1. MicroMath Scientific Software, Inc., P.O. Box 21550, Salt Lake City, UT 841210550,
Any number multiplied by zero equals zero. Any number multiplied by infinity
( ∞ ) equals infinity. Any number divided by zero is mathematically undefined.
Any number divided by infinity is mathematically undefined.
Large or small numbers can be expressed in a more compact way using indices.
5
How Does Scientific Examples: 316000 becomes 3.16 × 10
Notation Work?
–3
0.00708 becomes 7.08 ×10
n
A × 10
The value of the integer n is the number of places that the decimal point must be
moved to place it immediately to the right of the first nonzero digit. If the decimal
point has to be moved to its left then n is a positive integer; if to its right, n is a
negative integer.
A shorthand notation (AEn) may be used, especially in scientific papers. This may
n
be interpreted as A × 10 , as in the following example:
4
2.28E4 = 2.28 ×10 = 22800
Number of
Significant Significant
Value Figures Figures
(a) 572 2,5,7 3
(b) 37.10 0,1,3,7 4
(c) 10.65 x 104 0,1,6,5 4
(d) 0.693 3,6,9 3
(e) 0.0025 2,5 2
How do I determine the Examples (c) to (e) illustrate the exceptions to the above general rule. The value 10
number of significant raised to any power, as in example (c), does not contain any significant figures;
figures? hence in the example the four significant figures arise only from the 10.65. If one
or more zeros immediately follow a decimal point, as in example (e), these zeros
simply serve to locate the decimal point and are therefore not significant figures.
The use of a single zero preceding the decimal point, as in examples (d) and (e), is
a commendable practice which also serves to locate the decimal point; this zero is
therefore not a significant figure.
What do significant fig Significant figures are used to indicate the precision of a value. For instance, a
ures mean? value recorded to three significant figures (e.g., 0.0602) implies that one can reli
ably predict the value to 1 part in 999. This means that values of 0.0601, 0.0602,
and 0.0603 are measurably different. If these three values cannot be distinguished,
they should all be recorded to only two significant figures (0.060), a precision of 1
part in 99.
After performing calculations, always “round off” your result to the number of sig
nificant figures that fairly represent its precision. Stating the result to more signifi
cant figures than you can justify is misleading, at the very least!
(a) Multiplication
A n n+m
=  × B
n m n+m n m
A ×A = A A ×B
B
(b) Division
n n n n–m
A
 = A
n–m A
 = A × B
m m B
A B
n m nm
(A ) = A
–n 1 –n
A = n As n tends to infinity ( n → ∞ ) then A → 0 .
A
1

n n
A = A
0
A = 1
2.2.5 LOGARITHMS
What is a logarithm? Some bodily processes, such as the glomerular filtration of drugs by the kidney,
are logarithmic in nature. Logarithms are simply a way of succinctly expressing a
number in scientific notation.
n
A = 10 then log ( A ) = n
where ‘log’ signifies a logarithm to the base 10, and n is the value of the logarithm
of (A).
5
Example: 713000 becomes 7.13 × 10 ,
∞
1 Where x is an inte
e = 2.7182818 ... Strictly speaking, e = 1 + ∑ x!
x=1
ger ranging from 1 to infinity ( ∞ ) ,
n
In general terms, if a number (A) is given by A = e , then by definition,
ln ( A ) = n
Where, ‘ln’ signifies the natural logarithm to the base e , and n is the value of the
natural logarithm of A .
log ( A ) = 0.4343 × ln ( A )
Because logarithms are, in reality, indices of either 10 or e , their use and manipu
lation follow the rules of indices (See Section 2.2.4).
(a) Multiplication:
n m n m n+m
To multiply N × M , where N = e and M = e ; NM = e × e = e .
By definition, ln ( NM ) = n + m ; but
n = ln ( N ) and m = ln ( M ) , hence ln ( NM ) = ln ( N ) + ln ( M )
Thus, to multiply two numbers (N and M) we take the natural logarithms of each,
add them together, and then take the antilogarithm (the exponent, in this case) of
the sum.
(b) Division
ln  = ln ( N ) – ln ( M )
N
M
m
ln ( N ) = m × ln ( N )
) = – m × ln ( N ) = m × ln 
–m 1
ln ( N
N
–m
As m tends to infinity ( m → ∞ ) , then ln ( N ) → –∞
1

