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Pharmacokinetics and Pharmacodynamics
Pharmacokinetic Phase
Overview Pharmacokinetics
Absorption
Distribution
Metabolism
Excretion
Dose
Carrie K.
K Jones
Department of Pharmacology
Vanderbilt Program in Drug Discovery
Pharmacodynamic Phase
Blood
Receptor interaction
Concentration
&
Receptor response
Preclinical
or Clinical
ec
Effect
Pharmacokinetics: study of drug disposition-all processes by which the
body handles foreign chemicals including drugs (i.e. ADME)
“what body does to the drug”
Resources:
1. Gibson and Skett (2001) Introduction to Drug Metabolism, Nelson Thornes Publishers
2. Donald J. Burkett, (2002) Pharmacokinetics Made Easy McGraw-Hill Austarlia Pty Ltd
3. Slides adapted from DMPK lectures given Joseph Awad, MD
Pharmacodynamics: relationship between unbound (‘free’) drug concentration at
the receptor and the drug response (i.e. therapeutic effect)
“what drug does to the body”
Bioavailability
Overview of Drug Disposition
A – Absorption: Passage of drug from site of administration to circulation
D – Distribution: Distribution of drug from plasma to organs, tissues, etc…biophase
M – Metabolism: Conversion of xenobiotics into water soluble derivatives; liver
E – Excretion: Elimination of drugs & metabolites with adequate kinetics
• Slow elimination leads to drug/metabolite accumulation and toxicity
• Rapid elimination requires repeated dosing
• Routes: renal, rectal, pulmonary, oral, cutaneous
y Mutagenic,
g
, tetragenic
g
and ggeneral toxicity
y of drug
g and metabolites.
***T – Toxicity:
Bioavailability is a measurement of the rate and extent of a therapeutically
active drug that reaches the systemic circulation and is available at the
site of action.
Absolute bioavailability: comparison of bioavailability (estimated as the area under the curve, or AUC) of the
active drug in systemic circulation following non-intravenous administration (i.e., after oral, rectal,
transdermal, subcutaneous, sublingual administration), with bioavailability of the same drug following
intravenous administration.
I order
In
d tto determine
d t
i absolute
b l t bi
bioavailability
il bilit off a d
drug, a pharmacokinetic
h
ki ti study
t d mustt be
b done
d
tto obtain
bt i a
plasma drug concentration vs time plot for the drug after both intravenous (IV) and non-intravenous
administration. The absolute bioavailability is the dose-corrected area under curve (AUC) non-intravenous
divided by AUC intravenous. For example, the formula for calculating F for a drug administered by the oral
route (po) is given below.
****Therefore, a drug given by the intravenous route will have an absolute bioavailability of 1 (F=1) while drugs
given by other routes usually have an absolute bioavailability of less than one.
Relative bioavailability: measures the bioavailability (estimated as area under the curve, or AUC) of a
certain drug when compared with another formulation of the same drug, usually an established standard,
or through administration via a different route. When the standard consists of intravenously administered
drug, this is known as relative bioavailability.
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Routes of Administration / Bioavailability
Bioavailability
•
Factors affecting bioavailability
> Route of administration
•
•
Parenteral
>
>
>
>
Intravenous (iv)
Intramuscular (im)
Subcutaneous (sc, sq)
Intraperitoneal (ip)
Alimentary
> Oral (po)
> Sublingual (sl)
> per rectum (pr)
Miscellaneous
> Topical (skin or eye)
> Inhalation
> Spinal (it)
Bioavailability
Factors affecting bioavailability
> Route of administration
> Chemical properties of the drug
» Rapid, accurate, ?toxic
…control, but requires access
…perfusion, depot
…slower and longer
…rare for clinical applications
» Convenient, safer,
cheaper
…variable absorption
…bypass liver
…useful, but inconvenient
» Special Uses
…irritation, bypass liver
…rapid, limitations
…technically challenging
Chemical Properties / Bioavailability
• Most drugs must cross mucosal barriers.
• Dependent on chemical properties of drug.
