Basic Pharmacokinetics REV. 00.1.

11 1-1
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf/
CHAPTER 1 Introduction
Author: Michael Makoid and John Cobby
Reviewer: Phillip Vuchetich
OBJECTIVES
At the completion of this chapter, the successful student shall be able to:
1. define pharmacokinetics
2. state the overall objectives of the course
3. state the major themes of the course
4. state the course organizational structure with respect to study sections
5. state the objectives of each study section
6. state the examination structure and objectives
7. state student performance expectations
8. state the schedule and timeline
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-2
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
1.1 Basic Pharmacokinetics
What is pharmacokinet-
ics?
Pharmacokinetics is the mathematics of the time course of Absorption, Distribu-
tion, Metabolism, and Excretion (ADME) of drugs in the body. The biological,
physiological, and physicochemical factors which influence the transfer processes
of drugs in the body also influence the rate and extent of ADME of those drugs in
the body. In many cases, pharmacological action, as well as toxicological action, is
related to plasma concentration of drugs. Consequently, through the study of
pharmacokinetics, the pharmacist will be able to individualize therapy for the
patient.
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-3
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
1.2 Course Objectives:
The Roman numerals refer to the cognitive complexity as described in Bloom’s
Taxonomy of Educational Objectives described elsewhere in this document. At the
completion of this course, the successful student will be able to:
What will you be able to
do?
• Calculate (III) patient and drug specific pharmacokinetic parameters from patient data,
• Predict (calculate - III) the changes in relevant pharmacokinetic parameters in the patient with
selected diseases,
• Utilize the above parameters to individualize patient therapy (devise a dosage regimen - V),
• Communicate his/her therapy recommendations to another competent health professional (write
a consult - V).
1.2.1 COURSE ARRANGEMENT:
Two courses are described below. The first, a two credit (Creighton University
required) and the second, a three credit (CU optional) version. The two credit
course will consist of major themes one through three and exams one and two,
while the three credit course will add theme four and exam three. The four major
themes are entitled:
How is the course
arranged?
• Study Group 1: Learn the tools used by the discipline. Calculate patient and drug specific phar-
macokinetic parameters from single dose patient data,
• Study Group 2: Utilize the tools to optimize patient therapy under multiple dose conditions,
• Study group 3: Apply the tools to predict the changes in relevant pharmacokinetic parameters in
the compromised patient patient with selected diseases,
• Study group 4: Apply the tools in specialized drug classes.
Each major theme of the course is further broken down into study sections, each
with their own set of general objectives as shown below:
Introduction
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Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
1.2.2 STUDY GROUP 1: LEARN THE TOOLS USED BY THE DISCIPLINE.
CALCULATE PATIENT AND DRUG SPECIFIC PHARMACOKINETIC
PARAMETERS FROM SINGLE DOSE PATIENT DATA,
A. Basic Mathematical skills objectives:
What will I be required
to be able to do? How
will examination ques-
tions be written for this
material?
1. Given a data set containing a pair of variables, the student will properly construct (III) var-
ious graphs of the data.
2. Given various graphical representations of data, the student will calculate (III) the slope
and intercept by hand as well as using linear regression.
3. The student shall be able to interpret (V) the meaning of the slope and intercept for the
various types of data sets.
4. The student shall demonstrate (III) the proper procedures of mathematical and algebraic
manipulations.
5. The student shall demonstrate (III) the proper calculus procedures of integration and dif-
ferentiation.
6. The student shall demonstrate (III) the proper use of computers in graphical simulations
and problem solving.
7. Given the assumptions for the model, the student will construct (III) models of the ADME
processes using Laplace Transforms.
8. The student shall develop (V) integrated equations associated with the above models.
9. The student shall generate a pharmacokinetic model based on given information.
10. The student shall interpret a given model mathematically.
11. The student shall predict changes in the final result based on changes in variables through-
out the model.
B. Pharmacological Response objectives:
1. Given patient data of the following types, the student will be able to properly construct
(III) a graph and compute (III) the slope: response (R) vs. concentration (C), response (R)
vs. time (T), concentration (C) vs. time (T)
2. Given any two of the above data sets, the student will be able to compute (III) the slope of
the third.
C. IV one compartment model, plasma and urine objectives:
1. Given patient drug concentration and/or amount vs. time profiles, the student will calcu-
late (III) the relevant pharmacokinetic parameters available ( , K, , , , Clear-
ance, MRT) from IV data.
2. Given the appropriate pharmacokinetic parameters, the student shall simulate (III)
I.V. bolus/infusion dosing for parent compounds
Plasma concentration vs. time profile analysis
Rate vs. time profile analysis
3. Given patient specific pharmacokinetic parameters, the student shall provide professional
communication regarding IV bolus/infusion information
4. The student shall utilize computer aided instruction and simulation
5. Given patient drug concentration and/or amount vs. time profiles, the student will calcu-
late (III) the relevant metabolite (active vs. inactive) pharmacokinetic parameters avail-
able ( , K, , , , Clearance, MRT) from IV data.
V
d
k
m
k
r
AUC
V
d
k
m
k
r
AUC
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-5
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
D. Biopharmaceutical factor objectives: the student shall be able to discuss:
1. physiology and mechanisms of absorption
2. effects of diffusion, cardiac output / blood perfusion, physical properties of the drug and
body on distribution
3. biotransformation, first pass effect, and clearance
4. renal, biliary, mammary, salivary, other forms of excretion.
5. the effects of physiological changes with age, sex, and disease on the absorption, distribu-
tion, metabolism, and excretion of a drug.