m

1
ln ( m N ) = ln N =  × ln ( N )
m
ln ( 1 ) = log ( 1 ) = 0
–3
7.13 ×10 , or
0.85 –3
10 × 10 , or
– 2.15
10 .
Hence, log ( 0.00713 ) = – 2.15 , which is the result generated by most calculators.
The 3 prior to the decimal point is known as the characteristic of the logarithm; it
can be negative (as in this case) or positive, but is never found in logarithmic
tables. The .85 following the decimal point is known as the mantissa of the loga
rithm; it is always positive, and is found in logarithmic tables.
In fact 3 is a symbolic way of writing minus 3 (3) for the characteristic. In every
case the algebraic sum of the characteristic and the mantissa gives the correct
value for the logarithm.
The reason for this symbolism is that only positive mantissa can be read from anti
logarithmic tables, and hence a positive mantissa must be the end result of any log
arithmic manipulations. Note that while there are negative logarithms (when N <
1), they do not indicate that number itself is negative; the sign of a number (e.g., 
N) is determined only by inspection following the taking of antilogarithms.
Note that in both examples the value of the characteristic is the integer power to
which 10 is raised when the number is written in scientific notation.
How do I multiply using (c) Multiply 62.54 by 0.00329
logarithms?
log (62.54) = 1.7972
0.6866=1.3134
(d) We wish to find antilog (1.3134) Look up the antilog for the 0.3134 (man
tissa) in a table: it is 2058.
–1
Antilog (1.3134) = 2.058 ×10
2.2.9 DIMENSIONS
What is a unit? There are three fundamental dimensions which are used in various combinations to
express the properties of matter. Each of these dimensions has been assigned a def
inite basic unit, which acts as a reference standard.
Dimensional
Dimension Symbol Unit Unit Symbol
Length L meter m
Mass M gram g
Time T second sec
How are units made big In the metric system, which emerged from the French Revolution around 1799,
ger and smaller? there are various prefixes which precede the basic units and any derived units. The
prefixes indicate the factor by which the unit is multiplied. When the index of the
factor is positive the prefixes are Greek and have hard, consonant sounds. In con
trast, when the index is negative, the prefixes are Latin and have soft, liquid
sounds. (see Table 23).
How big is big? Examples: An average adult male patient is assumed to have a mass of 70 kilo
grams (70 kg). An average adult male patient is assumed to have a height of 180
centimeters (180 cm). A newly minted nickel has a mass of 5.000 g. Doses of
drugs are in the mg (103 g) range (occasionally g) never Kg (103 g) or larger. Stu
dents have told me that the dose that they have calculated for their patient is 108 g
(converting to common system  ~ 100 tons). I doubt it. Get familiar with this sys
tem. Note that the plural of Kg or cm is Kg or cm; do not add an “s”. In pharmacy
there are two derived units which are commonly used, even though they are
related to basic units. The Liter (L) is the volume measurement and is a cube 10
cm on a side (1L = (10cm)3 = 1000 cm3 ) while the concentration measurement
and has the units of Mass per Volume.
Why should I use units? Whenever the magnitude of a measured property is stated, it is imperative to state
the units of the measurement. Numbers are useless by themselves.
Example: The procainamide concentration range is 48 µ g/ml; stating the range
without units may lead to a potentially lethal error in which procainamide is
administered in a sufficient dose to attain a range of 48 mg/ml, which is 1000
times too large and would give rise to cardiac arrest.
mega M 6 nano n –9
10 10
kilo k 3 pico p –12
10 10
hecto h 2 femto f –15
10 10
deca da 1 atto a –18
10 10
TABLE 24
Dimensional Unit
Dimension Symbol Unit Symbol
Volume V liter l
Concentration C grams/liter g/l
Consider the following equation which defines the average concentration of a drug
FD
in blood after many repeated doses, ( C b )∞ = 
VKτ
Where:
• F is the fraction of the administered dose ultimately absorbed (Dimensions: none),
• D is the mass of the repeated dose (Dimension: M),
• V is the apparent volume of distribution of the drug (Dimension: V = L )
–1
• K is the apparent firstorder rate constant for drug elimination (Dimension: T ),
Writing the dimensions relating to the properties of the righthand side of the equa
tion gives:
M  M
 = 
–1 V
V⋅T ⋅T
M
Thus ( C b )∞ has the dimensions of  , which are correctly those of concentration.
V
2.3 Calculus
What is Calculus? Calculus concerns either the rate of change of one property with another (differen
tial calculus), such as the rate of change of drug concentrations in the blood with
time since administration, or the summation of infinitesimally small changes (inte
gral calculus), such as the summation of changing drug concentrations to yield an
assessment of bioavailability. In this discussion a few general concepts will be pro
vided, and it is suggested an understanding of graphical methods should precede
this discussion.
3
Consider the following relationship: y = x
As can be seen from the graph (Figure 21), a nonlinear plot is produced, as
expected.
70
60
50
40
30
20
10
0
1 2 3 4
(Question: How could the above data be modified to give a linear graph?)
y2 – y1 ∆y
 = 
x2 – x1 ∆x
But, as can be seen (Figure 1), the slope is not constant over the range of the graph;
it increases as x increases. The slope is a measure of the change in y for a given
change in x. It may then be stated that:
“the rate of change of y with respect to x varies with the value of x.”
3
We need to find the value of the slope of the line y = x when x = 2 (See Figure
1). Hence, we may choose incremental changes in x which are located around
x ≈ 2.
∆y