• Passive processes:
> filtration
> diffusion
diff i
> carrier-facilitated transport
(amino/nucleic acid-like drugs)
• Active processes:
>
>
>
>
>
up a gradient, energy requiring
protein transporter
substrate specificity, susceptible to competition
saturable
neural membranes, choroid plexus, liver and kidney cells
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Passive Diffusion
•
•
• Lipid:Water Partition
Accounts for most drug absorption
Fick’s Law:
dQ/dt = -D • A dC/dx
>
>
>
>
•
Lipid Solubility / Bioavailability
Coefficient (log P)
> e.g. Octanol:Water
> Site of action discussion!!!
dQ/dt - Quantity moving in time
D - constant depending on Temp and MW
A - surface area
dC/dx - dependent on lipid solubility of drug
• Ionization
I i ti Eff
Effects
t
> Ionized compounds have low
lipid:water partition coefficient
> Ionization status variable dependent on pH
• Weak acids not ionized at low
pH
• Weak bases not ionized at
high pH
Absorption dependent on drug:
> Molecular Weight (size)
> Lipid Solubility
•
Absorption dependent on host:
> Surface area
[1000
HA
-
A
Plasma
pH=7.4
Gastric Juice
pH=1.4
]
+H+
HA
7.0-7.5
4.3-4.7
3.4-4.2
• Aqueous Solubility
1001
Total [HA]+[A-]
> Confounds effect of pH
> Weak acids (+ other hydrophobic drugs) may
not be well dissolved in stomach
> Weak acids require special formulation
Lipid Mucosal Barrier
[1]
Blood
Mouth
Stomach
Duodenum
Jejunum and
Ileum
Colon
Sweat
Vagina
Nl pH
Range
7.2-7.6
6.2-7.2
1.0-3.0
4.8-8.2
7.5-8.0
Chemical Properties /
Bioavailability
Example of Weak Acid Partition
[1]
Compartment
• Chemical Stability
[0.001
A
-
]
+H+
Weak acid with pKa of 4.4
> Survival of drug in acidic gastric environment
> Intrinsic stability
> Protected by formulation
> Suppression of acid
1.001
[A-]/[HA]=10(pH-pKa)
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Drug Formulation
(Pharmaceutics)
Bioavailability
Factors affecting bioavailability
• Disintegration of drug delivery system must be
> Route of administration
> Chemical properties of the drug
> Formulation of the drug (Pharmaceutics)
reliable.
• Enteric coating - protection from gastric acidity
• Controlled
Controlled-release
release preparations
> reduce need for frequent dosing
> complexity = greater interpatient variability
> dose dumping
> target drug to particular area
• Bioequivalent
• Pharmaceutical Equivalent
Formulation for Preclinical
Studies
Bioavailability
For systemic administration: ***must pH solution ~ 6.5-7.5
Sterile water
Artificial CSF (cerebrospinal fluid)
Saline (0.9% NaCl)
1N NaOH and water
8.5% lactic acid and water
10-20% BCD
10% solutol
10% Tween 80
10% Tween 20
*** no EtOH !!!
Factors affecting bioavailability
10%-100% PEG 400
10% DMSO
0.5-1% methylcellulose
0.5% acacia
> Route of administration
> Chemical properties of the drug
> Formulation of the drug (Pharmaceutics)
> Metabolism-presystemic
M b li
i
> Site of administration relative to site of metabolism
ICV, IC, IT, or Direct Site administration: ***must pH solution ~
6.5-7.5
Sterile water
Artificial CSF (cerebrospinal fluid)
Buffer saline (0.9% NaCl)
10-20% BCD
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Metabolism / Bioavailability
Pre-Systemic Clearance
Systemic Circulation
• Drug must enter circulation faster than
•
Hepatic Veins
metabolized
Sites of metabolism
Hepatic Drug Transport and
Metabolism
> Liver
> Intestine
> Lung
> Kidney
((bile))
Drug
• Presystemic Clearance (“first pass”
Portal Vein
Metabolite
metabolism)
Intestinal Drug Transport
and Metabolism
CYP3A4
P-glycoprotein
p.o.
> PO dose >> IV
> Interindividual variability greater
Bioavailability
<100%
• Bioactivation - Prodrugs
Biotransformation and
Elimination
Metabolism Basics
• Drug Metabolism
Phase I (Degradative)
• Oxidation
• Reduction
• Hydrolysis*
>Phase I
>Phase II
• Enterohepatic Circulation / Hepatic
Elimination
Phase II (Conjugative)
Glucuronidation*
Sulfation
Acetylation/Methylation*
Amino Acids
•
•
•
•
> Glutathione
> Glycine
• Renal Excretion
• Pulmonary Excretion/Metabolism
• Placental Transfer
• Breast Milk
Exposes chemical
groups appropriate for
Phase II metabolism
Mostly ER
Energy requiring
Mostly Cytosol
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Focus on Metabolism-Phase I
• Cytochrome (CY) P450~75% of total
Focus on Oxidation
• Cytochrome P450
metabolism
> Inducibility
• CYP 2E1: ethanol, acetone, isoniazid
• CYP 3A4: anticonvulsants, rifampin, steroids
• CYP 1A: hydrocarbons
> Inhibition
> Genetic polymorphism
> Hepatic Dysfunction
> Superfamily of enzymes (12 human)
> Phase I oxidation and some reduction
> Oxidation
• CYP hemoprotein and CYP 450 reductase
• Oxygen and NADPH
> CYP 1, 2 & 3 responsible for most drug
biotransformations
> ****drugs may increase or decrease activity
• Non Endoplasmic Reticulum
> Alcohol dehydrogenase - cytosol
> Xanthine oxidase, monoamine oxidase
– Phenytoin induces CYP1A2, CYP2C9, CYP2C19, CYP3A4
– Problem if other drugs are substrates for activate CYP (i.e .
