review of pharmacokinetics jean d. deupree, ph.d. department of pharmacology university nebraska...
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Review of Pharmacokinetics
Jean D. Deupree, Ph.D.Department of Pharmacology
University Nebraska Medical Center3014 DRC559-4565
2
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
3
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?
4
Comparison of Transport Processes
Transport Mechanism
Energy Requirement
Saturability and Selectivity
Passive Diffusion
None No
Bulk Flow None No
Facilitated Diffusion
None Yes
Active Transport
Yes Yes
5
Henderson-Hasselbalch Equation
pH - pKa = LogConjugate Base
Acid= Log
IonizedUnionized
Weak acid
Weak base
pKa - pH = LogConjugate Acid
Base= Log
IonizedUnionized
Know and be able to use these equations
6
How much of a weak acid (pKa = 3) will diffuse from the stomach to the plasma?
StomachpH 2
PlasmapH 7
1 A
CB- + H +
A 1
CB- + H +
Log ------ = pH - pKa[CB-][A]
Log ------ =[CB-][A]
Log ------ = pH - pKa[CB-][A]
Log ------ =[CB-][A]
[A] + [CB-] = [A] + [CB-] =
2-3 = -1 7-3 = 4
[CB- ]
[A] = 0.11
0.1
1.1
[CB- ][A]
10,000
10,001=
10,0001
7
How much of a weak base (pKa = 7) will be absorbed from the stomach?
StomachpH 2
PlasmapH 7
1 B + H+
CA+
B + H+ 1
CA+
Log ------ = pKa - pH[CA+ ][B] Log ------ = pKa - pH[CA+]
[B]
Log ------ =[CA+][B] Log ------ =[CA+]
[B]
[CA+][B] =
[CA+][B] =
[CA+] + [B] = [CA+] + [B] =
7 - 2 = 5 7-7 = 0
100,000 =100,000
1
100,000
100,001
1 =11
1
2
8
When is ion trapping most likely to occur in these areas?
Note: You do not need to memorize the pH values for these tissues
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
12
• 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%
13
What are the advantages and disadvantages of the different routes of drug administration?
• See review on page 21
14
From which sites of drug administration do you get first-pass metabolism? First-pass hepatic metabolism?
15
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
16
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•KidneyIntermediate group•Muscle •Skin
17
What plasma proteins do drugs bind to?
• Albumin • Albumin• Glycoproteins• Lipoproteins
Acidic Drugs Basic Drugs
18
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.
19
What are the phase I reactions?
• Oxidation• Reduction• Hydrolysis
What are the phase II reactions?
Conjugation
20
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
21
Phase I and Phase II Reactions
Drug
Phase IIPhase I
Conjugation
Drug
Drug
Elimination
Active metabolite
Inactive metabolite
Conjugation
Conjugation
Hydrophobic Hydrophilic
What types of drug-drug interactions can occur?
22
23
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
24
• 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
25
• 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
26
• 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
27
Cytochrome P450 Enzyme Complex
28
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
29
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?
30
Phase II reactionsGlucuronidation
R-OH + UDP-glucuronic acid
R-O-glucuronide
UDP-glucuronyltransferase
R-OH + glucuronic acid
Beta-glucuronidase
COOH
O O-R(Liver)
Intestinal mucosa Intestinal bacteria
Bile Kidney
Intestine Excretion
31
• 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
How Does Age Affect Drug Metabolism?
32
• 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
Factors Affecting Drug Metabolism
33
What factors determining the amount of drug excreted in the urine?
Nephron
Glomerular Filtration
Tubular Reabsorption
TubularSecretion Excretion = glomerular filtration
- tubular reabsorption + tubular secretion - passive reabsorption +passive secretion
34
• How do you speed up the renal elimination of a weak acid?– Make the urine alkaline
35
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
36
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
37
• 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
38
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
39
Time After Drug Administration (hr)
0 2 4 6 8 10 12
5
4
3
2
1
0
Ser
um
Co
nce
ntr
atio
n (g
/ml)
Peak Drug Level
Time to Peak Drug Level
40
Time After Drug Administration (hr)
Ser
um
Co
nce
ntr
atio
n (g
/ml)
0 2 4 6 8 10 12
5
4
3
2
1
0
Therapeutic Threshold
Duration of Therapeutic Effect
41
Therapeutic Window
Time After Drug Administration (hr)
Ser
um
Co
nce
ntr
atio
n (g
/ml)
0 2 4 6 8 10 12
5
4
3
2
1
0
Therapeutic Effect
Toxic Effect
42
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
43
How do you determine bioavailability?
F = AUC for route being studiedAUC after IV administration
What factors will alter bioavailability?
44
What is the Volume of Distribution of a drug?
Vd (L) = Xo mgCp (mg/ml)
45
How do you measure the concentration of drug in the plasma at time T = 0?
0 10 20 30 40 50 60
10
8
6
4
2
Time (Hours)
Pla
sma
Dru
g C
on
cen
trat
ion
(μg
/ml)
Cp
46
What does it mean if a drug has the following Vd in a 70 kg person?
• 500 L
• 10 L
• 35 L
• 42 L
48
• 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
49
Is this drug being eliminated by first order or zero order kinetics?
