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Pharmaceutical Phase Drug Administration
Disintegration of the Dosage Form Drug and
Drug Dissolution
Pharmacokinetic Phase
(Time course of ADME processes)
Absorption
Metabolism
Distribution
Accumulation
Excretion
Active Site
Pharmacodynamic Phase
Pharmacological Effects
Therapeutic Effects
Toxic Effects
I.V. Bolus
k
10t
Cp  Cp   e

Oral administration
12
Drug Concentration
(ng/mL)
10
8
6
4
2
0
0
4
8
12
Time (hr)
16
20
24
Half-life
t1/ 2
0.693  Vd ln( 2) 0.693



CL
k 10
k 10
Volume
of
Distribution
Time for the concentration to decrease by half
Dose
Amount
Vd 

Cpo
Cp
Clearance
F .Dose
CL 
 K 1 0  Vd
AUC
SYSTEMIC EXPOSURE PARAMETERS
Peak Drug Concentration (Cmax)
and
AREA UNDER THE PLASMA CONCENTRATION TIME
CURVE (AUC)
Multiple I.V. Dosing (Bolus)
The AUC within a dosing interval at steady
state is equal to the total AUC of a single
dose.
Oral administration
Multiple Dose
CONCEPT
The absorption, distribution and
elimination of a drug may be
qualitatively similar in all
individuals. However, for several
reasons, the quantitative aspects
may differ considerably. Each
person must be considered
individually and doses adjusted
accordingly.
Variability in
Pharmacokinetics
Plasma Drug
Concentration (mg/L)
60
50
40
30
20
10
0
0
5
10
Daily Dose (mg/kg)
15
Co-variates affecting Drug
Disposition
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Age
Gender
Genetic Make-Up
Dietary Factors
Environmental Factors
Drug-Drug Interactions
Disease State
PHARMACOKINETIC
MODELING
Pharmacokinetic models are used to:

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Predict plasma, tissue and urine drug levels with any
dosing regimen
Calculate the optimum dosage regimen for each
patient individually
Estimate the possible accumulation of drugs and/or
metabolites
Correlate drug concentrations with pharmacologic or
toxicologic activity
Evaluate differences in the rate or extent of
availability between formulations (bioequivalence)
Describe how changes in physiology or disease affect
the ADME of the drug
Explain drug interactions
I. Physiologic Models
IV injection
QH
QM
QR
Urine
ke
QK
QL
km
Arterial blood
Venous blood
QS
I. Physiologic Models

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Important factors –
1. Organ tissue size
2. Blood flow
3. Drug tissue-blood ratios
Can be applied to several species
(extrapolation of human data from animal
data)
Also known as blood flow/perfusion models
II. Compartmental Modeling
1. Catenary Models
ka
k12
1
k23
2
k21
3
k32
2. Mammillary Modeling
P2
P1
Central
P3
P4
One-Compartment Open Model
I.V. bolus
DB1 Cp1 Vd
k10
K10 = overall
elimination rate constant
I.V. Bolus
k
10t
Cp  Cp   e

D
Cp  
Vd
Two-compartment Open
Model
tissue
I.V. bolus
Cp1 VC
k12
Dp
k21
Dt
Ct
Vt
Two-compartment model
103
103
C (ng/ml)
C (ng/ml)
C0
a
102
102
b
101
101
100
100
10-1
b
a
10-1
0
2
4
6
Time (hours)
8
10
0
1
2
3
Time (hours)
4
5
Two-compartment model
Plasma concentration (single dose)

1t
 t
Cp  C
C

1
2
z
1-phase: distribution phase
z-phase: elimination phase
Two-compartment model
103
C (ng/ml)
102
101
100
10-1
0
1
2
3
4
Time (hours)
5
6
7
8
Compartment Modeling Stochastic Approach
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http://vam.anest.ufl.edu/simulations/fir
storderstochasticsim.html#sim
http://vam.anest.ufl.edu/simulations/se
condorderstochasticsim2.html#sim
TWO COMPARTMENT MODEL
Central
K10
100
10
Elimination
LN Conc
IV BOLUS
Blood,
Liver
Kidney
1
K12
K21
0
Muscle
fatty
5
10
15
0.1
Time(hr)
Peripheral
Cp = Ae-1t + Be-zt
20
Blood flow to human tissues
Tissue
Percent Body
Weight
Percent Cardiac
Output
Adrenals
0.02
1
550
Kidney
0.4
24
450
Liver
2.0
25
Hepatic
Portal
Blood Flow
(ml/100 g
tissue/min)
5
20
20
75
Brain
2.0
15
55
Skin
7.0
5
5
Muscle
(basal)
40.0
15
3
Connective
Tissue
7.0
1
1
Fat
15.0
2
1
Extravascular dose
e.v. dose
Site of
absorption
ka
Dp
Cp
Vd
k10
Oral administration
12
Drug Concentration
(ng/mL)
10
8
6
4
2
0
0
4
8
12
Time (hr)
16
20
24
PRINCIPLE
Drugs appear to distribute in the body as if it
were a single compartment. The magnitude of
the drug’s distribution is given by the
apparent volume of distribution (Vd).
Vd = Amount of drug in body ÷ Concentration in Plasma
(Apparent) Volume of Distribution:
Volume into which a drug appears to distribute with
a concentration equal to its plasma concentration
Examples of apparent Vd’s
for some drugs
Drug
L/Kg
L/70 kg
Sulfisoxazole
0.16
11.2
Phenytoin
0.63
44.1
Phenobarbital
0.55
38.5
Diazepam
2.4
168
Digoxin
7
490