Exam 1 Bioavailability and Clearance Flashcards
What is bioavailability?
the fraction of the administered dose that reaches systemic circulation (the heart) → not 100% because of the first pass effect
How is bioavailability calculated?
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
What are some important things to note about bioavailability?
- bioavailability has no units
2. absolute bioavailability varies between 0 and 1
What is the meaning of the calculation of F (absolute bioavailability)?
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
What is AUC?
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
When given bioavailability, what should we assume?
that we are referring to absolute bioavailability unless otherwise indicated (aka use the IV data as reference)
Why does F usually indicate absolute bioavailability of oral dosage forms?
the oral route is the most popular route of extravascular drug administration
What is oral bioavailability and what is its equation?
oral bioavailability is the fraction of oral dose that reaches systemic circulation (F = AUCpo/dosepo / AUCiv/doseiv)
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?
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)
With IV route, how much of the dose reaches systemic circulation?
100%
What are the determinants of F (oral bioavailability)?
intestinal absorption, intestinal metabolism (insignificant for most drugs), and hepatic metabolism
What is the effect of insignificant intestinal metabolism?
low bioavailability is usually due to poor intestinal absorption and/or high hepatic metabolism during the first pass through the liver
What is the first pass effect?
significant loss of drug during the first pass through the liver after oral administration
How does intestinal absorption affect F?
- if a drug showed poor dissolution → increased intestinal retention time → increased extent of absorption → increased AUCpo of the drug → increased F of the drug
- 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
How are AUCpo and F related?
changes in AUCpo lead to changes in F
How does hepatic metabolism affect F?
- expression of hepatic CYP enzymes can be induced by drugs like rifampin → enzyme inducers
- CYP enzyme function can be impaired by drugs such as cimetidine → enzyme inhibitor
What is an example of fraction metabolized and F change with an enzyme inducer?
before rifampin → fraction metabolized is 80% so F is 20%
after rifampin → fraction metabolized is 90% so F is 10%
True/false: Drugs that are poorly absorbed from the intestine are expected to show low F values.
true → low F values is due to poor intestinal absorption and/or high hepatic metabolism during first pass through the liver
True/false: Drugs that experience significant first pass effect are expected to have low F values.
true → low F is due to poor intestinal absorption and/or high hepatic metabolism during first pass through the liver
What is clearance (CL)?
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
How are most drugs found?
they are found in plasma (protein bound or free) → certain drugs such as tacrolimus and cyclosporine bind to RBC significantly
For drugs that do not bind to blood cells, what is Cb relative to Cp?
Cb is less than Cp
What happens if all drug molecules are distributed in the plasma?
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
What is the blood/plasma ratio (Cb/Cp) of a drug that does not bind to blood cells (aka no distribution into blood cells)?
0.5-0.6 (since the drug does not bind to blood cells)
What is the blood/plasma concentration ratio (Cb/Cp) of a drug that distributes into RBCs significantly?
greater than 15 → these drugs bind to blood cells significantly (examples include tacrolimus and cyclosporine)
True/false: When a drug is distributed mainly in the plasma, Vd estimated from blood concentration is larger than that from plasma concentration.
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
What is CLb?
clearance from the measured blood concentration which is normally higher than CL for a drug that mainly distributes in the plasma
What is the relationship between CLb and CL for a drug that distributes in the plasma?
CLb > CL
What is the difference between systemic (plasma) clearance (CL) and blood clearance (CLb)?
- CL is the proportionality constant relating the rate of drug elimination and the drug concentration in plasma (dA/dt = -CL*Cp)
- 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!)
How is CLb calculated?
- can be estimated from CL and blood/plasma drug concentration ratio (Cb/Cp)
- rate of drug elimination from blood = rate of drug elimination from plasma → CLb = CL*(Cp/Cb) = CL/(Cb/Cp)
For drugs that are mainly distributed into plasma, what is the relationship between CLb and CL?
If CLb = CL/ (Cb/Cp) and Cb/Cp=0.5 then CLb = 2CL →→ CLb is two times greater than CL!!
How does AUC different for a drug that is mainly distributed in plasma?
CLb = doseiv/AUCiv so if CLb = 2CL then AUCblood = 1/2 AUCplasma
What is the equation relating CL, CLoral, and F?
CLoral = CL/F
The equation CLoral = doseoral/AUCoral = CL/F reflects what?
reflects both the rate of drug elimination and the extent of absorption or significant first pass metabolism
What causes a high CL/F value (aka high CLoral value)?
CL/F is larger for drugs that are eliminated faster and/or show decreased F (poor oral absorption or significant first pass effect)
What are the major organs of drug elimination?
liver and kidney
What is the equation for elimination (aka systemic clearance)?
elimination = hepatic metabolism + renal excretion CL = CLH + CLR
What are important things to know about renal excretion?
- most drugs are eliminated by metabolism to polar metabolites and the metabolites are excreted into the urine
- some drugs are eliminated unchanged in the urine → can be measured by collecting and analyzing urine concentration data
What can we assume if 20% of IV administered dose is found in the urine unchanged?
- assume that hepatic metabolism and renal excretion are major elimination pathways → urinary excretion accounts for 20% of total drug elimination
- fe is the fraction excreted unchanged into the urine (fe = 0.2)
What is the equation for the fraction of drug excreted unchanged in urine (fe)?
fe = total drug excreted unchanged / dose = CLR / CL
CLR = CL*fe AND CLH = CL - CLR
After oral administration of 1 g drug, you obtain plasma drug concentration v time. Using the data, you can estimate CL.
false → need IV data to estimate clearance!
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?
CLpo (order from largest to smallest is CLpo > CLb > CL > CLH > CLR)