E. Oral one compartment model objectives:
1. Given patient drug concentration and/or amount vs. Time profiles, the student will calcu-
late (III) the relevant pharmacokinetic parameters ( , K, , , , , Clearance,
MRT, MAT) available from oral data.
F. Bioavailability objectives:
1. Given sufficient data to compare an oral product with another oral product or an IV prod-
uct, the student will estimate (III) the bioavailability (compare AUCs) and judge (VI) pro-
fessional acceptance of the product with regard to bioequivalence (evaluate (VI) AUC,
and ).
2. The student will write (V) a professional consult using the above calculations.
1.2.3 STUDY GROUP 2: UTILIZE THE TOOLS TO OPTIMIZE PATIENT
THERAPY UNDER MULTIPLE DOSE CONDITIONS,
G. Dosage regimens objectives:
1. Given population average patient data, the student will devise (V) dosage regimens which
will maintain plasma concentrations of drug within the therapeutic range.
2. Given specific patient information, the patient will justify (VI) dosage regimen recom-
mendations.
3. Given patient information regarding organ function, the student will devise (V) and justify
(VI) dosage regimen recommendations for the compromised patient.
4. The student will write (V) a professional consult using the above calculations
1.2.4 STUDY GROUP 3: APPLY THE TOOLS TO PREDICT THE CHANGES IN
RELEVANT PHARMACOKINETIC PARAMETERS IN THE
COMPROMISED PATIENT PATIENT WITH SELECTED DISEASES,
H. Clearance objectives:
1. Given patient information regarding organ function, the student will calculate (III)
changes in clearance and other pharmacokinetic parameters inherent in compromised
patients.
V
d
k
m
k
r
k
a
AUC
T
p
C
p
( )
max
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-6
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
1.2.5 STUDY GROUP 4: APPLY THE TOOLS IN SPECIALIZED DRUG
CLASSES.
I. Two Compartment Model objectives:
1. Given patient Concentration and/or Amount of Drug vs. Time, profiles the student will
calculate (III) the relevant pharmacokinetic parameters( , Alpha, , Beta, ,
, , , , Clearance, compartmental amount ratios) available from two com-
partment data.
2. Given population average patient data, the student will devise (V) a dosage regimen which
will maintain plasma concentrations of drug within the therapeutic range.
3. Given specific patient information, the patient will justify (VI) the optimal dosage regi-
men.
4. Given patient information regarding organ function, the student will devise (V) and justify
(VI) the optimal dosage regimen for the compromised patient.
5. The student will write (V) a professional consult using the above calculations.
J. Non-linear kinetics objective:
1. Given population average patient data, the student will devise (V) a dosage regimen which
will maintain plasma concentrations of drug within the therapeutic range.
2. Given specific patient information, the patient will justify (VI) the optimal dosage regi-
men.
3. Given patient information regarding organ function, the student will devise (V) and justify
(VI) dosage regimens for the compromised patient.
4. The student will write (V) a professional consult using the above calculations.
V
d1
A
1
B
1
k
10
k
12
k
21
AUC
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-7
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
1.3 Exams
How are the exams
made?
Exams will consist of problems which will be linked directly back to an objective
(above) and a library assignment in which you will be asked to evaluate a research
article with the tools available to you by the time of the exam as discussed below.
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-8
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
1.3.1 LIBRARY ASSIGNMENT IN PHARMACOKINETICS
K. Library Assignment Objectives
What do I have to do in
the library?
1. Given a suitable primary research article in the area of pharmacokinetics, the student shall
calculate the pharmacokinetic parameters from the data using the tools learned in class
both by hand and utilizing the computer program, PK Solutions.
2. The student shall communicate in writing the results of such calculations with suitable
commentary regarding differences and interpretations.
Format of the “paper”:
How should the paper
look?
1. Tell me what type of paper you have chosen to evaluate:
The problem sets show what data you need for each of these.
First Exam
What content should I
look for in the paper and
what is its relative
worth?
IV Bolus Parent compound 50 pts
IV Bolus Parent metabolite 65 pts
IV Infusion 65 pts
Pharmacological Response 75 pts
Oral Dosing / Bioavailability 50 pts
Second Exam (Pharm.D. course)
Multiple dosing 50 pts
Clearance and disease 60 pts
Dosage Regimen 75 pts
Third Exam (Masters / Honors course)
Two compartment model 50 pts
Protein Binding and Disease 65 pts
Non-linear kinetics and disease 75 pts
2. Include a Xerox copy of the entire paper. I need to evaluate it, too.
3. Enlarge the graph by successive Xeroxes so that you can accurately evalu-
ate the data.
4. Do analysis of data by hand and by PK Solutions.
5. Compare your work with the author’s (short paragraph).
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-9
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
6. Comment on any differences of parameter calculation or interpretation. See
objectives above (Paragraph).
7. Write an exam question to obtain pharmacokinetic parameters. You know
from the first exam what they should look like.
Why do I need to do this
library assignment?
Each of the above sections is designed to bring the student an understanding of the
information and the processes necessary to operate as a competent professional in
the area of pharmacokinetic evaluation and consulting. Consequently, the
course will evolve from a quantitative, manipulative mathematics course to a
course which stresses communication skills. Consults will be graded not only on
content (the proper dosage regimen for the patient) but also grammar, punctuation,
spelling, organization and neatness. You may have the best medical information in
the world, but if it is poorly executed, it will be ignored.
Can I cram the night
before?
