Download Plasma Concentration - University of Nebraska Medical Center

Review of Pharmacokinetics
Jean D. Deupree, Ph.D.
Department of Pharmacology
University Nebraska Medical Center
3014 DRC
559-4565
[email protected]
Helpful Hints
• Be able to use the equations on p. 40-41.
– Equations will not be provided on the exam
– You will not be allowed to use a calculator on the exam
• Be able to use the pharmacokinetic terms which
have been defined
• Be able to calculate the ionization of acid and
bases in various biological media
• Understand the different types of drug-drug
interactions that can occur
• Be able to apply the information. Exam question
are not likely to be asked in the same manner as
in this review
• When reviewing old exams make sure you
understand why the wrong answers are wrong
and the right answers are right
2
What types of molecules (charged,
uncharged, chemical structural
requirements) can be transported by
these different mechanism?
•
•
•
•
Bulk flow
Passive diffusion
Facilitated transport
Active transport
What are the differences between
these transport processes?
3
Comparison of Transport
Processes
Transport
Mechanism
Passive
Diffusion
Energy
Requirement
Saturability
and Selectivity
None
No
Bulk Flow
None
No
None
Yes
Yes
Yes
Facilitated
Diffusion
Active
Transport
4
Henderson-Hasselbalch Equation
Know and be able to use these equations
Weak acid
pH - pKa = Log
Conjugate Base
Ionized
= Log
Acid
Unionized
Weak base
pKa - pH = Log
Conjugate Acid
Ionized
= Log
Base
Unionized
5
How much of a weak acid (pKa = 3) will
diffuse from the stomach to the plasma?
Stomach
pH 2
1 A
0.1 CB- + H +
Log
[CB-]
-----[A]
Log
[CB-]
-----[A]
[CB- ]
[A] =
= pH - pKa
= 2-3 = -1
0.1
1
[A] + [CB-] = 1.1
Plasma
pH 7
A
1
CB- + H + 10,000
Log
[CB-]
-----[A]
= pH - pKa
Log
[CB-]
-----[A]
= 7-3 = 4
[CB- ]
[A]
10,000
= 1
[A] + [CB-] = 10,001
6
How much of a weak base (pKa = 7) will be
absorbed from the stomach?
Plasma
pH 7
Stomach
pH 2
1 B + H+
100,000 CA+
Log
[CA+ ]
-----[B]
Log
[CA+]
-----[B]
[CA+]
[B]
= pKa - pH
=7-2=5
= 100,000 =
100,000
1
[CA+] + [B] = 100,001
B + H+
1
CA+
1
Log
[CA+]
-----[B]
= pKa - pH
Log
[CA+]
-----[B]
= 7-7 = 0
[CA+]
[B]
=
1
=
1
1
[CA+] + [B] = 2
7
When is ion trapping most likely to
occur in these areas?
Body Fluid
Range of pH
Breast Milk
6.4-7.6
Jejunum, ileum
7.5-8.0
Stomach
1.92-2.6
Prostatic secretions
6.5-7.4
Vaginal secretions
3.4-4.2
Urine
5.0-8.0
Note: You do not need to memorize the
pH values for these tissues
8
• Will a weak base (pka 8) be more
ionized at pH 6 or pH 8?
– pH 6
• Will a weak acid (pka 4) be absorbed
better from a stomach where the pH
is 2 or where the pH is 3?
– pH 2
• What percent of a weak acid (pKa 4 )
will be in the ionized form at pH 3
– [CB]/[A] = 0.1/1
– % in ionized form = 0.1/1.1*100 = 9%
12
What are the advantages and
disadvantages of the different routes
of drug administration?
• See review on page 21
13
From which sites of drug administration do you get
first-pass metabolism? First-pass hepatic
metabolism?
14
What are the factors which affect the
distribution of drugs to the different
tissues of the body?
•
•
•
•
Blood flow
Size of the tissue compartment
Ability of the drug to permeate the tissue
Extent of ionization in the different tissue
compartments
• Lipid solubility of the drug versus the lipid
content of the tissue
• Extent of plasma protein binding
15
Which are the vessel rich organs and how
does blood flow to an organ affect the
distribution of drugs?
Vessel-rich organs
•Brain
•Liver
•Heart
•Kidney
Intermediate group
•Muscle
•Skin
16
What plasma proteins do drugs bind
to?
Acidic Drugs
• Albumin
Basic Drugs
• Albumin
• Glycoproteins
• Lipoproteins
17
What are the characteristics of drugs
which cross the placenta and enter the
brain?
•Drugs which are lipid soluble can cross the blood
brain barrier and the placenta by passive diffusion.
The more lipid soluble the drug the faster it diffuses
into the brain and the faster it crosses the placenta
•The more aqueous soluble drugs can only enter the
brain or the fetus by active transport or facilitated
diffusion. Note: Many drugs are not recognized by
the transporters.