x1 x2 ∆x y1 y2 ∆y ∆x
0 4 4 0 64 64 16.000
1 3 2 1 27 26 13.000
1.5 2.5 1.0 3.375 15.625 12.250 12.250
1.8 2.2 0.4 5.832 10.648 4.816 12.040
1.9 2.1 0.2 6.859 9.261 2.042 12.010
1.95 2.05 0.1 7.415 8.615 1.200 12.003
As may be seen, the value of the slope ∆y tends towards a value of 12.000 as the
∆x
magnitude of the incremental change in x becomes smaller around the chosen
value of 2.0. Were the chosen incremental changes in x infinitesimally small, the
true value of the slope (i.e., 12.000) would have appeared in the final column of
the above table.
Calculus deals with infinitesimally small changes. When the value of ∆x is infini
tesimally small it is written dx and is known as the derivative of x. Hence,
dy
 = f ( x )
dx
Where dy/dx is the derivative of y with respect to x and f ( x ) indicates some func
tion of x.
3
y = x
Hence,
3
y + dy = ( x + dx ) (EQ 213)
Multiplying out:
3 2 2 3
y + dy = x + 3x ( dx ) + 3x ( dx ) + ( dx ) (EQ 214)
(c) The change in y is obtained by subtraction of the original expression from the
last expression. (i.e., Eq. 2  Eq. 1)
2 2 3
dy = 3x ( dx ) + 3x ( dx ) + ( dx ) (EQ 215)
dy
 = 3x 2 + 3x ( dx ) + ( dx )2
dx
dy
 = 3x 2 (EQ 216)
dx
2
Hence the derivative of y with respect to x at any value of x is given by 3x .
(d) In section 2.3.4 we saw how the true value of the slope (i.e., dy/dx) would be
12.0 when x = 2 . This is confirmed by substituting in Equation 116.
dy
 = 3x 2 = 3 ( 2 2 ) = 12
dx
Although the rate of change of one value with respect to another may be calculated
as above, there is a general rule for obtaining a derivative.
n
If y = Ax
then
dy
 = nAx n – 1
dx
The Rules of Indices may need to be used to obtain expressions in the form
n
y = Ax
(e.g., if y = 5 x)
0
(a) If y = Ax ,
dy
Hence,  = 0
dx
dy 1
then  =  .
dx x
Ax
(c) Accept that if y = Be where B and A are constants, and e is the natural
dy Ax
base then  = ABe
dx
This derivative will be useful in pharmacokinetics for finding the maximum and
minimum concentrations of drug in the blood following oral dosing.
n
(a) If y = Ax , then
dy n–1
 = nAx
dx
n
(b) If y = Ax + A ,
dy n–1 n–1
then  = nAx + 0 = nAx
dx
Both of the original expressions, although different, have the same derivative. This
fact is recognized later when dealing with integral calculus.
Thus,
dy
 = Ax n , or
dx
n
dy = Ax ⋅ dx
To integrate,
∫ dy ∫ Ax dx = A ∫ x dx
n n
y = =
n+1
Ax
A ∫ x dx =  + A
n
n+1
Where A is the constant of integration However, there is one exception  the rule
is not applicable if n = – 1
dy 2
Example: If  = 3x (See section 2.3.5),
dx
2+1
3x
then y =  + A , and
2+1
3
y = x +A
There has to be a constant in the final integrated expression because of the seeming
3 3
anomaly referred to in section 2.3.8. As mentioned, both y = x and y = x + A
dy 2
will give, on differentiation,  = 3x .
dx
So whether or not a constant is present and, if so, what is its value, can only be
decided by other knowledge of the expression. Normally this other knowledge
takes the form of knowing the value of y when x = 0 .
In the case of our graphical example we know that when x = 0 , then y = 0 . The
integrated expression for this particular case is:
3
y = x + A , therefore
3
0 = 0 + A , thus A = 0
In some examples, such as firstorder reaction rate kinetics, the value of A is not
zero.
It occurs when n = – 1
1
y = A ∫ x dx = A ∫  dx
–1
x
Upon integration, y = A ⋅ ln ( x ) + A
dy
 = Be Ax
dx
then,
Ax
Be
y =  + A
A
This integral will be useful for equations which define the bioavailability of a drug
product.
(a) Consider,
2
c = 3t ( t – 2 ) + 5
3 2
c = 3t – 6t + 5
dc
 = 9t 2 – 12t
dt
dc 2
(b) Consider,  = 3t ( t – 4 ) = 9t – 12t
dt
Then rearranging,
2
dc = 9t ⋅ dt – 12 ⋅ dt
∫ dc
3 2
c = = 3t + A – 6t + B
3 2
c = 3t = 6t + D
where D = A + B
2 2
c = 3t + 6t + 5
– dC p
 = KC p
dt
Rearranging,
1
– K ⋅ dt =  ⋅ dC p
Cp
1
– Kt = – K ∫ dt = ∫ 
 ⋅ dC p
Cp
– Kt = ln ( C p ) + A
Substituting, 0 = ln ( C p )0 + A
Or,
A = – ln ( C p )0
Hence
– Kt = ln ( C p ) – ln ( C p ) 0
or,
ln ( C p ) = ln ( C p ) 0 – Kt
or,
– Kt
Cp = ( C p )0 ⋅ e
2.4 Graphs
Why do we graph? We would like to organize the chaotic world around us so that we can predict (see
into the future) and retrodict (see into the past) what will happen or has happened.
Our recorded observations are collectively known as data. We make a theory
about what we think is happening and that theory is expressed in an equation. That
determines our paradigm of how we see the world. This paradigm is expressed as
a graph. The language of science is mathematics and graphs are its pictures.
TABLE 26
English Science
Observations Data
Theory Equations
Paradigms (pictures) Graphs
What is a graph? A graph is simply a visual representation showing how one variable changes with
alteration of another variable. The simplest way to represent this relationship
between variables is to draw a picture. This pictorializing also is the simplest way
for the human mind to correlate, remember, interpolate and extrapolate perfect
data. An additional advantage is it enables the experimenter to average out small
deviations in experimental results (nonperfect, real data) from perfect data. For
example:
Perfect Real
3 5 4.6
2 3 3.4
1 1 0.6
0 +1 +0.8
+1 +3 +3.4
+2 +5 +4.4
2
4
6
3 2 1 0 1 2
Simply looking at the columns x and y (real) it might be difficult to see the rela
tionship between the two variables. But looking at the graph, the relationship
becomes apparent. Thus, the graph is a great aid to clear thinking. For every graph
relating variables, there is an equation and, conversely for every equation there is a
graph. The plotting of graphs is comparatively simple. The reverse process of find
ing an equation to fit a graph drawn from experimental data is more difficult,
except in the case of straight lines.
The ‘y’ variable, known as the dependent variable, is depicted on the vertical axis
(ordinate); and the ‘x’ variable, known as the independent variable, is depicted on
the horizontal axis (abscissa). It is said that ‘y’ varies with respect to ‘x’ and not
‘x’ varies with ‘y’.
A decision as to which of the two related variables is dependent can only be made
be considering the nature of the experiment. To illustrate, the plasma concentration
of a drug given by IV bolus depends on time. Time does not depend on the plasma
concentration. Consequently, plasma concentration would be depicted on the ‘y’
axis and time on the ‘x’ axis.
Any point in the defined space of the graph has a unique set of coordinates: 1) the
‘x’ value which is the distance along the ‘x’ axis out from the ‘y’ axis and always
comes first; and 2) the ‘y’ value which is the distance, along the ‘y’ axis up or
down from the ‘x’ axis, and always comes second. Several points are shown in
Figure 2. For example, (0,1) is on the line and (1,0) is not.
The intersection of x and y axis is the origin with the coordinates of (0,0). In two
dimensional spaces, the graph is divided into 4 quadrants from (0,0), numbered
with Roman numerals from I through IV. It should be readily apparent that the
coordinates for all points within a particular quadrant are of the same sign type i.e.,
y = mx + b
Where:
• y = dependent variable
• x = independent variable
• m = slope of the straight line = ∆
y
∆x
• b = the y intercept (when x = 0)
• or if the equation can be “linearized”, e.g.,
mx′
y′ = b′e is not linear. However. ln y′ = ln b′ + mx′
– Kt
C p = C p0 e
y = b + mx
The graphs that yield a straight line are the ones with the ordinate being ln C p0 ,
and the abscissa being t .
• C p versus t
• C p versus ln t
• ln C p versus ln t
The appropriate use of a natural logarithm in this case serves to produce linearity.
However, the use of logarithms does not automatically straighten a curved line in
all examples. Some relationships between two variables can never be resolved into
( n – m) (n – m + 1) x
a single straight line, e.g., y = k 0 + k 1 x + k2 x + … + ( k n )x
where n ≥ 2 ;n = m + 1 or
K a FD Kt –K t
C p =  ⋅ ( e – e a )
V ( Ka – K )
(It is possible to resolve this equation into the summation of two linear graphs
which will be shown subsequently.)
µg
C p 
t (min) mL ln C p
12 3.75 1.322
40 2.80 1.030
65 2.12 0.751
90 1.55 0.438
125 1.23 0.207
173 0.72 0.329
The differences in both the yvalues and the xvalues may be measured graphically
to obtain the value of the slope, m. Then knowing the value of m, the value of K
may be found.
101
g/mL)
u
Caffeine Concentration (
100
101
0 50 100 150 200
Time (min)
y = m⋅x+b
• y is the dependent variable
• x is the independent variable
• m is the slope of the line
• b is the intercept of the line
The equation for the slope of the line using linear regression is:
( Σ ( x ) ⋅ Σ ( y ) ) – ( n ⋅ Σ ( x ⋅ y ) )
m = 
2 2
[ Σ ( x ) ] – ( n ⋅ Σ( x ) )
2
X Y X X⋅Y
12 1.322 144 15.864
40 1.030 1600 41.2
65 0.751 4225 48.815
90 0.438 8100 39.42
125 0.207 15625 25.875
173 0.329 29929 56.917
ΣX = 505 ΣY = 3.239 2
ΣX = 59623 ΣXY = 114.257
2
( ΣX ) = 255025
Σx Σy
x =  = 4.167 y =  = 0.5398
n n
Using the data from table 210 in the equation for the slope of the line
( 505 ⋅ 3.239 ) – ( 6 ⋅ 114.257 ) ·
m =  = – 0.01014
255025 – ( 6 ⋅ 59623 )
It is important to realize that you may not simply take any two data pairs in the
data set to get the slope. In the above data, if we simply took two successive data
pairs from the six data pairs in the set, this would result in five different slopes
( ∆x ⁄ ∆y ) ranging from 0.0066 to 0.0125 as shown in table 211. Clearly, this is
unacceptable. Even to guess, you must plot the data, eyeball the best fit line by
placing your clear straight edge through the points so that it is as close to the data
as possible and look to make sure that there are an equal number of points above
the line as below. Then take the data pairs from the line, not the data set.
∆y