This course will probably be one of the more rigorous ones that you will have
experienced in your college career to date. It will be one of the first ones which
attempt to show some clinical relevance. The course can be successfully com-
pleted with your current skills and background. It is not difficult IF (and that is a
big IF) taken slowly, in small bites. Its just like eating an elephant - you can’t do it
all in one sitting. Some of you may try to get it all the night before the exam,
regardless of my admonitions and those of your upper-class friends (ask them!). In
many cases, that has been more than sufficient to get A’s and B’s on exams in pre-
vious courses. Past experience tells many of you that you can do it. I suggest that
the requirements and expectations of a professional school are considerably more
than your undergraduate experience and it most likely will not work in many
courses which require assimilation of the information presented, as is expected in a
professional program.
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Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
1.4 Blooms taxonomy for the Hierarchy of Educational Objectives
Blooms taxonomy for the Hierarchy of Educational Objectives describes the
expectations of a course in increasing order of complexity as:
What is cramming good
for? Lowest level of cog-
nitive skills.
I. To Know: means to memorize (recognize, recall) (Many college courses
require only this level of cognitive effort, hence the extensive experience with
“multiple guess” exams).
II. To Comprehend: means to translate; to be able to put information into your
own words. (Essay exams routinely call for this level of effort on the part of the
student).
This is where we begin. III. To Apply: means to be able to use knowledge, rules and principles in an
unfamiliar situation. (This is the lowest level of skill necessary to function at a
technician level).
This is where we need
to be in school.
IV. To Analyze: means to be able to critically examine a body of knowledge
and to be able to identify the relationships. (This is where a B.S. graduate should
operate. Education obviates the need for teachers.)
This is where we need
to be as graduates.
V. To Synthesize: means to put together information, not necessarily previ-
ously so organized, in order to get a new piece of information. (This is the begin-
ning level of professional judgment).
VI. To Evaluate: means to be able to judge the worth of an idea, form hypothe-
ses and do problem solving, research, invent new knowledge. (This is the doctoral
level of participation in the area).
Can’t I just do it the
same way that I have
always studied?
A professional routinely operates at level IV and V with occasional forays into
level VI. This is where you will operate in this course and in most subsequent
courses in the professional curriculum. You will note that each of the objectives for
the course contains specific action words followed by the level in the taxonomy at
which you will operate. These are the standard descriptive terms for use in instruc-
tional objectives. You will be asked to do critical thinking, not simply recite or
recognize the right answer. Problems challenge thinking skills and demand the
synthesis of material into concepts. To facilitate this transition we both must work
very hard.
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Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
1.5 Course Contract
I Will:
What will the teacher do
in this class? Act as a
facilitator.
1. Provide individualized learning methods: Some students learn by hearing
and others by seeing (auditory or visual learners). I have designed the course to
accommodate both types of learners. In class, I will provide you with executive
summaries of what you read. I will provide group leaders with detailed reviews of
materials for which they are responsible. I will tell you what I’m going to say, say
it, and then tell you what I said. I will also attempt to write it out and draw appro-
priate graphs, charts and pictures as well as appropriate visual aids in class and
with the homework problems. I will provide you with ample examples of the types
of manipulations that you will be expected to do. I will provide you with ample
problem sets so that you may practice those manipulations. I will provide you
with computer simulations so that you may see these manipulations in action and
begin to get a feel for the numbers and their magnitude. Feedback and interaction
is encouraged. If I am not meeting your perceived needs, you must tell me. Some
students might feel too intimidated to ask questions. To obviate this problem, you
will elect a group team leader, an ombudsman, whose job it will be to carry your
questions, concerns, and comments to me. It is your job and his responsibility to
see that the group interaction facilitates the learning process. This is not to prevent
you coming to see me but offered as another avenue of communication.
Will I learn anything rel-
evant in this course?
2. Provide clinical relevance to the practice of pharmacy. This will be stressed
at all times. I will also relate real clinical experiences; virtually all of the problems
come from real patients. Some educators believe examples must fit the theory
exactly. This gives the student a false set of reality parameters. Consequently,
when “the data does not fall on the line” the student rejects relevant information.
You will become familiar with real data, and the problems associated with real
data.
How will I know how I’m
doing?
3. Give adequate feedback: Evaluation of your performance will be available
to you at all times. A running evaluation, updated weekly will be on my door for
your review. You may check any thing with me at any time. I expect that you will
see me outside of class time either individually if you need help or in supervised
review sessions. You must see me for assistance if your performance is unsatis-
factory.
What will the teacher be
doing? Engaging you in
an active learning pro-
cess.
4. Teach: As an operational definition this means: clarifying what you read,
demonstrating how and why things work as they do, and unifying the material -
attempting to generate the A - HA! syndrome. The correlate of teach from the stu-
dent view is learn. Neither is a passive process. I can not open your head and pour
the knowledge in. A saying in education is: “Knowledge maketh a bloody
entrance”. You must expend the effort necessary for you to learn.
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What must I do in this
active learning process?
You MUST participate in
class and in your
assigned groups!!!
5. Facilitate Learning. You received objectives (above) and a summary for
each study section (chapters in this text), of exactly what is expected of you with
examples in the problem sets at the end of each chapter. We will have ample time
during class to field questions generated by the correlated reading and problem
sets, as well as homework assignments. I will not be duplicating any book’s efforts.
