How is bioavailability calculated?

A

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

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3
Q

What are some important things to note about bioavailability?

A
  1. bioavailability has no units

2. absolute bioavailability varies between 0 and 1

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4
Q

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

A

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

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5
Q

What is AUC?

A

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

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6
Q

When given bioavailability, what should we assume?

A

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

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7
Q

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

A

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

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8
Q

What is oral bioavailability and what is its equation?

A

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

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9
Q

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?

A

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)

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10
Q

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

A

100%

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11
Q

What are the determinants of F (oral bioavailability)?

A

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

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12
Q

What is the effect of insignificant intestinal metabolism?

A

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

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13
Q

What is the first pass effect?

A

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

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14
Q

How does intestinal absorption affect F?

A
  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
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15
Q

How are AUCpo and F related?

A

changes in AUCpo lead to changes in F

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16
Q

How does hepatic metabolism affect F?

A
  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
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17
Q

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

A

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

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

18
Q

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

A

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

19
Q

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

A

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

20
Q

What is clearance (CL)?

A

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

21
Q

How are most drugs found?

A

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

22
Q

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

A

Cb is less than Cp

23
Q

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

A

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

24
Q

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

A

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

25
Q

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

A

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

26
Q

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

A

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

27
Q

What is CLb?

A

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

28
Q

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

A

CLb > CL

29
Q

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

A
  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!)

30
Q

How is CLb calculated?

A
  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)
31
Q

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

A

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

32
Q

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

A

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

33
Q

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

A

CLoral = CL/F

34
Q

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

A

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

35
Q

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

A

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

36
Q

What are the major organs of drug elimination?

A

liver and kidney

37
Q

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

A 
elimination = hepatic metabolism + renal excretion 
CL = CLH + CLR
38
Q

What are important things to know about renal excretion?

A
  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
39
Q

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

A
  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)
40
Q

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

A

fe = total drug excreted unchanged / dose = CLR / CL

CLR = CL*fe AND CLH = CL - CLR

41
Q

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

A

false → need IV data to estimate clearance!

42
Q

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?

A

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

Pharmacokinetics (14 decks)

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