Time (x) ln Conc. (y) ∆x ∆y ∆x
12 1.322 28 0.292 0.0104
40 1.030 25 0.28 0.0112
65 0.751 25 0.312 0.0125
90 0.438 35 0.231 0.0066
125 0.207 48 0.536 0.0112
173 0.329
(a) Not knowing the value of m; The graph may be extrapolated, or calcu
lations performed, at the situation where t = 0 . In this case b = ln C p0 .
• Secondly, the graph may be extrapolated or calculations performed, at the situation where
t = 0 . In this case, b = ln C p
If the size of the graph does not permit physical extrapolation to the desired value,
the required result may be obtained by calculation. The values of m and b must be
found as shown above. Then: y' = mx' + b , where x' is the selected value of x,
and y' is the new calculated value for y.
The more closely the experimental points fit the best line, and the higher the num
ber of points, the more significant is the relationship between y and x. As you may
expect, statistical parameters may be calculated to indicate the significance.
What good is a straight By using all the experimental data points, calculations may be made to find the
line? optimum values of the slope m, and the intercept, b. From these values the corre
lation coefficient (r).and the tvalue may be obtained to indicate the significance.
Exact details of the theory are available in any statistical book, and the calculations
may most easily be performed by a computer using The Scientist or PKAnalyst in
this course.
The advantage of computer calculation is that it gives the one and only best fit to
the points, and eliminates subjective fitting of a line to the data.
In mathematical studies, the scales of the x and y are almost always equal but very
often in plotting chemical relations the two factors are so very different in magni
tude that this can not be done. Consequently, it must be borne in mind that the rela
tionship between the variables is given by the scales assigned to the abscissa and
ordinate rather than the number of squares counted out from the origin.
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
0 2 4 6 8 10
10
8
6
4
2
0
0 2 4 6 8 10
For example (shown in Figure 25), these two parabolic curves represent the same
equation the only difference is the scales are different along the y axis.
Frequently it is not convenient to have the origin of the graph coincide with the
lower left hand corner of the coordinate paper. Full utilization of the paper with
suitable intervals is the one criteria for deciding how to plot a curve from the
experimental data. For example, the curve below (Figure 26) is poorly planned,
where the following (Figure 27) is a better way of representing the gas law
PV = nRT
50
40
30
20
10
0
0 4 8 12 16 20
25
20
15
10
5
0
1 2 3 4 5 6 7 8 9 10
P ( )
2
Previously variables were raised to constant powers; as y = x . In this section
x
constants are raised to variable powers; as y = 2 . Equations of this kind in which
the exponent is a variable are called (naturally) exponential equations. The most
x
important exponential equation is where e is plotted against x .
ng
Concentration 
Time (hours) ml
0.25 1900
.75 1500
1.5 1300
4 900
6 600
8 390
These can be illustrated in three different ways (Figures 28, 29, 210),
• Concentration vs. time directly
• Log concentration vs. time directly
• Log concentration vs. time with concentration plotted directly on to log scale of ordinate.
2000
1800
1600
1400
1200
1000
800
600
400
200
0 1 2 3 4 5 6 7 8
3.200
Log Concentration  Time Curve
3.100
3.000
2.900
2.800
2.700
2.600
2.500
2.400
2.300
0 1 2 3 4 5 6 7 8
10000
1000
100
0 1 2 3 4 5 6 7 8
Graphing is much easier because the graph paper itself takes the place of a loga
rithmic table, as shown in Figure 110.
Only the mantissa is designated by the graph paper. Scaling of the ordinate for the
characteristic is necessary. The general equation y = Be ax can be expressed as a
straight line by basic laws of indices.
ax
ln y = ln B + ln ( e ) → ln y = ln B + ax or ln y = ax + ln B
One axis is printed with logarithmic spacing, and the other with arithmetic spac
ing. It is used when a graph must be plotted as in the example (Figure 14)
y = log [ C p ] and x = t .
b) obtaining the value of the slope is difficult. In this instance the slope is given by:
y2 – y1 ln [ C p ] 2 – ln [ C p ] 1
m = 
 = 
x2 – x1 t2 – t1
Hence, before calculating the value of m, the two selected values of [ Cp ] 1 and [ Cp ] 2
must be converted, using a calculator, to ln [ Cp ] 1 and ln [ C p ] 2 in order to satisfy the
equation. The same problem may arise in obtaining the intercept value, b.
The two problems may be avoided by plotting the same data on ordinary paper, in
which case the vertical axis is labelled “log plasma concentration”. However, in
this instance the ordinary values of [ C p ] must be converted to ln [ Cp ] prior to plot
ting. It is the ln [ Cp ] values which are then plotted.
The calculation of the slope is direct in this case, as the values of y 1 and y 2 may be
read from the graph. Hence, one must consider the relative merits of semilogarith
mic and ordinary paper before deciding which to use when a log plot is called for.
In the case of semilog graphs the slope may be found in a slightly different manner,
i.e., taking any convenient point on the line ( y 1 ) we usually take the as the second
point, ( y 2) one half of ( y 1 ) . Thus,
y1
ln  ln 
 1
ln y 1 – ln ( ( 1 ⁄ 2 )y 1 ) ( 1 ⁄ 2 )y 1 1⁄2 ln 2  0.693
m = 
 = 
 =  =  = 
t 1 – t2 t 1 – t2 t 1 – t2 t1 – t2 –t1 ⁄ 2
(in which case, t 2 – t 1 is called the halflife t½ ). Since t1 < t2 , then t1 – t2 = –t1 ⁄ 2
0.693 0.693
because m =  = – k
–t1 ⁄ 2
and k =  .
t1 ⁄ 2
a
Functions of the type y = Bx give straight lines when plotted with logarithms
along both axis.
The utility of these procedures requires proper graphing techniques. The picture
that we draw can cause formation of conceptualizations and correlations of the
data that are inconsistent with the real world based simply on a bad picture. Conse
quently the picture must be properly executed.
The most common error is improper axes labelling. On a single axis of rectilinear
coordinate paper (standard graph paper), a similar distance between two points
corresponds to a similar difference between 2 numbers. Thus,
40
30
20
10
0
0 5 10 15 20 25 30
40
30
20
10
1
0
0 2 5 10 20 30
Obviously, the distance (Time) on the graph 12 between 0 and 2 hours should not
be the same as the distance between 10 and 20 hours. It is, and therefore Figure 2
12 is wrong.
Similarly, the use of similar paper may result in some confusion. With logarithms
the mantissa for any string of numbers, differing only by decimal point placement,
is the same. What differentiates one number from another, in this case, is the char
acteristic. Thus,
Logarithmic Plot
103
234
102
23.4
101
Y axis (units)
2.34
100
0.234
101
1.0 1.5 2.0 2.5 3.0 3.5 4.0
X axis (units)
Thus, we see, in Figure 213, the cycle on the semilog paper to relate to orders of
magnitude (e.g., 1, 10, 100, 1000, etc.) and consequently the characteristic of the
exponent.
The third common problem is labelling the log axis as log “y”. This is improper. It
is obvious from the spacing on the paper that this function is logarithmic, and thus
the axis is simply labelled “y”.
There are almost as many different errors as there are students and it is impossible
to list them all. These few examples should alert you to possible problems.
0 1 2 3 4 5
Find the slope by taking any two values on the Y axis such that the smaller value is
one half of the larger. The time that it takes to go from the larger to the smaller is
the halflife. Dividing 0.693 by the halflife yields the rate constant.
0 2 4 6 8 10 12
FIGURE 216. Curved line which goes up and then straight down on semilog paper.
0 5 10 15 20 25
Find the terminal slope by taking any two values on the Y axis such that the
smaller value is one half of the larger. The time that it takes to go from the larger to
the smaller is the halflife. Dividing 0.693 by the halflife yields the rate constant.
Plot type one is reasonably easily evaluated. There are 2 important things that can
be obtained: Slope and Intercept. However, the slope and intercept have different
meanings dependent on the data set type plotted. The slope is the summation of all
the ways that the drug is eliminated, K.
Plot type two is not usually evaluated in its present form as only the plateau value
can be obtained easily. But again it has different meanings dependent on the data
plotted.
Usually urine data of this type (parent compound  IV bolus) is replotted and eval
uated as plot 1 (above). Infusion data can be replotted using the same techniques,
but usually is not.
Plot type 3 must be stripped of the second rate constant from the early time points,
thus:
There are 3 things that can be obtained from the plot: the terminal slope (the
smaller rate constant), the slope of the stripped line (the larger rate constant) and
the intercept. The rate constants obtained from a caternary chain (drug moving
from one box to another in sequence in compartmental modeling) are the summa
tion of all the ways that the drug is eliminated from the previous compartment and
all the ways the drug is eliminated from the compartment under consideration. See
LaPlace Transforms for further discussion.
Again, dependent on the data set type being plotted they will have different values.
Data
Type Y axis X axis S1 S2 Intercept
IV Bolus Metabolite conc. Time K small Klarge km ⋅ X 0
Parent 
( K l arg e – K smal l ) ⋅ V dm
IV Bolus dXmu
 excretion
Time K small Klarge k mu ⋅ k m ⋅ X 0
Parent dt (mid) 