Carbamazepine)
Focus on GlucuronidationPhase II
Focus on Glutathione
(GSH)-Phase II
• Yields highly polar conjugates
• Conjugates generally inactive
• Actively excreted bile and urine
• Potential for enterohepatic circulation
• Enzyme Quantity: birth, induction, liver
•
•
•
•
•
disease
Glucose-1-PO4 + UTP + 2 NAD +H2O>>> UDPGA + 2 NADPH + 2H
UDPGA + Drug ---------> Glucuronyl-Drug
UDP-glucuronosyl transferase
Tripeptide substrate for GSH-transferases
Detoxifies electrophilic intermediates
Conjugates further metabolized
mM quantities in liver
Acetaminophen overdose-use N -acetylcysteine (NAC), precursor
of glutathione.
SH
NH 2
CH 2
α | H H γ
|
H
O=C-C-C-C-C--N-C-C--N-C-C=0
| H H H
H H
H H OH
OH
Glutamate
Cystiene
Glycine
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Hepatic Elimination
Renal Elimination
Excretion versus Metabolism
• Metabolite Disposition
•
>Enter circulation
Glomerular Filtration
> perfusion
• Glucuronide metabolites largely excreted by
y
kidney
> size, lipid solubility and protein binding
•
Tubular Secretion - active
> less dependent on protein binding
>Excreted in bile
> probenicid
•
• Enterohepatic Circulation
Tubular Resorption - passive
> weak acids - alkalinize urine
> weak bases - acidify urine
> helpful in treating some poisonings
Bioavailability
Assorted Topics
• Pulmonary Elimination
Factors affecting bioavailability
> Route of administration
> Chemical properties of the drug
> Formulation of the drug (Pharmaceutics)
> Metabolism-presystemic
M b li
i
> Site of administration relative to site of metabolism
> Site of drug action
> Pharmacodynamic parameters
> Host factors (“Patient" factors)
>Exhalation of volatile lipid soluble drugs
• Alcohol, anesthetic gases
Some biotransformation
>Some
• Placental Transfer
>Not a barrier to most drugs
• Breast Milk
>Lipid soluble drugs pass well
>Acidic compared to plasma
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Patient Factors / Bioavailability
Pharmokinetics and Dosing
• Metabolic Differences
• Discuss factors which affect initial
> Genetic
> Age
> Gender
> Medical Conditions
> Concurrent Drug Use
concentration of drug after administration.
• Discuss two common time courses of drug
elimination.
elimination
• Gastrointestinal (GI) Tract
> 1st order - linear
> Zero order - non-linear
> Achlorhydria (no acid)
> Gastric stasis
> Gastric surgery
> Small bowel problems
> Colonic resection
*** How does age and health of preclinical species affect
• Discuss factors affecting drug dosing.
> Repeated dosing
> Changing dosing
> Loading doses
bioavailability?
Experimental Determination of
Vd
Drug
500 F
Drug Con
ncentration
Vd = Dose / C0
Elimination
7
100
%
400
300
F 50%
200
F
100
12.5%
F
6.25%
F
F
0
Plasma
Vascular organs
25%
0
1
2
3
4
5
Time after Administration
LN Drug Concentration
Drug Distribution
6
F
F
5
F
F
4
lnCt = lnC -k(t)
3
F
0
F
2
1
0
0
1
2
3
4
5
Time after Administration
Measure plasma drug concentrations after dose
and back-extrapolate to time 0. Vd = Dose / C0
Fat (reservoir)
Volume of Distrubution of compound:
concentration of drug in plasma to total amount of drug in the body
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Can Vd be > Volume Patient?
•
•
Implications
• Changes in concentration with dose
Yes: Vd is a
Virtual Volume
> Small Vd, small dose to increase concentration
and vice versa
Drugs with high
Vd are being
sucked into fat
and reservoir
sites.