Student participation in class is required. You will answer (as well as ask) ques-
tions, do problems in class. You will sound things out and get feedback from me
and your fellow colleagues. Remember - the class is to help you learn. It is not the
sole means of learning, nor am I the source of all knowledge. Its’ only reason for
being is to help you organize and summarize what you learn. It has a relatively
simple plan with multiple examples. From these examples you will develop con-
cepts which will obviate the need for memorizing individual facts (or actually me
entirely). I will assist you in the formation of these concepts. It is patently obvious
that I can not give you every possible example of every type of question that you
will be asked during your professional career. For one thing I don't know what
questions you will be asked nor problems you will encounter. Going from the spe-
cific to the general forms concepts which will allow you to go from the general to
the specific, even if you have never been there before. The total medical knowl-
edge is now doubling at a rate of every 4 years. I can not teach you the content nec-
essary to operate 5 years in the future, let alone 40. You must learn to learn.
Hence, if you plan to become a competent professional, you must operate at least
in Bloom's level V.
How do I get in touch
with the teacher?
6. Be available: I do not have office hours. I believe them to be restrictive
from your view point. What I do have is a schedule calandar preparede weeks in
advance of when I am NOT available. You may set an appointment, at least a 1/2
day in advance to guarantee that I see it, any other time. Of course, appointments
are not necessary if I'm in my office, but you take the chance of my not being there
or someone else being there ahead of you if you do not sign up. You may contact
me by e-mail: makoid@creighton.edu, or by phone: 402-280-2952. You may also-
contact my secretary, Dawn Trojanowski in the departmental office or by phone
402-280-2893 to make an appointment.
How can I tell the
teacher how things are
going?
7. Be responsive: Each day, you will be asked to provide me with a one
minute summary of the topic consisting answering the following questions:
a. What was the main thrust of the study section (What did you read)?
b. What was clear about the study section? What was done well?
c. What was unclear? How could it be done better?
This will provide me with a running monitor of my effectiveness as well as a
framework of what to stress and what to change.
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-13
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Do I have any say in the
examination questions?
After each exam, in addition to working out the problems, we will decide whether
any individual question was not covered by the objectives. Note: Not that it was
tough, not that you got it wrong, not that it didn’t allow you to tell me what you
knew, but did I tell you that I was going to ask you to do it? (Was it covered by the
objectives?)
How are the exams
graded?
8) Evaluate your performance fairly and honestly: Quite simply, I’m going to tell
you what I expect that you will do. I will show you how to do it. I will provide you
with practice in doing it. I will provide you with an exam which tests your ability
to do it. The exams, as well as the whole course, will use real data and/or pharma-
cokinetic parameters for real drugs in real patient settings, much like the state
board exams (and hopefully real life). Like both of these situations, all answers are
interconnected. What that means is, if you improperly calculate a parameter which
is needed to make another calculation which is used to make a third, etc. ALL are
wrong. Conversely, if you can’t get a particular calculation by one method or equa-
tion, try another. That’s simply the way it is. You probably wouldn’t get much sym-
pathy if you calculated a dosage regimen properly based on a wrong elimination
rate constant and ended up killing your patient.
You Will:
What do I have to do?
How much work is really
expected?
1) Come prepared to participate in class. This is your full time job. If you are
working full time, it is usually 40 to 60 hours per week. If you go to college 15 to
18 credits and prepare/study 2 hours for each credit, you work 45 to 55 hour per
week - you have a full time job. Your commitment is the 45 to 50 hour week not
just the contact hours and a night for each exam. This specifically means for each 1
hour class, I expect no less than 2 hours of preparation on your part. Each of you
will be assigned to a study group. You will work the problems together and teach
each other both in and out of class. We will have group discussion of class as well
as group problem solving. It will be your responsibility that every member of
your group be adequately prepared to answer for the group during recitation. There
will be a grade for group participation. Part of your grade will be based on your
peer evaluation.
Do I have to read the
text?
2) Read the text. When you read, read critically. Do you understand each idea?
Each page in the HTML version has an evaluation section. If you get it you will be
asked to be a resource for that page for your peers. If you don’t get it, you will be
directed to your peers to seek help. Come prepared to ask about it in class.
Why do I have to do the
problem sets?
3) Work the problems. Check the answers. These come from old exams, so they
are the type that you are likely to see. Work them in your study groups so that
everyone can see your thought processes. Bring them to class if you can not do
them or come and see me privately. Be prepared to show me your attempts at solv-
ing the problem. I will show you how to get started and give direction to your
thought. I will not work the problem for you. You would not learn if I did it for
you. It is crucial that you work the problems. Each has a specific objective. Over-
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-14
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
all, they contribute to your gaining facility in the processes that a pharmacokineti-
cist must know how to do.
Can I just coast
through?
4) Do not delude yourself with respect to your performance. If you received a
grade that was less than satisfactory for you, do not simply console yourself by
saying “I knew the stuff, I just made a little error.” Can you get it right consis-
tently? That's when you know the stuff. That is not a laudable goal. That's what a
professional does. There have been several students in the past that “knew that
stuff” right up till the time that they had to repeat the course (and sometimes
beyond).
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Basic Pharmacokinetics REV. 00.1.11 1-15
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1.6 Computers in the course
Can I get through with
just paper and pencil?
Computer literacy is necessary in this field. Consequently computers will pervade
the course. The homework problems (above) are to done both by hand and
checked with the computer. This will help your understanding of pharmacokinetics
in general and that homework objective in particular. Computers are natural
adjunctive tools in the teaching of pharmacokinetics. The are able to simulate the
concentration vs. time profiles and do difficult repetitive calculations which allow
the student to get a broad view of the processes involved.
What are the programs
that I will be using?
Program that is becomming the industry standard and is currently being used in the
course is PK Solutions. We have a site licence for it and a working copy is in the
computer lab. It is a required text for the course. You will need to learn to use the
software as complete instructions are available with its purchase.