K l arg e – K smal l
rate of metabolite
into urine
Oral Drug conc. Time K small Klarge k a ⋅ fX 0


( K l arg e – K smal l ) ⋅ V d
Models are simply mathematical constructs (pictures) which seem to explain the
relationship of concentration with time (equations) when drugs are given to a per
son (or an animal). These models are useful to predict the time course of drugs in
the body and to allow us to maintain drug concentration in the therapeutic range
(optimize therapy). The simplest model is the one used to explain the observations.
We model to summarize data, to predict what would happen to the patient given a
dosage regimen, to conceptualize what might be happening in disease states and to
compare products. In every case, the observations come first and the explanation
next. Given that a data set fits a model, the model can be used to answer several
different types of questions about the drug and how the patient handles the drug
(its disposition), for example: if the drug were to be given by an oral dose, how
much is absorbed and how fast? Are there things which might affect the absorp
tion, such as food or excipients in the dosage form itself. What would happen if the
drug were to be given on a multiple dose regimen? What if we increased the dose?
etc.
Again, the rate constant, k , tells the magnitude of the rate, k⋅X.
k12 k23
X1 X2 X3
The building blocks are k 12 ⋅ X1 and k 23 ⋅ X2 . Every arrow that touches the compart
ment of interest becomes part of the differential equation. If the arrow goes to the
box, it’s positive; if it goes away from the box, it’s negative.
To find dX1 ⁄ dt (the rate of change of X 1 with time), we simply add up all of the
rates which affect X1 (all of the arrows that touch X1 )
dX 1
 = – k 12 ⋅ X 1
dt
and thus:
dX 2
 = k 12 ⋅ X 1 – k 23 ⋅ X2
dt
dX 3
 = k 23 ⋅ X 2
dt
(Note: the first subscript of the rate constant and the subscript of the box from
which it originates are the same.)
You should be able to integrate any differential equation developed from any
model (within reason) that we can conceptualize.
(Note: Each subsequent variable is dependent on the ones that precedes it. In fact,
the solutions to the preceding variables are substituted into the differential to
remove all but one of the time dependent functions  the one that we are currently
attempting to solve.)
A simplified picture (mathematical construct) of the way the body handles drug is
one where the body can be conceived to be a rapidly stirred beaker of water (a sin
gle compartment). We put the drug in and the rate at which the drug goes away is
proportional to how much is present (first order). Thus the assumptions are:
• Body homogeneous (one compartment)
• Distribution instantaneous
• Concentration proportional to dose (linear)
• Rate of elimination proportional to how much is there. (First order)
It is important to note that we know some of these assumptions are not true. It is of
little consequence, as the data acts as if these were true for many drugs. The visual
image which is useful is one of a single box and a single arrow going out of the
box depicting one compartment with linear kinetics. The dose is placed in the box
and is eliminated by first order processes. In many cases, more complicated mod
els (more boxes) are necessary to mathematically mimic the observed plasma ver
sus time profile when one or more of these assumptions are not accurate. For
example, the two compartment (or multicompartment) model results when the
body is assumed to not be homogeneous and distribution is not instantaneous.
Basically, the LaPlace Transform is used to solve (integrate) ordinary, linear differ
ential equations. In pharmacokinetics such equations are zero and firstorder rate
equations in which the independent variable is time. For instance, if a differential
equation describing the rate of change of the mass of drug in the body with time is
integrated, the final equation will describe the mass of drug actually in the body at
any time.
2.6.2 SYMBOLISM
“a bar will be placed over the dependent variable which is being transformed”.
Example:
If X is the mass of unchanged drug in the body at any time, then X is the LaPlace
Transform of this mass.
When drugs enter the body, they will encounter many different fates. It is impor
tant to set up the possible fates of the drug by creating a well thought out flow
chart or scheme in order to follow all the events that are occurring in the body as
described by the pharmacokinetic description of the drug. For example, a drug
may be excreted unchanged or may undergo hepatic metabolism to yield active or
inactive metabolites. All of these components are part of pharmacokinetics, which
by definition, includes ADME (the Absorption, Distribution, Metabolism and
Excretion of drugs), and must be considered. This flow chart becomes the back
bone or the framework upon which to build the equations which describe the phar
macokinetics of the drug. The differential equations result as a direct consequence
of the flow chart. Using Laplace transforms, the integration of these differential
equations are simplified and provide the pharmacokineticist to (easily?) keep track
of all of the variables in the equation. If the drug scheme or flow chart is set up
incorrectly, this would have a definite negative impact or the expected equations
(as well as the answers and your grade). Below are two examples of how to con
struct a flow chart. Note that not all drugs follow the same flow chart and it is
quite possible that you will need only to use a portion of these examples when con
struction your own.
Dose
Parent Compound kf ku
Xf X Xu
km
kmf kmu
Metabolite Xmf Xm Xmu
Using the pharmacokinetic symbolism from chapter one, the compartments are
named and placed: metabolites below (or above the plane of the parent com
pound): compounds going into the urine, to the right; and compounds going into
the feces, to the left of the compounds in the body. The rate constants connecting
the compartments also follow the symbolism from chapter one. In the above flow
chart, K, the summation of all the ways that X is removed from the body, is ku + kf
+ km while K1, the summation of all the ways that Xm is removed from the body,
is kmu +kmf.
Only those compartments are used which correspond to the drug’s pharmacoki
netic description, thus when a drug is given by IV bolus and is 100% metabolized
with the metabolite being 100% excreted into the urine the model would look like