18
What are the phase I reactions?
• Oxidation
• Reduction
• Hydrolysis
What are the phase II reactions?
Conjugation
19
What are the consequences of drug
metabolism?
•Pro-drug → Drug
•Drug → Active and inactive metabolite
•Drug → Reactive intermediate
•Hydrophobic → Hydrophilic
•Exposure of functional groups: -OH, -COOH, -NH2
20
Phase I and Phase II Reactions
Phase I
Drug
Phase II
Elimination
Conjugation
Active metabolite
Conjugation
Inactive metabolite
Conjugation
Drug
Drug
Hydrophobic
Hydrophilic
What types of drug-drug interactions can occur?
21
22
What is the principle enzymes involved
in Phase I reactions and what are some
of the other names for this enzyme?
• Cytochrome P450
• Microsomal mixed function oxidase
• Microsomal drug metabolizing enzyme
23
• Is there more than one cytochrome P450
isozymes?
• How is the enzyme be regulated?
– Induction
– Inhibition
– Note: Not all drugs will induce or inhibit the
CYP isozymes, only selective isozymes will be
inhibited.
– NOTE: COMPETION OF ONE DRUG FOR
ANOTHER ONLY BECOMES A PROBLEM IF
THE DRUGS ARE IN HIGH CONCENTRATIONS.
Remember for most drugs you are very low on
the place of rate of elimination versus drug
concentration
– Note: Induction or inhibition of a CYP 450
isozyme will affect the metabolism of all drugs
metabolized by that isozyme
24
• What CYP isozyme is induced by
cigarette smoke?
– CYP1A family
• Which CYP isozyme is inhibited by
grapefruit juice?
– CYP 3A4 in the wall of the intestine
25
• What is the principle location of CYP
isozymes?
– Liver
• What are the substrates, enzymes and
cofactors of the CYP450 complex?
• Which isozyme is responsible for
metabolism of over 50% of the drugs?
– CYP 3A4
• What is the significance of the CYP 2D6
enzymes?
– Numerous polymorphism have been found
26
Cytochrome P450 Enzyme
Complex
27
What are the other types of phase I
reactions and what is the primary
location of these enzymes?
• Oxidative reactions
– Flavin monooxygenases (liver)
– Amine oxidase (liver and nerve endings)
– Dehydrogenase (liver)
• Reductive reactions
– Liver
– Intestinal microflora
• Hydrolytic
– Esterases: Plasma
– Amidases: Liver
28
What are the different types of
conjugation reactions that can occur?
•
•
•
•
•
•
Glucuronidation
Sulfate conjugation
N-acetylation
Methylation
Glutathione conjugation
Amino acid conjugation
What are the enzymes involved in
glucuronidation and hydrolysis of the
glucuronide product?
29
Phase II reactions
Glucuronidation
R-OH + UDP-glucuronic acid
UDP-glucuronyltransferase
COOH
(Liver)
O
O-R
R-O-glucuronide
Bile
Kidney
Intestine
Excretion
Beta-glucuronidase
Intestinal mucosa
Intestinal bacteria
R-OH + glucuronic acid
30
How Does Age Affect Drug Metabolism?
• Age
– Less cyc P450 in
• Very young
• Elderly
– Phase II reactions are usually not affected in
the elderly
– Decreased blood flow to liver in elderly
31
Factors Affecting Drug Metabolism
• Pharmacogenetic
– Genetic differences in the activities of many
metabolic enzymes
• Altered activity of CPY enzymes and enzymes
involved in conjugation
– 2D6 enzymes
– N-acetyltransferase: Slow vs fast acetylators
32
What factors determining the amount
of drug excreted in the urine?
Glomerular Filtration
Tubular
Reabsorption
Tubular
Secretion
Nephron
Excretion = glomerular filtration
- tubular reabsorption
+ tubular secretion
- passive reabsorption
+passive secretion
33
• How do you speed up the renal
elimination of a weak acid?
– Make the urine alkaline
34
How are drugs or metabolites excreted
from liver to bile?
• Passive diffusion
• Transporters for
–
–
–
–
anions
bile salts
cations
neutral organic compounds
• How do you enhance biliary excretion?
– polar groups
– high molecular weight
– Conjugation add polar groups and molecular
weight
35
What drugs go through the
enterohepatic recirculation
pathway?
Drugs which enter the bile and are:
•Lipid soluble enough to be reabsorbed from the
wall of the gut
•Hydrolyzed in the gut and then reabsorbed
•Transported by transporters across the wall of
the gut
36
• What is the major route by which
drugs are eliminated from the body?
– Kidney
• What are the minor routes?
– bile
– skin
– lungs
– sweat glands
– saliva
– breast milk
37
What are the basic types of
pharmacokinetic drug- interactions?
