PKPD Exam 2 assessment questions + short answer

A patient has experienced substantial weight gain over the past several months, which may lead to an increase in tissue binding of a lipophilic medication. Under conditions of distribution equilibrium, an increase in drug binding within tissues would be expected to result in a decrease in which of the following?

Concentration of bound drug in plasma

What is the usual clinical impact of decreased plasma protein binding?

Minimal effect on half-life

After oral administration of bisoprolol, the drug exhibits an oral bioavailability of 88%, and 40% of the dose is excreted unchanged in the urine. Given a total clearance (CL) of 15.6 L/h, the corresponding renal clearance (CLr) is (in L/h):

7.08

Rate of renal excretion = Rate of secretion

+ (Rate of filtration – Rate of reabsorption)

Candesartan is a weakly acidic compound with a pKa value of 6.0 and serves as a substrate for specific active transporters. It exhibits 98% plasma protein binding and possesses a renal clearance of 0.8 L/h. Assuming a glomerular filtration rate (GFR) of 120 mL/min, which of the following factors is most likely to increase its renal clearance?

Induction of active transporters

Regarding the influence of urinary pH on the renal clearance of weakly acidic and weakly basic drugs, which of the following statements is generally correct, assuming that tubular reabsorption contributes to the drug’s renal excretion?

A decrease in urinary pH is expected to increase the renal clearance of a weak base with a pKa of 7, which is nonpolar in its unionized form.

Which of the following factors is most likely to influence the glomerular filtration of a drug?

The rate of renal blood flow

Which of the following types of drugs is most likely to exhibit a large volume of distribution?

small‑molecule, lipophilic drug

Under conditions of distribution equilibrium, the total plasma concentration of a drug is 5.5 mg/L. In the tissue compartment, the total drug concentration is 10 mg/L, with a bound concentration of 6 mg/L. The fraction bound (f_b) of the drug in plasma is:

0.27

Under conditions of distribution equilibrium, an increase in the plasma protein binding of a drug leads to:

A decrease in the total drug concentration within tissues.

Km

Km reflects the binding affinity of an enzyme for its substrate or drug.

The metabolic clearance (CL_m) is defined as follows:

The ratio of the rate of metabolism of the parent drug to the plasma concentration of the parent compound (CLm = (dAm/dt)/C).

For a particular drug, the equilibrium distribution ratio between renal tissue and blood (Kp) is 31.5. The renal blood perfusion rate (Q/V_T) is 3.5 mL·min⁻¹·g⁻¹ of tissue. Under the assumption that drug distribution is limited solely by perfusion, determine the time required (in minutes) for the drug to achieve 75% of its distribution equilibrium within the kidneys.

12.5

Under conditions of passive diffusion, which of the following factors exerts the greatest influence on the rate at which a drug penetrates biological membranes?

The lipophilicity of the drug

Regarding drug binding in plasma and tissues, which of the following statements is true?

Alterations in plasma protein binding produce larger changes in the volume of distribution for drugs that are highly protein‑bound than for those with low protein binding.

Regarding flip‑flop kinetics, which of the following statements is true?

The absorption process serves as the rate‑limiting step for drug elimination.

Compared with the fasting state, the administration of a heavy meal is likely to:

Prolong the time required to reach the maximum plasma concentration (tmax) of a drug administered in an enteric‑coated tablet.

For an orally administered drug, if the volume of distribution decreases, how should the time required to reach the maximum plasma concentration (t_max) be expected to change?

Decrease

Which of the following is considered the link between systemic absorption and elimination?

First‑pass events in the intestine and liver

In a bioavailability study, a healthy volunteer received 100 mg of Drug A intravenously, resulting in AUC_0–24h and AUC_0–∞ values of 1.34 and 1.76 mg·h/L, respectively. After the same subject received a 250‑mg oral dose of Drug A, the corresponding AUC_0–24h and AUC_0–∞ values were 1.71 and 2.34 mg·h/L. The oral bioavailability (F; in %) of Drug A in this subject is calculated to be:

53

Given a total plasma drug concentration of 40 µg/L, a bound plasma drug concentration of 30 µg/L, and a total drug clearance of 4 L/h, what is the corresponding unbound clearance (in L/h)?

16

Under conditions of distribution equilibrium, which of the following statements is true?

The ratio of protein‑bound drug concentration in plasma to that in tissues remains constant.

For a low–extraction ratio drug, in which total clearance is effectively equivalent to hepatic clearance, a reduction in plasma protein binding will lead to which of the following outcomes?

A decrease in the total drug concentration at steady state

For a high extraction‑ratio (high ER) drug that is primarily eliminated by hepatic mechanisms, which of the following statements is true?

Its elimination half‑life (t1/2) is directly related to the fraction unbound in plasma (fu).

For any given drug, the theoretical upper limits of the following pharmacokinetic parameters are:

The maximum renal clearance is equivalent to the renal plasma flow rate.

Biliary clearance is defined as the proportionality constant that relates the concentration of unchanged drug in:

Plasma to the rate of excretion of unchanged drug into the bile.

Drug A exhibits an oral bioavailability (F) of 42%. After a 10‑mg oral dose, 2.8 mg of unchanged drug is recovered in the feces. Biliary excretion is assumed negligible and the liver is the only site of metabolism. What should be its extraction ratio (ER) value? 

0.42

Which of the following leads to a modification in the metabolic activity of an enzyme toward a drug?

The presence of a non‑competitive inhibitor

Define flip-flop kinetics?

Absorption-rate limited kinetics

List three characteristics of flip-flop kinetics.

ka <<k; absorption rate approximates elimination rate; absorption

half-life approximates the half-life of drug declining in the body

Graph of relationship between rate of absorption in the GI tract has what

absorption in GI tract and rate of elimination in blood become parallel

Under distribution equilibrium, displacement from plasma protein binding is

expected to result in (indicate decrease, increase or no change): _________ in

the fraction of drug bound within tissue

no change

Under distribution equilibrium, displacement from plasma protein binding is

expected to result in (indicate decrease, increase or no change): _________ in the total drug

concentration in plasma

decrease

Under distribution equilibrium, displacement from plasma protein binding is

expected to result in (indicate decrease, increase or no change): _________ in the concentration of protein‑bound drug

within tissues,

increase

Under distribution equilibrium, displacement from plasma protein binding is

expected to result in (indicate decrease, increase or no change): _______ in the volume of distribution

increase

T/F When the distribution

equilibrium is reached, movement of drug molecules between blood and tissue

stops, and unbound drug concentrations in blood and tissue must be equal

False

define Vmax

maximal metabolic reaction rate - efficacy

Define Km

substrate concentration to achieve 50% of maximal metabolic reaction rate -affinity

how will changing substrate concentrations affect the Vmax and Km values?

Changing substrate concentrations will not affect Vmax and Km

How would Vmax change in the presence of a competitive inhibitor

Vmax will not change

How would Kmax change in the presence of a competitive inhibitor

Km would increase

bioavailability and bioequivalence study design

Cross-over or IV micro-dosing

bioavailability and bioequivalence sample duration and intensity

ntensive sampling around the range of tmax. Sampling for ~ 5 half-lives

bioavailability and bioequivalence analytical methods must have

Sensitivity and specificity

bioavailability and bioequivalence PK analysis test for

AUC, tmax, Cmax, and F

bioavailability and bioequivalence statistical analysis

Standard t-test (2 groups), ANOVA (> 2 groups)