this:
Dose
km
kmu
Xm Xmu
Thus in this flow chart, K, the summation of all the ways that X is removed from
the body, is km while K1, the summation of all the ways that Xm is removed from
the body, is kmu.
Drugs sometimes are metabolized to two (or more) different metabolites. In the
first case, the drug is metabolized by two separate pathways resulting in this flow
chart:
Dose
km1
kf X ku Xu
Xf
km2
In this flow chart, K, the summation of all the ways that X is removed from the
body, is ku + kf + km1 + km2 while K1, the summation of all the ways that Xm1 is
removed from the body, is kmu1 +kmf1 and K3, the summation of all the ways
that Xm2 is removed from the body, is kmu2 + kmf2.
While in a second case, the drug is metabolized and the metabolite is further
metabolized resulting in this flow chart:
Dose
kf X ku Xu
Xf
km1
kmf1 kmu1
Xmf1 Xm1 Xmu1
km2
In this flow chart, K, the summation of all the ways that X is removed from the
body, is ku + kf + km1 while K1, the summation of all the ways that Xm1 is
removed from the body, is kmu1 +kmf1+ km2 and K3, the summation of all the
ways that Xm2 is removed from the body is kmf2 + kmu2.
Both of these flow charts result in very different end equations, so it is imperative
that the flow charts accurately reflect the fate of the drug.
(Scheme I)
ku
X Xu
X u is the cumulative mass of unchanged drug in the urine up to any time, and k u is
the apparent firstorder rate constant for excretion of unchanged drug.
a. The building block is the arrow and what it touches. This first box (compart
ment) of interest is [ X ] . The arrow ( k u) is going out, therefore, the rate is going out
and is negative, thus
dX
 = –k u X (EQ 217)
dt
sX – X0 = – k u X (EQ 218)
Note that because the independent variable (time) did not appear on the righthand
side of equation 217, neither did the LaPlace Operator, s, appear there in equation
218. All that was necessary was to transform the dependent variable ( X ) into X .
Hence, the table was only required for transforming the lefthand side of equation
218.
sX + k u X = X0
X ( s + k u ) = X0
X0
X =  (EQ 219)
s + ku
A
LetX0 = A Letk u = a X =  (EQ 220)
(s + a)
Note that X is the only transformed dependent variable and is on the lefthand side
of equation 219.
–ku t
X = X0e (EQ 221)
A
Note that the righthand side of equation 221 was analogous to  in the
(s + a)
table, because X0 is a constant (the initial dose administered). The lefthand side
of equation 221 could be converted back without the table.
Look at Scheme I again. Consider how the drug goes from the body into the urine.
The next box of interest is Xu . The arrow is coming in, therefore the rate is com
ing in and is positive. thus,
dXu
 = k u X (EQ 222)
dt
sX u – ( X u ) 0 = k u X (EQ 223)
But, at zero time, the cumulative mass of unchanged drug in the urine was zero:
that is ( Xu ) 0 = 0 .
sX u = k u X (EQ 224)
ku X
Xu = 
 (EQ 225)
s
Note that there are two transformed dependent variables. One of them ( X ) can be
replaced by reference to equation 219.
ku X0
Xu = 
 (EQ 226)
s(s + ku)
A
Let ( k u X0 ) = A Let ( k u ) = a X =  (EQ 227)
s(s + a)
–k t
kuX0 ⋅ ( 1 – e u )
X u = 
ku
Where k u X 0 and k u are analogous to “A” and “a” respectively in the table. Sim
plifying,
– kut
Xu = X0 ( 1 – e ) (EQ 228)
During the intravenous infusion of a drug, its excretion may be represented by the
following pharmacokinetic scheme:
(Scheme II)
Infusion Q ku
X Xu
Where Q is the zeroorder infusion rate constant (the drug is entering the body at a
constant rate and the rate of change of the mass of drug in the body is governed by
the drug entering the body by infusion and the drug leaving the body by excretion).
The drug entering the body does so at a constant (zeroorder) rate.
dX
 = Q – k u X (EQ 229)
dt
Q
sX – X 0 =  – k u X
s
Note that because Q is a rate, and is therefore a function of the independent vari
able (time), its transformation yields the LaPlace Operator. In this case, Q was
analogous to “A” in the table. But, at zero time, the mass of unchanged drug in the
body was zero: that is, X0 = 0
Q
sX =  – k u X (EQ 230)
s
Q
X =  (EQ 231)
s ( s + ku )
A
Let ( Q = A ) Let ( k u = a ) X =  (EQ 232)
s( s + a)
2.6.8 CONCLUSIONS
The final integrations (Eqs. 24, 24, and 28) are not the ultimate goal of pharmaco
kinetics. From them come the concepts of:
1. (a) elimination halflife
1. (b) apparent volume of drug distribution
2. (c) plateau drug concentrations
These, and other concepts arising from still other equations, are clinically useful.
It is also possible to see certain patterns which begin to emerge from the derivation
of the equations. For example, for a drug given by IV bolus the equation is
monoexponential, with the exponent being K, summation of all the ways that the
drug is removed form the body. A graph of the data (Cp v T on semilog paper)
results in a straight line the slope of which is K, always. If the drug is entirely
metabolized K = km. If the drug is entirely excreted unchanged into the urine, K =
ku. If the drug is metabolized and excreted unchanged into the urine, K = km +ku.
thus K can have different meanings for different drugs, depending on how the
body removes the drug. Following the drug given by IV bolus a second example
of a pattern would be that of the data of the metabolite of the drug. From the
LaPlace, the equation for the plasma concentration of the metabolite of the drug
has in it K and K1, the summation of all the ways that the metabolite is removed
from the body, always. K1 would have different meanings depending on how the
metabolite is removed from the body.
After several years teaching, I was fortunate to have a resident rotate through our
pharmacokinetic site. She had come with a strong Pharmacokinetcs background
and during our initial meeting, she had told me that she had a copy of John Wag
ner’s new textbook on pharmacokinetcs. She was excited that, finally, there was a
compilation of all the equations used in pharmacokinetics in one place.
“There are over 500 equations in the new book and I know every one,” she said.
“I’m not sure which one goes with which situation, though.” OOPS!
Throughout this text and on each exam, each equation is derived from first princi
ples using scientific method, modeling and LaPlace Transforms in the hopes that
memorization will be minimized and thought (and consequently proper interpreta
tion) would be maximized.
m is a power constant
A A