• Involving metabolism
– Induction of cyc P450 enzymes
– Inhibition of cyc P450 enzymes
– Competition of two drugs for the same enzyme
– Depletion of endogenous compounds used in
conjugation reactions
• Displacement from albumin
• Competition for transporters
• Blood flow to an organ
• Changes in pH of a body of fluid
38
Serum Concentration (mg/ml)
5
4
Peak Drug Level
3
2
1
0
0
2
4
6
8
10
12
Time After Drug Administration (hr)
39
Serum Concentration (mg/ml)
5
Duration of
Therapeutic Effect
4
3
2
Therapeutic Threshold
1
0
0
2
4
6
8
10
12
Time After Drug Administration (hr)
40
Serum Concentration (mg/ml)
5
4
Toxic Effect
3
Therapeutic Window
2
Therapeutic Effect
1
0
0
2
4
6
8
10
12
Time After Drug Administration (hr)
41
What is the difference between
therapeutic window and therapeutic
index?
• Therapeutic window is the plasma
concentration range where therapeutic
effect occurs without toxic effects
• Therapeutic index is: TD50/ED50
42
How do you determine bioavailability?
F=
AUC for route being studied
AUC after IV administration
What factors will alter bioavailability?
43
What is the Volume of Distribution of a
drug?
Xo mg
Vd (L) =
Cp (mg/ml)
44
Plasma Drug Concentration
(μg/ml)
How do you measure the concentration of
drug in the plasma at time T = 0?
10
Cp
8
6
4
2
0
10
20
30
40
50
60
Time (Hours)
45
What does it mean if a drug has the
following Vd in a 70 kg person?
•
•
•
•
500 L
10 L
35 L
42 L
46
• What is meant by t1/2?
• How many half-lives does it take for the
drug concentration to reach steady-state?
– 4 to 5 half-lives
• How many half-lives does it take for the
drug to be eliminated from the body?
– 4 to 5 half-lives
• What is kel?
– Rate constant for elimination
• What are the units for kel?
– 1/time
• How does kel change with plasma
concentration?
– It remains constant at low concentrations of
drug
48
Plasma Drug
Concentration (μg/ml)
Is this drug being eliminated by first order or zero
order kinetics?
100
80
60
Zero order
40
20
2
4
Time (Hrs)
6
8
What is the half-life of this drug? Half-life
changes with plasma concentration
If you double the dose how long does it take to
eliminate the drug from the body? Twice as long
What happens to steady state plasma levels if you
double the dose? Greater than 2x plasma level
49
Plasma Concentration (mg/L)
Effects of Doubling Dose
Zero Order Kinetics
25
20
15
10
8 16 24 32 40 48 56 64 72 80 88 96
Time (hrs)
NOTE: Drug is entering the body faster than it leaves51the
body
Plasma Drug
Concentration (μg/ml)
Is this drug being eliminated by first order or
zero order kinetics?
10
8
6
1st order
4
2
0 10 20 30 40 50 60
Time (Hours)
What is the half-life of this drug? 10 hours
If you double the dose how long does it take to
eliminate the drug from the body? 4 to 5 half-lives or
40-50 hours --- time is independent of plasma levels
What happens to steady state plasma levels if
52
you double the dose? Plasma levels double
Plasma Concentration (mg/L)
Effects of Doubling Dose
1st Order Kinetics
8
6
4
2
8 16 24 32 40 48 56 64 72 80 88 96
Time (hrs)
Note: Drug enters body at the same rate it is leaving the
53
body
Is this drug being eliminated by first order or
zero order kinetics?
1st order
What is the half-life of this drug? 10 hours
How long will it take to reach steady state plasma
concentration if this drug is given by continual IV
infusion? 40 to 50 hours
54
1st Order
Zero Order
Elimination
Exponential
Linear
Half-life
Constant with
Changes with
changing plasma plasma
concentrations
concentration
Eliminated per
unit time
Constant
Fraction
Constant Amount
Clearance
Rate of
elimination/Cp
Time required to
eliminate drug
Double the dose
4-5 Half-lives
Maximum rate of
elimination
process
Based on amount
of drug given
Double plasma
concentration
Greater than
twice plasma
concentration 57
What is meant by the clearance of a drug
from the body, how is it calculated and what
are the units?
• Theoretical volume of fluid from which a drug is
completely removed in a given period of time.
• For a drug eliminated by first order kinetics
Rate of elimination (mg/min)
Clearance (CL)(ml/min) =
Concentration (mg/ml)
58
How is clearance related to Vd and t1/2?
CLT =
0.7 X Vd
t1/2
If CL changes but not Vd what happens
to the t1/2 ?
Half-life is inversely proportional to clearance. If
volume of distribution does not change and
clearance decreases then the half-life will
increase.