In addition to the above course objectives, there are specific objectives for the use
of computers in the course. They are:
What will I be expected
to do with the comput-
ers?
• Simulation. The student will be able to utilize appropriate graphs and histograms used classical
pharmacokinetics in the course. The student will demonstrate effects of changes in pharmacoki-
netic parameters on the ADME processes and correlated pharmacological / therapeutic
response.
• Graphical Solutions. Many thing become more understandable in graphical form, or at least we
are able to predict what would happen if a trend were to continue.
• Numerical solutions. The computer would accurately and repeatedly calculate convoluted, diffi-
cult equations quickly and easily.
These objectives will be met in a variety of ways. Clearly, the most direct method
is the solution of the problem sets by computer. First, I expect that you would do
the problem by hand, complete with graphs and other supporting calculations fol-
lowed by computer simulation and data analysis. Just how close did you come to
the best fit? Next, a portion of each exam will be a library exercise in which you
will find and evaluate a published article according to the principles that you
learned in class utilizing the computer facilities. How close did you come the
authors numbers? Do you, in fact, even agree with the authors? You will prepare a
short consult in which you describe the patient and what the authors did along with
your support (or non-support) of the authors conclusions.
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-16
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
1.7 Survival Kit
1.7.1 THINGS FOR YOUR SURVIVAL KIT!
What do I need to buy
RIGHT NOW?
1. You will need a good calculator - One with and functions. You must
have it ASAP. You will use it in class.
2. You will also need 2 cycle semilog paper and a clear straight edge ruler for
use in class. These are available in the book store or at an office supply store. You
can also downoad a copy of graph paper printer for you own personal use. A copy
is available in the computer lab.
3. You will need access to a pentium computer. The software, PK Solutions,
is pre-loaded in the Criss computer lab. Purchase is required for home use.
4. You will need a 3” D three-ring binder for collecting and maintaining all
the pages in this book as well as your class notes.
What do I need to do in
and out of class?
Work in your study groups. You never learn it so well as when you teach it to
someone else. Everyone benefits from a well run prepared study group. You are
not in competition with your fellow classmates. If everyone earns an “A”, then
everyone will receive one.
How can I organize this
material?
Organize and label your study notes. This is basic survival. This is one strategy
that I find works well. I recommend it highly. Good study notes are formatted on
loose-leaf in a three ring binder. The individual pages have a line drawn down
about 1/3 the way in. The notes are taken on the right (2/3) of the page, while
labels go in the left. The labels on the left are often written as questions, which are
answered in the text on the right. Loose leaf binders allow for the incorporation of
reading summaries as well as relevant problems and homework to be organized
with a divider all in one place. You should write intelligently, with proper punctua-
tion and spelling as if you were preparing a consult for a physician. Organization is
the key.
Remember: you may have all the information in the world at your fingertips; be
able to solve the most difficult therapy problem and no one will listen to you if you
can't communicate intelligently. You will be required to communicate in this
course utilizing both written and verbal skills.
Chapters in the book will be organized as above.
e
x
x ln
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-17
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
1.7.2 WHAT YOU WILL GAIN: (YOUR GOALS)
How is the course to be
graded?
1. At the lowest level, a decent grade for a significant course. Specific grades
will be earned by attaining the following points:
• A 900 and above
• B+ 850 to 899
• B 800 to 849
• C+ 750 to 799
• C 700 to 749
• D 600 to 699
• F 599 and below
Points in the course are assigned for various activities:
You will be require to pass the first exam before you are allowed to take the
second.
2. At the next higher level, I will guarantee that if you comprehend this mate-
rial at level V, you will have no trouble passing any state board anywhere with
regard to pharmacokinetics.
3. You will gain a useful skill that will make you an integral part of the health
care team.
Do I really need a
teacher to learn?
4 You will learn to learn. There is an old proverb which goes: “Give a man a
fish and you feed him for a day. Teach a man to fish and you feed him for a life-
time.” The B.S. Degree is designed to eliminate teachers. An educated man is one
who has learned to how to learn, not one who memorized a page in a book. That
is what you need to be a professional. The total medical knowledge is doubling at a
rate of every 3-4 years. That means that you will be out of date shortly after gradu-
ation (if not before) if you simply memorized content and don't learn to learn and
continue to learn throughout your career.
TABLE 4-1
Exam 1 410
Exam 1 grp/ind 40
Library 1 50-75
Exam 2 410
Exam 2 grp/ind 40
Library 2 50 to 75
Total 1000 to 1050
Group Bonus -50 to +50
Group Total 950 to 1100
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-18
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
What about cheating? One last piece of information: Neither you nor I will not tolerate any academic
misconduct. Anyone caught will minimally receive an “F” for their efforts and I
will recommend dismissal from the program. The profession has no room for
unprofessional behavior. I will prosecute.
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-19
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
1.8 Tentative Schedule
1.8.1 STUDY GROUP 1: LEARN THE TOOLS USED BY THE DISCIPLINE.
CALCULATE PATIENT AND DRUG SPECIFIC PHARMACOKINETIC
PARAMETERS FROM SINGLE DOSE PATIENT DATA,
A: Introduction
1. Texts
2. Literature
3. Grading Policy
4. Course Philosophy
B: Math review
1. Numbers and exponents
2. Graphs and reaction order
3. Calculus
4. Laplace transform
5. Computer Introduction
6. Computer simulation and problem sets
C: Pharmacokinetic modeling
1. What a model is and what it isn’t.
2. Why we model
3. Philosophy of modeling
D: Pharmacological Response
1. Michaelis - Menton Mass balance equation
2. Interrelationships between Concentration, time and response.
E: I.V. Bolus dosing
1. Parent compound
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II Urine
a. Amount vs. time profile analysis
b. Rate vs. time profile analysis
c. Computer aided instruction and simulation
d. Problem sets
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-20
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
e. Professional communication.