• It may take a long time to fill
f the tank
when the volume of distribution is
quite large.
> Example: drugs which accumulate in fat.
• It may take a long time to empty the
tank, to get rid of a drug.
Protein Binding of Drugs
PK Assumptions / Givens
Free drug is generally active form (word about plasma; 92% water, 8%
blood plasma proteins)
• Drug effects are related to [Drug]
• [Drug] in the circulation or biophase is related
> Albumin, alpha1-acid glycoproteins, lipoproteins
***remember unbound or free fraction drug only exerts biological effects,
metabolized and excreted
•
to dose
• [Drug] changes with time
• Drug therapy is enhanced by knowledge of
Binding affects distribution of drugs
> generally passive process
> dependent on free drug concentration
> *** If the amount of plasma protein is decreased (such as in catabolism,
malnutrition, liver disease, renal disease), there would also be a higher
fraction unbound
•
the relationship of [Drug] to drug dose and
the expected changes with time, thus
Drugs can compete for or saturate binding sites
> avoiding ineffective therapy
> avoiding drug toxicity
> can affect free drug concentration
> can affect elimination
> Example: drug A % free fraction double=
effects doubled
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Scenario 1: Data
•
blood pressure (BP)
• Assume instantaneous mixing and
•
drug distribution
• Measure plasma drug concentration
•
over time
500 × 100%
Constant proportion of
g disappears
pp
with
drug
each time period
Exponential (firstorder) decay
•
300
Ū ×
200
25%
Ū × 12.5%
Ū × 6.25%
Ū ×
Ū Ū
×
100
0
Mean Arterial BP
•
×
1
0
0
5
1
2
3
4
5
Time
6
5
4
3
2
×
Ū ×
Ū ×
Ū ×
Ū ×
Ū ×
Ū
1
0
Cls = kel • Vd
or
kel = Cls / Vd
0
1
2
3
4
5
Time
> Clearance (Clsystemic) the virtual volume completely
cleared of drug / unit time
75
•
70
0
Allows calculation of kelimination (kel)
> units = time-1
> proportion of drug eliminated
•
-1
4
2
7
lnCt = lnC0 - k • t
85
80
3
4
3
Time
Log plot of data is
linear
Ū ×
90
2
5
Starting the Number Crunch to T1/2
×
Ū Ū
Ū ×
Ū ×
Ū ×
95
1
LN Drug Concentration
• Blood pressure
50%
×
Ū ×
Ū ×
Ū ×
Ū ×
Ū ×
Ū
6
lnCt = lnC0 - k • t
Scenario 1: Data (cont.)
100 Ū
×
7
400
0
• Measure BP response over time
• Repeat with half the dose
response is
proportional to:
>dose and
> Ct
C0 is proportional to
dose
LN Drug Con
ncentration
• Administer medicine IV which lowers
Drug Conce
entration
Empiric Approach: Scenario 1
1
2
3
4
Allows prediction of the effect of changes of Vd on
drug half-life (T1/2)
5
Time
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Half-life
•
Solving for T1/2
A convenient way to think of how long
drug sticks around
kel • t = ln (C0 /Ct)
> Comparisons, dosing, etc.
t = ln (C0 /Ct) / kel [5]
l Ct = ln
ln
l C0 - kel • t
[1]
kel • t = ln C0 - ln Ct
[2]
kel • t = ln (C0 /Ct)
[3]
At T1/2, C0 /Ct = 2
Relating T1/2 to Vd
T1/2 = 0.693 / kel
kel = Cls / Vd
[3]
[6]
T1/2 = ln (2) / kel
[7]
T1/2 = 0.693 / kel
[8]
Critical Factors
Clearance of compound: efficiency of irreversible
elimination of drug from system
[8]
Elimination rate (mg/hr)= clearance (Cl) (L/hour) * plasma drug
concentration (C) (mg/L)
[[10]]
Maintenance dose rate (DR) (mg/hr)= clearance (CL)( L/hr)* steady
state drug concentration (Css) (mg/L)
T1/2 = 0.693 • Vd / Cls [11]
Clearance (L/hr) = dose (mg)/ AUC (mg*hr/L)
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What does it mean?
