1. Review of Pharmacokinetics
Jean D. Deupree, Ph.D.
Department of Pharmacology
University Nebraska Medical Center
3014 DRC

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 are the differences between these transport processes?
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
Facilitated Diffusion
Yes
Active Transport

5. Henderson-Hasselbalch Equation
Know and be able to use these equations
Weak acid
Conjugate Base
Acid
Ionized
Unionized
pH - pKa = Log
= Log
Weak base
pKa - pH = Log
Conjugate Acid
Base
= Log
Ionized
Unionized

6. How much of a weak acid (pKa = 3) will diffuse from the stomach to the plasma?
pH 2
Plasma
pH 7
1 A
CB- + H + A
CB- + H +
0.1
10,000
Log = pH - pKa
[CB-]
[A]
Log =
Log = pH - pKa
[CB-]
[A]
Log =
2-3
= -1
7-3
= 4
[CB- ]
[A] =
0.1 1
[CB- ]
[A]
10,000 1 =
[A] + [CB-] =
1.1
[A] + [CB-] =
10,001

7. How much of a weak base (pKa = 7) will be absorbed from the stomach?
pH 2
Plasma
pH 7
1 B + H+
CA+
B + H
CA+
100,000 1
Log = pKa - pH
[CA+ ]
[B]
Log = pKa - pH
[CA+]
[B]
Log =
[CA+]
[B]
Log =
[CA+]
[B]
7 - 2
= 5
7-7
= 0
100,000 1
[CA+]
[B] =
[CA+]
[B] = 1
100,000 = 1 =
[CA+] + [B] = 2
[CA+] + [B] =
100,001

8. When is ion trapping most likely to occur in these areas?
Body Fluid
Range of pH
Breast Milk
Jejunum, ileum
Stomach
Prostatic secretions
Vaginal secretions
Urine
Note: You do not need to memorize the pH values for these tissues

9. Weak Acids and Bases % Protonation 100 50 pH 1 14 pKa50
This is a plot of the % protonation of different drugs (weak acids and bases) at different pH. Every cruve on the graph represents a drug with a different pka. The pka of a drug is the pH where the drug is 50% protonated and 50% unprotonated. If you start at the pka and decrease the pH (go towards pH of 1) of the solution, all drugs will become more protonated because you are increasing the hydrogen ion concentration of the medium. If you raise the pH you will decrease the protonation. If the drug is a weak acid what will happen to the degree of ionization as you raise or lower the pH of the medium? Go to next slide for answer. pH 1 14
pKa

10. Weak Acid % Charged (Ionized) 100 50 pH 1 14 pKa50
This is a plot of the degree of ionization of a weak acid as a function of the pH of the medium. Note for a weak acid as you lower the pH (increase protonation) the drug becomes more unionized. As the pH increases the acid molecules start to loses protons and become more ionized (more conjugate base is formed). If the drug is a weak base what will happen to the degree of ionization as you raise or lower the pH of the medium? Go to next slide for answer. pH 1 14
pKa

11. Weak Bases % Charged (Ionized) 100 50 pH 1 14 pKa50
This is a plot of the degree of ionization of a weak base as a function of the pH of the medium. Note for a weak base as you lower the pH (increase protonation) the drug becomes more ionized (more conjugate acid is formed). As the pH increases the conjugate acid molecules start to loses protons and becomes more unionized (neutral base is formed). Click on the arrow to return to the slides from lecture pH 1 14
pKa

12. Will a weak base (pka 8) be more ionized at pH 6 or pH 8?
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
Kidney
Intermediate group
Muscle
Skin

17. What plasma proteins do drugs bind to?
Basic Drugs
Acidic Drugs
Albumin
Albumin
Glycoproteins
Lipoproteins

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
Elimination
Drug
Conjugation
Active metabolite
Conjugation
Drug
Inactive metabolite
Drug
Hydrophobic
Hydrophilic
What types of drug-drug interactions can occur?