2. Metabolite
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II. Urine
a. Rate vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
F: I.V. infusion
1. Parent compound
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II. Urine
a. Amount vs. time profile analysis
b. Rate vs. time profile analysis
c. Computer aided instruction and simulation
d. Problem sets
e. Professional communication.
1. Metabolite
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II. Urine
a. Amount vs. time profile analysis
b. Rate vs. time profile analysis
c. Computer aided instruction and simulation
d. Problem sets
e. Professional communication.

G: Biopharmaceutical factors
1. Absorption
I. Physiology
II. Mechanisms
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-21
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
III. Physiological changes with age, sex, disease
2. Distribution
I. Diffusion
II. Cardiac output / blood perfusion
III. Physical properties of the drug
IV. Physical properties of the body
V. Physiological changes with age, sex, disease
3. Metabolism
I. Biotransformation methods
II. First pass effect
III. Clearance
IV. Physiological changes with age, sex, disease
4. Excretion
I. Renal
II. Biliary
III. Mammary
IV. Salivary
V. Misc.
VI. Physiological changes with age, sex, disease
H: Oral dosing
1. Parent compound
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II. Urine
a. Amount vs. time profile analysis
b. Rate vs. time profile analysis
c. Computer aided instruction and simulation
d. Problem sets
e. Professional communication.
2. Metabolite
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II. Urine
a. Amount vs. time profile analysis
b. Rate vs. time profile analysis
c. Computer aided instruction and simulation
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-22
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
d. Problem sets
e. Professional communication.
I: Bioavailability, Bioequivalence, Drug product selection
1. Relative and Absolute Bioavailability
2. Factors Influencing Bioavailability
3. Methods of Assessing Bioavailability
I. in vivo
II. in vitro
III. Correlation
4. Bioequivalence
5. Bioavailability
6. Drug Product Selection
1.8.2 STUDY GROUP 2: UTILIZE THE TOOLS TO OPTIMIZE PATIENT
THERAPY UNDER MULTIPLE DOSE CONDITIONS,
J: Dosage regimen (Healthy, aged and diseased patients)
1. Multiple dose kinetics
2. Optimization of dosage regimen
3. Computer aided instruction
4. Computer simulation and problem sets
5. Computer aided consultation
6. Professional consultation process
1.8.3 STUDY GROUP 3: APPLY THE TOOLS TO PREDICT THE CHANGES IN
RELEVANT PHARMACOKINETIC PARAMETERS IN THE
COMPROMISED PATIENT PATIENT WITH SELECTED DISEASES,
L. Clearance objectives:
1. Given patient information regarding organ function, the student will calculate (III)
changes in clearance and other pharmacokinetic parameters inherent in compromised
patients.
1.8.4 STUDY GROUP 4: APPLY THE TOOLS IN SPECIAL CASES.
K: Multicompartment Modeling
1. Parent compound plasma vs. time profile analysis
2. Multiple dose considerations
3. Computer aided instruction
4. Computer simulation and problem sets
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-23
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
5. Computer aided consultation
6. Professional consultation process
L: Protein Binding (healthy, aged and diseased patients)
1. Mass balance considerations / drug interactions
2. Effects of protein binding on pharmacokinetic parameters
3. Computer aided instruction
4. Computer simulation and problem sets
5. Computer aided consultation
6. Professional consultation process
M: Non - linear (Michaelis - Menton) kinetics
1. Computer aided instruction
2. Computer simulation and problem sets
3. Computer aided consultation
4. Professional consultation process
End of material for Masters / Honors course
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-24
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
1.9 Competency Statements Related To Pharmacokinetics
The profession of pharmacy has determined that there are minimum, entry level
abilities necessary for a pharmacist. These form the Standards of Practice for the
profession of pharmacy, as written by The National Association of Boards of Phar-
macy (who make the NABPLEX, coincidentally). It is important to note that these
abilities are not thought up by some faculty member who sits in his ivory tower
saying what he thinks is important. These are what pharmacists do. They have
been promulgated as competency statements They are also the basis for the state
board exams as well as the basis far your coursework while in the School of Phar-
macy. They are broken down into five general areas:
1.00.00 Interpreting and dispensing prescriptions/ medication orders,
2.00.00 Assessing prescriptions/ medication orders and the drugs used in dispensing them,
3.00.00 Compounding and calculations involved in extemporaneous preparation of prescriptions/ medication
orders,
4.00.00 Monitoring drug therapy,
5.00.00 Counseling patients and health professionals.
For a complete listing of competency statements please refer to the NABPLEX
Candidate’s Review Guide, published by the National Association of Boards of
Pharmacy.
1.9.1 SPECIFIC COMPETENCY STATEMENTS ADDRESSED IN THIS
COURSE
1.00.00 Interpreting and Dispensing Prescriptions/ Medication Orders
1.04.00Given a prescription or medication order, the candidate shall identify or explain the rationale for the
dosage regimen.
1.04.03The candidate shall calculate the dose or rate of administration of a drug when given appropriate data.
2.00.00 Assessing Prescriptions/Medication Orders and the Drugs Used in Dispensing Them
2.01.00 The candidate shall identify, interpret, or explain patient or pharmacokinetic factors that affect either the
efficacy or safety of individual drug therapy.