Summary: Single Compartment-1st
Order
T1/2 = 0.693 / kel or T1/2 = 0.693 • Vd / Cls
• Simplistic model that describes PK of most
drugs
• Assumes
• T1/2 not intrinsic to a drug
> Drug in faster than drug out
> Equilibration
E ilib ti relatively
l ti l quick
i k
> Can sum all elimination routes in single equation
>not same for every person
>not same for an individual at all times
• T1/2 dependent on:
Drug In
>Individual’s elimination capacity (clearance)
>Individual’s Vd
Circulation
kel Drug out
(or rapidly equilibrated Vd)
Summary: Single Compartment-1st
Order
Drug In
Circulation
Half life Related to Vd and Cls
• T1/2 = 0.693 • Vd /
kel Drug out
Cls
(or rapidly equilibrated Vd)
T1/2 = 0.693 • Vd / Cls
* Shows us that T1/2 dependent on Vd and Cls
* Predicts effect of organ impairment on T1/2
* Clearance is sum of all contributions to clearance
* Constant proportion (not amount) is eliminated per
unit time
* Regardless of initial amount, >95% gone in 4-5
half-lives
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Scenario 2: Zero-order Elimination
Scenario 2: Alcohol Elimination
• Students celebrate
time, not proportion
• Limited capacity for metabolism or other
•
elimination mechanism
•
• Elimination is saturable
• Part or whole dose-concentration range
• Example: ethanol zero-order throughout
•
concentration range
•
2
×
1.6
12
1.2
×
Ū
×
Ū
×
Ū
0.8
×
Ū
×
×
Ū
0.4
Ū
×
0
0 1 2 3 4 5 6 7
Time (hours)
Scenario 3: Repeated Dosing, 1st
Order
•
•
•
• The usual situation in treating disease
• Repeated administration before total
elimination (>4-5 half-lives) leads to drug
accumulation.
accumulation
•
Dose given every half-life
Peak with first dose = 500
The median [SS] is 1.5
times the initial [peak]
After 3 half-lives
half lives 87.5%
87 5% of
SS has been achieved
After 5 half-lives >95% if
SS has been achieved
CSS = 1.5 • (T 1/2/τ) • C0
•
Zero order not the same
•
• If a constant schedule is followed, a steady
•
state concentration of drug will result.
• At steady state (SS): Drug in = Drug out
• If the drug is given in boluses, the blood
1200
Drug Concen
ntration
Repeated Dosing: First-order
Kinetics
end summer
course
Student 1: 6 oz.
Jack Daniels
Student 2: 4.5 oz.
Jack Daniels
T1/2 does not apply
with zero order
kinetics
Time per drink
Blood EtOH
H (g/L)
• Constant amount of drug removed /
1000
×
800
×
×
×
×
×
×
×
×
×
×
×
600
×
400
200
×
×
×
0 ×
0 1 2 3 4 5 6 7 8 9
Multiple of Half-lives
[Drug] will vary around a SS concentration
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Therapeutic Window on
Intervals
Determining Drug Dose and Interval
• Dose (quantity) must give non-toxic peak
level
• Frequency
q
y must not allow trough
g level to
be sub-therapeutic, or drug effect must last
longer than the drug
•
• Dosing interval must be conducive to
•
patient compliance
First-Order Dose Changing
Narrow Swings: same dose more frequently
(divided in smaller intervals)
If wider swings can be tolerated, give more drug
over wider interval
Zero-order Difficulties
• Concentration directly proportional to dose
• New dose= [desired]/[current] x old dose
• Lack of Predictability
> Transition from first to zero order unpredictable
> Drug level can rise precipitously
> Ethanol, ASA, Theophyline, and Phenytoin (Dilantin®)
• Steady State Equation (in = out)
> Css x Cls = F x Dose /τ
> Css = (F x Dose /τ ) / Cls
> Cls = (F x Dose /τ ) / Css
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Loading Dose
Loading dose: initial higher dose administered at beginning of
a course of treatment before dropping down to a lower dose (when
you need to get there sooner.)
> C0 = F x Dose / Vd
> i.e. digoxin, phenytoin
Example: Hypothetical drug X,X long half-life w/ only 10% cleared from blood/day by kidney
and liver; drug optimal efficacy when total dose in body = 1 gram; maintenance dose= 100 mg per
day
No loading dose: start with 100 mg of drug X per day…take many days to reach optimal drug levels
Day 1: 100 mg; clear 10 mg = total 90 mg
Day 2: 100 mg; 100+ 90= 190 mg; clear 19 mg = total 171 mg
Day 3: 100 mg; 100+ 171= 271 mg; clear 27 mg = total 244 mg
Loading dose: start with 1000 mg
Day 1: 1000 mg; clear 100mg = total 900 mg
Day 2: 100 mg; 100+ 900= 1000 mg; clear 100 mg = total 900 mg
Day 3: 100 mg; 100+ 900= 1000 mg; clear 100 mg = total 900 mg, etc.
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