59
How does rate of elimination change with
drug concentration for a drug eliminated by
zero order kinetics?
• V = Vmax
• Rate of elimination of the drug from the body is
based on the maximum rate of the rate limiting
step in the elimination process (metabolizing
enzyme, transporter ect.)
60
What is meant by saturation kinetics?
• Low doses first order kinetics occur
• As dose increases the half-life increases and
elimination is by Michaelis-Menton kinetics
• At high doses rate of elimination is dependent on
the maximum rate of the elimination pathway
What is meant by flow dependent
elimination?
• Rate of clearance is dependent on the rate of
blood flow through the organ
62
Plasma Concentration
µg/ml
Are drugs A or B being eliminated by first or
zero order kinetics?
10.0
A
1st order
1.0
B
Zero order
0.1
0
25
50
75
100 125 150
Time (min)
Why isn’t the curve for Drug B linear?
Two compartment distribution
63
Plasma Concentration
µg/ml
Two Compartment Model
10.0
1st Order
One compartment
a
1.0
b
Two
Compartment
0.1
0
25
50
75
100 125 150
Time (min)
What is determines the two phases of the curve for
Drug B?
Alpha-slope is due to redistribution of the drug from the
vessel rich compartment to other compartments. Betaphase is due to metabolism and/or excretion
64
Two Compartment Model for Drugs Acting
on the CNS
• Note: The more lipid soluble the drug the faster
the rate of on set of action
– More lipid soluble the faster the drug crosses
the blood brain barrier
• Note: `The more lipid soluble the drug the
shorter the duration of action
– The faster the redistribution phenomenon
65
How do you calculate the maintenance dose
for IV administration?
Dosing rate (mg/min/kg) = CL X Css
How do you calculate loading dose?
LD = Vd x Css
How do you calculate the oral dose?
Dose =
(CLp (ml/min) x Cpavg (mg/ml)) x Dosing interval (Hr)
F
66
How do decreases in body weight
affect the following parameters?
•
•
•
•
•
•
t1/2 No change
Vd Decrease
CL Decrease
Loading dose Decrease
Oral dose Decrease
IV maintenance dose
Decrease
67
Given the following properties of a drug for a 70 kg man:
Bioavailability = 0.8
CL = 3.5 L/hr
Half-life = 8 hours
Effective plasma concentration = 1 mg/ml
What is the Vd for a 70 kg male?
0.7 x Vd
CL =
t1/2
CL x t1/2
Vd =
0.7
3.5 L/hr x 8 hr
Vd =
0.7
Vd = 40 L
68
Given the following properties of a drug for a 70 kg man:
Bioavailability = 0.8
CL = 3.5 L/hr
Half-life = 8 hours
Vd = 40 L
Effective plasma concentration = 1 mg/ml
What is the t1/2 for an individual whose CL is ½ the
normal rate?
0.7 x Vd
CL =
NOTE: If CL is decreased by
t1/2
50%, t1/2 will increase by 50%
t1/2 = 0.7 x Vd
CL
0.7 x 40 L
t1/2 =
1.75 L/hr
t1/2 = 16 hours
69
Given the following properties of a drug for a 70 kg man:
Bioavailability = 0.8
Vd = 40 L
CL = 3.5 L/hr
Half-life = 8 hours
Effective plasma concentration= 1 mg/ml
What is the loading dose for a 70 kg male?
LD = Vd X Css
LD = 40 L x 1 mg/ml x 1000 ml/L x 1 mg/1000 mg
LD = 40 mg
LD = 40 L x 1 mg/L = 40 mg
LD = 40 mg/70 kg = 0.57 mg/kg
70
Given the following properties of a drug for a 70 Kg man:
Bioavailability = 0.8
Vd = 40 L
Cl = 3.5 L/hr
Half-life = 8 hours
Effective plasma concentration= 1 mg/ml
What is the dose required for IV maintenance in a 100
kg male?
Dose = CL/70 kg x Css x Body Weight
Dose = 3.5 L/hr x 1 mg/L x (100 kg/70 kg)
Dose = 5 mg/hr
71
Given the following properties of a drug for a 70 kg man:
Bioavailability = 0.8
Vd = 40 L
Cl = 3.5 L/hr
Half-life = 8 hours
Effective plasma concentration= 1 mg/ml
What would the oral dose be for a 100 kg if
you wanted to give the drug every 8 hours?
Dose =
CL x Cavg x Dosing interval x body weight
F x 70 kg
Dose = 3.5 L/hr x 1 mg/L x 8 hr x 100 kg
0.8 x 70 kg
Dose = 50 mg every 8 hours
72
Plasma Concentration (mg/L)
Fluctuations in Plasma Concentration
with Dosing Intervals
25
20
15
10
5
8 16 24 32 40 48 56 64 72 80 88 96
Time (hrs)
73