2.01.01The candidate shall relate the influence of patient factors (e.g., age, weight, sex, occupation, compli-
ance, exercise, stress, placebo effect, vital organ function) to the choice or dosage of drug therapy.
2.01.02 The candidate shall explain or apply biopharmaceutical principles or pharmacokinetic factors (e.g.,
absorption, distribution, metabolism, excretion) as they relate to dosage regimen design or evaluation of experi-
mental or patient data, including the: definition or explanation of biopharmaceutical terminology; recognition of
the effects of patient health status or concurrent drug therapy on bioavailability; determination of pharmacokinetic
parameters or dosing regimens (e.g., loading dose estimations, maintenance dose calculation, elimination half-
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-25
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
life, determinations of clearance, or volume of distribution); or recognition of biosocial factors that affect pharma-
cokinetic parameters (e.g., smoking, alcohol consumption, work environment.
2.03.00 Given appropriate information or data regarding bioavailability, the candidate shall demonstrate proper
judgment to assure safe and effective drug therapy.
2.03.01The candidate shall interpret or utilize in vitro dissolution test results that are used to predict bioequiv-
alence or shall distinguish these from in vivo tests.
2.03.02 The candidate shall differentiate between relative and absolute bioavailability.
2.03.03 The candidate shall interpret area under plasma concentration versus time curves as an assessment
of bioavailability.
2.03.04 The candidate shall explain or interpret the effect of rate of absorbtion on maximum plasma concentra-
tions and times of maximum plasma concentrations after drug administration.
2.04.00 The candidate shall identify, interpret, or evaluate sources of information for clarifying or answering
questions related to prescriptions, medication orders, or health care.
2.04.01 The candidate shall select appropriate books or references containing needed information (e.g.,
bioequivalence, incompatibility, drugs for emergency situations, physicochemical stability).
2.04.02 The candidate shall evaluate the suitability, accuracy, or reliability of information (e.g., pharmacokinetic
characteristics untoward effects, therapeutic efficacy) from literature sources.
4.00.00 Monitoring Drug Therapy
4.01.02 The candidate shall identify, collect, or evaluate patient information that relates to the effectiveness of
drug therapy (e.g., clinical observations, pharmacokinetic data, laboratory test results, sensitivities).
5.00.00 Counseling Patients and Health Professionals
5.01.00 The candidate shall counsel a patient or health professional regarding the indications, benefits, admin-
istration, storage, or untoward effects of prescription medications.
5.01.01 The candidate shall explain the proper procedure for taking or administering the drug (e.g., dosage,
time of day, method or time of administration -- before or after meals, duration of use), or for providing auxiliary
instructions about the medication.
5.01.03 The candidate shall explain cautions regarding food, drugs, chemicals, or nutrients that should be
avoided while particular medications are taken.
5.05.00 The candidate shall advise consumers regarding the selection, proper use, effects, precautions, or
contraindications of OTC products.
5.05.03 The candidate shall explain how a drug is to be taken (e.g., dosage, time of day, frequency, before or
after meals).
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-26
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
1.10 Pharmacokinetic Symbolism
Pharmacokinetics was developed in several locations simultaneously. Because of
this, the symbols used in the literature are not consistent. Provided each symbol is
rigorously defined prior to use, this inconsistency should not prove an insurmount-
able difficulty when assessing the literature. In this book, the symbolism below
will be generally used, though, as an illustration of the variety, some deviation may
be anticipated on occasions.
1.10.1 AMOUNT TERMS (UNIT: MASS)
amount remaining to be eliminated (excreted)
dose (or maintenance dose)
loading dose
amount of drug remaining to be absorbed at any time
amount of unchanged drug in body at any time
amount of metabolite in body at any time
cumulative amount of unchanged drug excreted into urine up to any time
cumulative amount of metabolite excreted into urine up to any time
maximum amount of unchanged drug in body
minimum amount of unchanged drug in body
average amount of unchanged drug in body (also Laplace transform)
minimum amount of unchanged drug in body necessary for pharmacologi-
cal response
ARE
D
D
L
X
a
X
X
m
X
u
X
mu
X
max
X
min
X
X
eff
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-27
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
1.10.2 CONCENTRATION TERMS (UNITS MASS/VOLUME)
concentration of drug in blood at any time
concentration of drug in plasma at any time
Concentration of metabolite in plasma (or blood) at any time
“average” steady-state concentration of drug in plasma during a dosing
interval
maximum concentration of drug in plasma
minimum concentration of drug in plasma
average concentration of drug in plasma
dissociation constant of drug-protein complex
Michaelis-Menton rate constant
dissociation constant of drug-receptor complex
minimum effective concentration of drug or metabolite
minimum toxic concentration of drug or metabolite
C
b
C
p
C
m
C
p
( )
ss
avg
C
p
( )
ss
max
C
p
( )
ss
min
C
p
K
A
K
M
K
R
MEC
MTC
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-28
