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• MS Excel sheet with Calculations

PHARMACOKINETIC BASICSLecture #2

Factors in Measuring Systemic Exposure

• Sites of Measurement (Where?)• Unbound [Drug]• Exposure-Time Profile• Observation Period

Exposure-Time Profile

In addition to the concentration, what other factor should we consider with exposure?

Sites of Measurement

• Invasive– Whole Blood, Plasma and Serum• Unbound Drug Concentration and Fraction Unbound

• Non-invasive– Breath– Milk– Saliva– Feces– Urine

Chemical Purity/Enantiomers

anticoagulant

stimulant

Decreases Rapidly

[drug] very low

Active Metabolites and Prodrugs

Sites of Administration• Intravascular Systemic Circulation

– Intravenous (IV)– Intra-arterially (IA)

• Extravascular Absorption Systemic Circulation– Buccal (Between Cheek and Gum)– Intradermal (ID)– Intramuscular (IM)– Oral – Pulmonary (Inhalation)– Subcutaneous (Subcut, Fat under Skin)– Rectal– Sublingual (SL, under the tongue)

Typical Exposure-Time Profiles

0 2 4 6 8 10 120

2

4

6

8

10

12

time (hr)

[Dru

g]pl

asm

a

Intravascular Extravascular

Lag due to absorption

[Dru

g]pl

asm

a

Parenteral Administration

• Restricted to Injected– Intravascular– Intramuscular– Subcutaneous

How a drug ends up- Drug Disposition

(i.e. Amount Absorbed)

ExcretedMetabolite

Terms

• Elimination– Drug Metabolism– Amount/time (mg/hr)

• Excretion– Drug Removal from the Body– Amount/time (mg/hr)

• Clearance– Volume/time (L/hr)

D[Drug] = [Drug]in –[Drug]out

DDrugDrug In

Drug Out

Representing PK

• Equations• Physiologic Models• Compartment Models

Equations

Why?

Physiologic Models

Compartmental Models

ADME

Systematic Absorption

First Pass Loss

Systemic Circulation

Bioavailability (F)

Enterohepatic Cycle: Drugs Recycled

PK Terms

• Maximum Concentration (Cmax)

• Maximum Time (tmax)• Area Under the Curve (AUC)

Cmax and tmax

Cmax

tmax

What factors determine how much exposure that you have to a “poison”?

• systemic exposure = How long * How much[D

rug]

plas

ma

time

Systemic Exposure

How longHow

much

What factors determine how much exposure that you have to a drug?

• AUC = How long * How much[D

rug]

plas

ma

time

Area Under the Curve (AUC)

How longHow

much

Area Under the Curve (AUC)

tmax

AUC(µg/L)*hr

Area Under the Curve

Drug Plasma After Intravenous (IV) Bolus Dose

0 2 4 6 8 10 120

2

4

6

8

10

12

time (hr)

[Dru

g]pl

asm

a

C(0)

k=rate (/hr)

Drug Plasma After Intravenous (IV) Bolus Dose

0 2 4 6 8 10 120

2

4

6

8

10

12

time (hr)

[Dru

g]pl

asm

a

C(0)

AUC

Cmax and tmax?

Trapezoid Area

a b

c

Trapezoid AreaCi

tfti

Cf

time

[Dru

g]

Drug Plasma After Intravenous (IV) Bolus Dose

0 2 4 6 8 10 120

2

4

6

8

10

12

time (hr)

[Dru

g]pl

asm

a

C(0)

Drug Plasma After Intravenous (IV) Bolus Dose

0 2 4 6 8 10 120

2

4

6

8

10

12

time (hr)

[Dru

g]pl

asm

a

C(0)

Ct

Drug Plasma After Intravenous (IV) Bolus Dose Only

0 2 4 6 8 10 120

2

4

6

8

10

12

time (hr)

[Dru

g]pl

asm

a

C(0)

Only works when the curve is shaped like this.