Pharmacokinetics and Drug Disposition

Question 1

What is pharmacokinetics (PK)?

Answer 1

The study of how the body absorbs, distributes, metabolizes and eliminates (ADME) a drug (what the body does to the drug)

Question 2

What are the uses of PK?

Answer 2

To determine rates of absorption, metabolism and excretion
To determine bioavailability
To predict plasma (blood) concentrations related to drug dose
To optimize dose regimens
To correlate activity (pharmacodynamics) with circulating drug concentration
To assess factors that may alter drug disposition

Question 3

What are the different routes of administration?

Answer 3

Oral
Intravenous
Subcutaneous
Intramuscular
Transdermal (patch)
Rectal
Inhalation
Sublingual

Question 4

What are key terms in PK?

Answer 4

Volume of distribution (Vd)
Clearance
Drug half life (t1/2)
Drug accumulation
Bioavailability

Question 5

What is the volume of distribution?

Answer 5

The measure of the apparent space in the body available to contain a drug - how a drug is distributed in the body relative to the plasma

Question 6

What can we use Vd for?

Answer 6

Needed for determining clearance of a drug from the body
Needed for determining loading dose of a drug
A high Vd means that a drug is not staying in the vascular compartment (i.e., it is extensively distributed)

Question 7

Mathematically, what is the loading dose?

Answer 7

Loading dose = Vd x desired plasma concentration

Question 8

Mathematically, what is the volume of distribution?

Answer 8

Amount of drug in the body (mg/kg) divided by the drug plasma concentration (mg/L)

Question 9

What is the loading dose?

Answer 9

The used to get the dose in the body in the therapeutic window very quickly

Question 10

What is the maintenance dose?

Answer 10

It follows the loading dose

It’s used to maintain the dose in the body within the therapeutic window

Question 11

What are factors that influence drug distribution in the body

Answer 11

pKa of cpd and pH of the tissue compartment (acidic drugs are more likely to be concentrated in the blood compartment whereas basic drugs are more likely to be concentrated in the tissue)
Drug binding
Specialized distribution barriers (BBB, placenta)

Question 12

What is clearance?

Answer 12

The measure of the ability of the body to eliminate the drug.
The volume of plasma that would contain the amount of drug excreted per unit of time (minute).
Volume of plasma that would have to lose all of the drug that it contains within a unit of time (usually 1 minute) to account for an observed rate of drug elimination

Question 13

What are the major routes of elimination?

Answer 13

Liver
Bile
Urinary excretion

Question 14

What are the two major sites of elimination?

Answer 14

The kidneys and the liver

Question 15

What is the importance of clearance?

Answer 15

Provides an index of the efficiency by which a drug is removed from the body
Is subject to changes due to disease state, genetic and environmental factors
Needed for determining dosing rate and maintenance dose

Question 16

What is dosing rate?

Answer 16

Clearance x target concentration

Mathematically: (vol/time)(amount/vol) = amount/time

Question 17

What is the maintenance dose, mathematically?

Answer 17

(dosing rate/F)(dosing interval)

Mathematically: (amount/time)(time) = amount

Question 18

How do the factors affecting Vd affect the half life?

Answer 18

Aging (decreased muscle) decreases the half life
Obesity (increased adipose) increases the half life
Pathologic fluid increases the half life

Question 19

How do factors affecting clearance affect the half life?

Answer 19

Induction of Cyp450 decreases the half life
Inhibition of Cyp450 increases the half life
Organ failure increases the half life

Question 20

What is the definition of half life?

Answer 20

The time required to change the amount of drug in the body by one-half during elimination

Question 21

What are half-lives in PK?

Answer 21

The time it takes for drug concentration in plasma to decline by 50%
Most drug PK is first order - equal proportions of drug are removed per unit of time

Question 22

What is drug accumulation?

Answer 22

Drug accumulation is inversely proportional to dose lost

Question 23

What is bioavailability?

Answer 23

The fraction of unchanged drug reaching the systemic circulation following administration by any route
It measures the extent of absorption

Question 24

How is bioavailability calculated?

Answer 24

(AUCdose (oral, inhalation, etc.) / AUCiv)*100

Question 25

How is drug absorption determined?

Answer 25

Time to peak concentration (rate)
Peak concentration (rate and extent)
Area under the plasma concentration vs time curve (extent)

Question 26

What are the limitations for drug absorption?

Answer 26

Tissue perfusion (blood flow)
Diffusion-limited absorption (partition coefficient)
First pass effect (distribution and metabolism)

Question 27

What are the factors influencing drug absorption?

Answer 27

Formulation
Water solubility
Lipid solubility
pKa
GI motility
Gastric pH
Posture
Other drugs

Question 28

What are the factors influencing the PK of a drug?

Answer 28

Environmental factors (diet, lifestyle, other medications, dietary supplements, etc.)
Genetics
Physiological/pathophysiological

Question 29

Mathematically, what is clearance?

Answer 29

(0.693/half life)*Vd

Question 30

Mathematically, what is half life?

Answer 30

(0.693*Vd)/Cl

Question 31

What is drug accumulation?

Answer 31

Accumulation factor = 1/dose lost (i.e., elimination fraction)