Lecture 10

Question 1

Classical Kinetics

Answer 1

• Predicts blood and tissue levels based on transfer into and out of
  “compartments”.
• No attempt to model individual organs or tissues.
• Concepts to be discussed:
  – One and two compartment models.
  – Elimination kinetics.
  – Apparent volume of distribution.
  – Clearance.
  – Half-life.
  – Saturation toxicokinetics.
  – Bioavailability.

Question 2

What is Pharmacokinetics?

Answer 2

• A quantitative description of ADME.
• Measured by blood/tissue
  concentrations at times after dosing.
• End result of kinetics is a biologically
  effective (or toxic) dose of the drug.

Question 3

First Order Elimination

Answer 3

• A nonlinear decrease in drug
  concentration over time.
• A constant fraction of drug
  eliminated per unit time.
• Results in constant t1/2 and kel over
  time (and dose).
• Most common kinetic profile for
  drugs.

Question 4

Zero Order Elimination

Answer 4

• A linear decrease in drug
  concentration over time.
• A constant amount of drug eliminated
  per unit time.
• Results in decreasing half-life over
  time.
• t1/2 and kel depend on the dose and
  are not constant.
• Seen when a metabolic pathway is
  saturated.

Question 5

Drugs that are stored in fat or are highly protein-bound have

Answer 5

very large Vd (>total body water).

Question 6

Large drug molecules that cannot leave the blood compartment

Answer 6

have small Vd (<total body water).

Question 7

Clearance

Answer 7

Clearance
* Clearance (Cl) is the rate of drug elimination from the body expressed as
the volume of fluid containing the xenobiotic that is “cleared” per unit of
time. CL has units of flow (e.g., mL/min)

Question 8

Half-Life

Answer 8

• The elimination half-life (t1/2) is the time required for the blood or plasma
  drug concentration to decrease by 50%.
• It is dependent on both Vd and Cl

Question 9

Bioavailability

Answer 9

• The fraction (F) of the dose of a drug that reaches the
  systemic circulation:
  – For i.v. dose, F = 1.0.
  – For other routes, F = 0 – 1.0

Question 10

Advantages of PBPK Models

Answer 10

• Provide estimates of the time course of drug distribution to any organ or
  tissue.
• Allow estimation of the effects of changing physiologic parameters on
  organ/tissue concentrations.
• Can predict toxicokinetics in different species using “allometric scaling”.
• Complex dosing and processes such as metabolism and binding are
  easily accommodated

Question 11

Disadvantages of PBPK Models

Answer 11

Need lots of data to build a valid model.

Question 12

Flux

Answer 12

rate of transfer (mg/min) of xenobiotic across a boundary.
– Dependent on permeability coefficient, surface area, and xenobiotic concentration

Question 13

Perfusion (blood flow) limited
compartment

Answer 13

– Transfer of drug into cells is very rapid.
– Amount of drug that enters cells is limited
only by blood flow into organ

Question 14

Diffusion (membrane) limited
compartment

Answer 14

– Transfer of drug into cells is slow.
– Amount of drug that enters cells is limited
by flux across cell membranes