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
1.10.3 VOLUME TERMS (UNIT: VOLUME)
apparent volume of unchanged drug distribution in compartment
apparent volume of metabolite distribution in compartment
physiological volume of plasma water
1.10.4 TIME TERMS (UNIT: TIME)
time since administration of dose
duration of zero-order input
time since cessation of zero-order input
lag time
mean time during sampling interval
elimination half-life (“biological half-life”)
time for 50% removal
time when maximum amount or concentration occurs
duration of effective pharmacological response
dosing interval (greek theta)
time variable used in association with zero-order input
V
d
V
m
V
w
t
T
t'
t
0
t
t
½
t
0.5
t
max
t
dur
τ
b
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-29
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
1.10.5 RATE CONSTANT TERMS (UNIT: RECIPROCAL TIME (*), MASS/TIME
(**))
, apparent first-order rate constant for elimination, Summation of all the
ways the drug is eliminated (*)
apparent first-order rate constant for absorption (*)
apparent first-order rate constant for urinary (renal) excretion of unchanged
drug (*)
apparent first-order rate constant for metabolism of unchanged drug (*)
apparent first-order rate constant for excretion of metabolite (*)
apparent first-order transfer rate constant (*)
zero-order input rate constant (**)
zero-order infusion rate constant (**)
rate constant for decline in pharmacological effect (usual units:%/time)
hybrid first-order rate constant (*) (greek alpha)
hybrid first-order rate constant (*) (greek beta)
K k
e
K
i
, ,
k
a
k
u
k ,
r
k
m
k
mu
k
ij
k
0
Q
R
α
β
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-30
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
1.10.6 CLEARANCE TERMS (UNITS: VOLUME/TIME)
total body clearance (TBC)
renal clearance (RC)
metabolic clearance (MC)
creatinine clearance
hepatic clearance (HC)
1.10.7 RATE TERMS (UNITS: MASS/TIME (*), MASS/TIME, VOLUME (**),
VOLUME/TIME (***)
instantaneous rate of change of amount of unchanged drug (*)
measured rate of change of amount of unchanged drug (*)
rate of plasma flow through the liver (***)
rate of plasma flow through the kidney (***)
theoretical maximum rate of a process (**)
1.10.8 OTHER TERMS
area under the plasma concentration-time curve (units: time * mass/vol-
ume)
area under the first moment of the plasma concentration-time curve (units:
)
Mean Residence Time (units: )
Cl
Cl
r
Cl
m
Cl
cr
Cl
H
dX
dt
-------
X
t
----
R
H
R
r
V
M
AUC
AUMC
time
2
mass ⋅ volume ⁄
MRT time
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-31
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
Mean Absorption Time (units: )
Mean Dissolution Time (units: )
intensity of pharmacological effect
steady-state hepatic extraction ratio
steady-state renal extraction ratio
maximum intensity of pharmacological effect
fraction of administered dose ultimately absorbed
fraction remaining to be eliminated (excreted)
hematocrit (fractional volume of erythrocytes in whole blood)
number of elimination half-lives in a dosing interval
accumulation factor
intercept
fraction of drug that is free (unbound)
fraction of steady-state
slope (sometimes specifically for log dose-response plot)
number of doses
Laplace operator
indicates molar concentration
MAT time
MDT time
E
E
H
E
r
E
max
F
FRE
H
N
R
b
f
f
ss
m
n
s
[ ]
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-32
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
1.10.9 SUBSCRIPTS
at time zero
at time infinity
during steady-state
at time t
at time T
following dose n
difference between extrapolated and observed
intrinsic
index (i.e., 1,2,3)
index (i.e., 1,2,3)
1.10.10 SUPERSCRIPTS
extrapolated
last measured value
0

ss
t
T
n
diff
int
i
j
x

Introduction
Basic Pharmacokinetics REV. 00.1.11 1-33
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
1.11 First Lesson in Pharmacokinetics
It should be intuitively obvious to the most casual observer that the relative bio-
availability of 2 simultaneous I.V. bolus doses of a drug is equal to the following:
(EQ 4-1)
given that 100% bioavailability of a single I.V. bolus dose is equal to 1, and both
doses contain an equal mass of active drug.
For the struggling pharmacokinetics student, we would like to show the veracity of
this statement. Of course, it is obvious that; the reverse of the transpose is equal to
the transpose of the inverse in matrix theory. i.e.:
(EQ 4-2)
Also, it should be obvious that:
(EQ 4-3)
Consequently,
(EQ 4-4)
which means that:
(EQ 4-5)
By definition,
(EQ 4-6)
and
(EQ 4-7)
Thus:
x
1
[ ]
1 –
x
1 –
[ ]
1
– ( )!
1
δ
--- +
. ,
| `
δ
δ ∞ →
lim
¹ ¹
' '
¹ ¹
ln q sin ( )
2
q cos ( )
2
+ +
p 1 p tanh ( )
2
– cosh
2
n
--------------------------------------------------
n 0 =


=
x
1
[ ]
1 –
x
1 –
[ ]
1
=
0! 1 =
x
1
[ ]
1 –
x
1 –
[ ]
1
– ( )! 1 =
1
1
δ
--- +
. ,
| `
δ
δ ∞ →
lim
¹ ¹
' '
¹ ¹
ln q sin ( )
2
q cos ( )
2
+ +
p 1 p tanh ( )
2
– cosh
2
n
--------------------------------------------------
n 0 =


=
e 1
1
δ
-- - +
. ,
| `
δ
=
1 p 1 p tanh ( )
2
– cosh =
Introduction
Basic Pharmacokinetics REV. 00.1.11 1-34
Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
(EQ 4-8)
Also,
(EQ 4-9)
and
(EQ 4-10)
and
(EQ 4-11)
So, as we observed in equation 1,
(EQ 4-12)
under the stated conditions, two I.V. bolus doses given simultaneously will have
twice as much available drug as a single I.V. bolus dose.
You will agree, however, equation 1-1 is obvious and therefore is more easily
understood by a pharmacokineticist!
e ln q sin ( )
2
q cos ( )
2
+ +
1
2
n
-----
n 0 =


=
2
1
2
n
-----
n 0 =


=
1 e ln =
1 q sin ( )
2
q cos ( )
2
+ =
1 1 + 2 =

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