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 reactions Glucuronidation
R-OH + UDP-glucuronic acid
UDP-glucuronyltransferase
COOH O
O-R
(Liver)
R-O-glucuronide
Bile
Kidney
Intestine
Excretion
Beta-glucuronidase
Intestinal mucosa
Intestinal bacteria
R-OH + glucuronic acid

31. How Does Age Affect Drug Metabolism?
Less cyc P450 in
Very young
Elderly
Phase II reactions are usually not affected in the elderly
Decreased blood flow to liver in elderly

32. 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

33. What factors determining the amount of drug excreted in the urine?
Nephron
Glomerular Filtration
Tubular
Reabsorption
Secretion
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. 5 4 3 2 1
Peak Drug Level
Serum Concentration (mg/ml)
Time to Peak Drug Level
Time After Drug Administration (hr)

40. Time After Drug Administration (hr)
Serum Concentration (mg/ml) 5 4 3 2 1
Duration of Therapeutic Effect
Therapeutic Threshold

41. Time After Drug Administration (hr)
Serum Concentration (mg/ml) 5 4 3 2 1
Toxic Effect
Therapeutic Window
Therapeutic 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 studied
AUC after IV administration
What factors will alter bioavailability?

44. What is the Volume of Distribution of a drug?
Vd (L) =
Xo mg
Cp (mg/ml)

45. Plasma Drug Concentration
How do you measure the concentration of drug in the plasma at time T = 0? 10 8 6 4 2
Time (Hours)
Plasma Drug Concentration
(μg/ml) Cp

46. What does it mean if a drug has the following Vd in a 70 kg person?

48. What are the units for kel?
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?
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?
Time (Hrs)
Concentration (μg/ml)
Plasma Drug
100 80 60 40 20
Zero order
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

50. Concentration (μg/ml)
Time (Hrs)
Concentration (μg/ml)
Plasma Drug
100 80 60 40 20

51. Effects of Doubling Dose Zero Order Kinetics25 20
Plasma Concentration (mg/L) 15 10
Time (hrs)
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? 10 6 4 2
Time (Hours)
Concentration (μg/ml)
Plasma Drug 8
1st order
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 hours --- time is independent of plasma levels
What happens to steady state plasma levels if you double the dose? Plasma levels double

53. Effects of Doubling Dose 1st Order Kinetics8 6
Plasma Concentration (mg/L) 4 2
Time (hrs)
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?
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

56. Concentration (μg/ml) 10 6 4 2
Time (Hours)
Concentration (μg/ml)
Plasma Drug 8

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 (mg/min)
Concentration (mg/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.)

61. What is meant by flow dependent elimination?
Rate of clearance is dependent on the rate of blood flow through the organ

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
What is meant by flow dependent elimination?
Rate of clearance is dependent on the rate of blood flow through the organ

63. Are drugs A or B being eliminated by first or zero order kinetics?
10.0 A
1st order
Plasma Concentration
µg/ml
1.0 B
Zero order
0.1 25 50 75
100
125
150
Time (min)
Why isn’t the curve for Drug B linear?
Two compartment distribution

64. Two Compartment Model 1st Order Plasma Concentration One compartment a
Time (min) a b 25 50 75
100
125
150
Plasma Concentration
µg/ml
10.0
1.0
0.1
One compartment
Two
Compartment
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 (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

67. How do decreases in body weight affect the following parameters?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 = 0.8
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
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 = 0.8
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
t1/2
CL =
NOTE: If CL is decreased by 50%, t1/2 will increase by 50% =
0.7 x Vd CL
t1/2
t1/2 =
0.7 x 40 L
1.75 L/hr
t1/2 = 16 hours

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 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

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 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 = 0.8
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?
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 =
Dose = 50 mg every 8 hours

73. Fluctuations in Plasma Concentration with Dosing Intervals25 20
Plasma Concentration (mg/L) 15 10 5
Time (hrs)