PHA 328: Nonlinear Pharmacokinetics

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1

True or False: In linear PK, ADME all obey first order kinetics.

True

2

In linear PK, paramaters ______________ with different or multiple doses.

Remain constant

3

True or False: In linear PK, plasma drug concentrations at a given time and AUC are directly proportional to the dose.

True

4

In linear PK, concentrations of the drugs in plasma and tissues are (above/below) protein binding saturation and remain constant.

Below

5

In linear PK, drug plasma concentration-time profiles are ___________ when normalized by dose

Superimposable

6

In linear PK, Tmax remains _____________

Unchanged

7

Linear PK is considered dose- (independent/dependent) PK

Independent

8

In nonlinear PK, are plasma levels porportional to dose?

No

9

True or False: In nonlinear PK, drug plasma concentration-time profiles are superimposable when normalized by dose.

False

10

How is Tmax affected in nonlinear PK?

It may or may not change

11

Nonlinear PK is considered dose- (independent/dependent) PK

Dependent

12

Drugs that demonstrate saturation kinetics usually show the following characteristics:

  1. Elimination of drug does not follow first-order kinetics
  2. Elimination half-life changes as dose is increased
  3. AUC is not proportional to amount of bioavailable drug
  4. Saturation of capacity-limited processes may be affected by other drugs that require the same enzyme / carrier-mediated system
  5. Composition and/or ratio of the metabolites of a drug may be affected by a change in the dose
13

What can cause nonlinear PK?

  1. Gastrointestinal absorption
  2. Distribution
  3. Renal Excretion
  4. Hepatic metabolism
14

What is the biggest source of nonlinear PK?

Hepatic metabolism

15

Gastrointestinal absorption causes of nonlinear PK

  • Saturable transport in gut wall
  • Drug comparatively insoluble
  • Saturable gut wall or hepatic metabolism on first pass
16

What parameter and how does "Saturable transport in gut wall" affect?

F, decreases

17

What parameter and how does "Drug comparatively insoluble" affect?

F, decreases

18

What parameter and how does "Saturable gut wall or hepatic metabolism on first pass" affect?

F, increases

19

Distribution causes of nonlinear PK

  • Saturable plasma binding
  • Saturable tissue binding
20

What parameter and how does "Saturable plasma binding" affect?

V and fu, increases

21

What parameter and how does "Saturable tissue binding" affect?

V and fuT, decrease and increase respectively

22

Renal excretion causes of nonlinear PK

  • Active secretion (saturable)
  • Active reabsorption (saturable)
  • Decrease in urine pH
  • Saturable plasma ptn binding
  • Nephrotoxicityb
  • Increase urine flowb
23

Hepatic Metabolism causes of nonlinear PK

  • Capacity-limited kinetics, cofactor limitation, etc.
  • enzyme inductionb
  • hepatotoxicityb
  • Saturable plasma ptn binding
  • Decreased hepatic blood flow
  • Inhibilitation by metaboliteb
24

What are the 4 most common sources for nonlinear pharmacokinetics?

  • Capacity-limited oral absorption
  • Saturable ptn binding
  • Capacity-limited excretion
  • Capacity-limited metabolism
25

Capacity-limited oral absorption causes:

  • Limited dissolution/solubility as the oral dose increases
  • Saturable transport across the intestinal mucosa as the oral dose increases
  • Saturable first-pass metabolism in the intestinal epithelium (gut wall) and/or liver as the oral dose increases
26
  • Griseofulvin is poorly water-soluble.
  • Less proportion of the drug is dissolved and absorbed w/ higher dose.
  • F decreases as dose increases and tmax remains the same.

What is this an example of?

Capacity-limited oral absorbtion - limited dissolution w/ dose increase

27
  • Amoxicillin is actively transported by peptide transporter in the SI.
  • Active transport becomes saturated as dose increases.
  • F decreases as dose increases and tmax remains the same

What is this an example of?

Capacity-limited oral absorbtion - Saturable transport across the intestinal mucosa as oral dose increases

28
  • Nicardipine is metabolized by CYP3A4 in intestinal epithelium and hepatocytes
  • 1st-pass metabolism is saturated as dose increases
  • F increases as dose increases

What is this an example of?

Capacity-limited oral absorbtion - Saturable first-pass metabolism in the intestinal epithelium (gut wall) and/or liver as the oral dose increases

29

Drug-plasma protein binding is _______________

Saturable

30

What is the saturation drug concentration for binding with plasma albumin?

600mM

31

What is the saturation drug concentration for binding with α1-acid glycoprotein?

15 mM

32

Drug-plasma binding may ________ CLH and/or CLR

Increase

33

Drug-plasma binding may ____________ V

Increase

34

Trandolaprilat is eliminated by ______________

Glomerular filtration

35

Active secretion and active reabsorption are saturable processes according to _______________

Capacity-limited excretion

36

Saturated tubular _________ decreases CLR

Secretion

37

Saturated tubular __________ increases CLR

Reabsorption

38

How is vitamin C reabsorbed from the urine?

Active transport

39

Tubular reabsorption becomes __________as Cp increases.

Saturated

40

CLR approaches _______ as Cp increases.

GFR

41

True or False: Enzymatic reactions are not saturable.

False

42

According to Michaelis-Menten Kinetics, ______ is the drug concentration at which half of the active sites on enzymes are occupied

Km

43

What type of reaction do you get when Cp << Km?

First order

44

What type of reaction do you get when Cp >> Km?

Zero order

45

In linear PK, clearance is ___________ of Cp

Independent