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
Time (Hrs)
Pla
sma
Dru
g C
on
cen
tra
tion
(μ
g/m
l)
2 4 6 8
100
8060
40
20
Zero order
51
8 16 24 32 40 48 56 64 72 80 88 96
20
15
10
25
Time (hrs)
Pla
sma
Co
nce
ntr
atio
n (
mg
/L)
Effects of Doubling DoseZero Order Kinetics
NOTE: Drug is entering the body faster than it leaves the body
52
Is this drug being eliminated by first order or zero order kinetics?
What is the half-life of this drug? 10 hoursIf 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 levelsWhat happens to steady state plasma levels if you double the dose? Plasma levels double
0 10 20 30 40 50 60
10
6
42
Time (Hours)
Pla
sma
Dru
g
Co
nce
ntr
atio
n (
μg
/ml)
8
1st order
53
8 16 24 32 40 48 56 64 72 80 88 96
6
4
2
8
Time (hrs)
Pla
sma
Co
nce
ntr
atio
n (
mg
/L)
Effects of Doubling Dose1st Order Kinetics
Note: Drug enters body at the same rate it is leaving the body
54
Is this drug being eliminated by first order or zero order kinetics?
What is the half-life of this drug?
1st order
How long will it take to reach steady state plasma concentration if this drug is given by continual IV infusion?
10 hours
40 to 50 hours
57
1st Order Zero Order
Elimination Exponential Linear
Half-life Constant with changing plasma concentrations
Changes with plasma concentration
Eliminated per unit time
Constant Fraction
Constant Amount
Clearance Rate of elimination/Cp
Maximum rate of elimination process
Time required to eliminate drug
4-5 Half-lives Based on amount of drug given
Double the dose Double plasma concentration
Greater than twice plasma concentration
58
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
Clearance (CL)(ml/min) = Rate of elimination (g/min)
Concentration (g/ml)
59
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.
60
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.)
62
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
• Rate of clearance is dependent on the rate of blood flow through the organ
What is meant by flow dependent elimination?
63
Are drugs A or B being eliminated by first or
zero order kinetics?
Why isn’t the curve for Drug B linear?
Time (min)
0 25 50 75 100 125 150Pla
sma
Co
nce
ntr
atio
nµ
g/m
l10.0
1.0
0.1
A
B
1st order
Two compartment distribution
Zero order
64
Two Compartment Model
Time (min)
0 25 50 75 100 125 150Pla
sma
Co
nce
ntr
atio
nµ
g/m
l
10.0
1.0
0.1
One compartment
TwoCompartment
1st Order
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. Beta-phase is due to metabolism and/or excretion
65
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
66
How do you calculate the maintenance dose for IV administration?
Dosing rate (g/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 (g/ml)) x Dosing interval (Hr)F
67
How do decreases in body weight affect the following parameters?
• t1/2
• Vd
• CL
• Loading dose
• Oral dose
• IV maintenance dose
No change
Decrease
Decrease
Decrease
Decrease
Decrease
68
Given the following properties of a drug for a 70 kg man:
Bioavailability = 0.8CL = 3.5 L/hrHalf-life = 8 hoursEffective plasma concentration = 1 g/ml
What is the Vd for a 70 kg male?
0.7 x Vd
t1/2
CL =
Vd =CL x t1/2
0.7
Vd = 3.5 L/hr x 8 hr
0.7
Vd = 40 L
69
Given the following properties of a drug for a 70 kg man:
Bioavailability = 0.8CL = 3.5 L/hrHalf-life = 8 hoursVd = 40 LEffective plasma concentration = 1 g/ml
What is the t1/2 for an individual whose CL is ½ the normal rate?
0.7 x Vd
t1/2
CL =
t1/2 = 0.7 x 40 L1.75 L/hr
t1/2 = 16 hours
=0.7 x Vd
CLt1/2
NOTE: If CL is decreased by 50%, t1/2 will increase by 50%
70
Given the following properties of a drug for a 70 kg man:
Bioavailability = 0.8Vd = 40 LCL = 3.5 L/hrHalf-life = 8 hoursEffective plasma concentration= 1 g/ml
What is the loading dose for a 70 kg male?
LD = Vd X Css
LD = 40 L x 1 g/ml
x 1000 ml/L x 1 mg/1000 g
LD = 40 mg
LD = 40 L x 1 mg/L = 40 mg
LD = 40 mg/70 kg = 0.57 mg/kg
71
Given the following properties of a drug for a 70 Kg man:
Bioavailability = 0.8Vd = 40 LCl = 3.5 L/hrHalf-life = 8 hoursEffective plasma concentration= 1 g/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
72
Given the following properties of a drug for a 70 kg man:
Bioavailability = 0.8Vd = 40 LCl = 3.5 L/hrHalf-life = 8 hoursEffective plasma concentration= 1 g/ml
What would the oral dose be for a 100 kg if you wanted to give the drug every 8 hours?
CL x Cavg x Dosing interval x body weightF x 70 kg
Dose =
3.5 L/hr x 1 mg/L x 8 hr x 100 kg0.8 x 70 kg
Dose =
Dose = 50 mg every 8 hours
73
8 16 24 32 40 48 56 64 72 80 88 96
20
15
10
25
Time (hrs)
Pla
sma
Co
nce
ntr
atio
n (
mg
/L)
Fluctuations in Plasma Concentration with Dosing Intervals
5