s
At A

2
s
At
m A ( m! )

m+1
s
– at A
Ae 
s+a
m – at A
At e 

m+1
(s + a)
– at A
A(1 – e ) 
 s (s + a )
a
– at A 
At (1 – e )
 – A
 
2
a a
2 s (s + a)
– at As – B
– at B( 1 – e ) 
Ae –  s (s + a )
a
– at As – B 
A + B
  – Bt
1–e
 
a a a
2
s (s + a)
– bt – at A
A ( e – e ) 

 (s + a)(s + b)
(a – b)
– bt – at A
A
 1
– e  
1 – e  

(a – b) b –
a s( s + a )( s + b )
1 – e –bt 1 – e –at A
At 
A 

 –  –  2
s ( s + a) ( s + b)
ab ( a – b ) b2 a2
1 – at – bt As – B 
 [ ( B + Aa )e – ( B + Ab )e ] 
( a – b) (s + a)(s + b)
As – B 
1 ( 1 – e –bt ) ( 1 – e – at ) 
 – bt – at
A ( e – e ) – B  –  s( s + a )( s + b )
(a – b) b a
( 1 – e –bt ) ( 1 – e – at ) As – B
1 B B Bt 
( a – b ) b 
 A + 
  – A + 
 –  2
s ( s + a) ( s + b)
b a a ab
– ct – bt – at A
e e e 

A  +  +  (s + a)(s + b)(s + c)
(a – c)(b – c) (a – b )(c – b) (b – a )(c – a)
– ct – bt – at A
(1 – e ) (1 – e ) (1 – e ) 
A  +  +  s( s + a )( s + b )( s + c )
c( a – c )( b – c ) b( a – b)( c – b ) a( b – a )( c – a)
– ct – bt – at A
At (1 – e ) ( 1 – e )  
(1 – e )  

 – A  +  + 2 2
bc 2 2 s ( s + a) ( s + b ) ( s + c )
c ( a – c) ( b – c ) b ( a – b) ( c – b) a ( b – a )( c – a)
dX
 sX – X 0
dt
(m + 1 ) A
At 
 m
(m + 1) s
Dose
X ku Xu
sX – X0 = –kuX
sX + kuX = X o
X ( s + k u )= Xo
Xo
X = 
s + ku
A
Let ( X0 ) = A , k u = a ,X = 
(s + a)
– kut
X = Xo e
Dose
X ku Xu
dX
 = – k u X
dt
sX – X0 = –kuX
sX + kuX = X o
X ( s + k u )= Xo
Xo
X =  You only need to go this far because you
s + ku
need to know X to put it in the equation for Xu. Thus:
dX
u = k u X
dt
X o ku
sX u = 

(s + ku)
Xo ku
X u = 

s(s + ku)
A
Let ( X0 k u ) = A , k u = a , X u = 
s( s + a )
– kut
ku X o ( 1 – e )
X u = 

ku
km ⋅ Xo
X m = 

( s + k mu ) ( s + k m )
Dose Let ( k m X 0 ) = A , k m = a = K , k mu = b = K1
A
X m = 
X (s + a)(s + b )
( km ⋅ X o ) –k t –k t
 ⋅ ( e mu – e m ) or
X m = 
km ( k m – k mu )
( km ⋅ Xo )
Xm kmu Xmu  ⋅ ( e – K 1t – e –K t ) in general terms.
X m = 
( K – K1 )
Xo
X = 
s + km
A
Let ( X0 ) = A , k m = a , X = 
(s + a)
– kmt
X = Xo e
dX
m = k m X – k mu X m
dt
sX m – Xm0 = k m X – kmu X m
Xm kmu Xmu
dXm
 = k m X – k mu X m
dt
sX m – Xom = k m X – kmu X m
sX m + k mu Xm = k m X
o X
substitute previously solved X = 
s + km
km Xo
X m ( s + k mu ) = 
s + km
km X o
X m = 

( s + k mu ) ( s + k m )
– kmt – kmut
km Xo ( e –e )
X m = 

( k mu – k m )
dXmu

 = k mu Xm
dt
sX mu – Xom = k muX m
Remember at time zero,
sX mu = K1X m
Dose
( k mu ) ( kmXo )
sX mu = 
( s + K1 ) ( s + K )
ku Xu
X ( k mu ) ( k m ) ( Xo )
X mu = 

s ( s + K1 ) ( s + K )
km
k mu k m X o 1 – e – Kt 1 – e – K1t
X m u =   – 
K1 – K K K1
Xm kmu Xmu
dX
 = – k u X – k m X
dt
sX – Xo = – k u X – k m X
sX + k u X + k m X = X o
X ( s + ku + km ) = Xo
( ku + km ) = K
Xo
X = 
s+K
– Kt
X = Xo e
dXm
 = k m X – k mu Xm = k m X – K1Xm
dt
sXm – X om = k m X – K1Xm
sX m + K1Xm = k m X
km Xo
X m = 
( s + K1 ) ( s + K )
Q X ku Xu
Q –k t
X =  ( 1 – e u ) or X = Q
 ( 1 – e –Kt )
ku K
Q X ku Xu
Here K = ku
dX
 = Q – k u X
dt
Q
sX – Xo =  – k u X
s
Q
sX + k u X = 
s
Q
X ⋅ ( s + k u ) = 
s
Q
X = 
s ⋅ (s + ku )
dX
u = k u X
dt
sX u – Xo = k u X
sX u = k u X
ku Q
sX u = 

s ⋅ (s + ku)
ku Q
X u = 
2

s ⋅ ( s + ku )
k u Qt 1 – e –kut
X u =  – Qk u 

ku k2 u
– kut – Kt
(1 – e ) (1 – e )
X u = Qt – Q  or Xu = Qt – Q 
ku K
km Q 1 – e – k m t 1 – e – k mu t
X m =   –  or
( k mu – k m ) k m k mu
Q X
k m Q 1 – e –Kt 1 – e –K1t
Xm = 
  – 
( K1 – K ) K K1
km
Xm kmu Xmu
dX
 = Q – k m X
dt
Q
sX – Xo =  – k m X
s
Q
sX + k m X = 
s
Q
X ( s + k m ) = 
s
Q
X = 
s ( s + km )
– kmt
(1 – e )
X = Q 
km
dX
m = k m X – k mu X m
dt
sX m – Xo = k m X – k mu Xm
sX m = k m X – k mu Xm
km Q
X m = 
s ( s + k mu ) ( s + k m )
sX mu – Xomu = k mu X m substitute X m
k mu k m Q
Q X mu = 
2

X s ( s + k m ) ( s + k mu )
k mu k m Qt k mu k m Q ( 1 – e –kmut ) ( 1 – e – k mt )
km X mu =  –   –  or
k m ⋅ k mu k m – k m u k
2
k
2
mu m
dX
 = Q – k m X
dt
Q
sX – Xo =  – k m X
s
Q
sX + k m X = 
s
Q
X ( s + k m ) = 
s
Q
X = 
s ( s + km )
dX
m = k m X – k mu X m
dt
sX m – Xo = k m X – k mu Xm
sX m + k mu X m = k m X
km Q
X m ( s + k mu ) = 
s ( s + km )
km Q
X m = 
s ( s + k m ) ( s + k mu )
k m Q 1 – e –kmut 1 – e –kmt
X m =   – 
k m – k mu k mu k m
sX – Xo = – k u X – k m X
sX + k u X + k m X = X o
X ( s + ku + km ) = Xo
Xo
X = 
( s + k u + km )
K = ( ku + km )
k mu = K1
Xo
X = 

(s + K)
– Kt
X = Xo e
Dose
km1
X ku Xu
km2
kmu2 Xmu2
Xm2
dX
 = – k u X – k m1 X – k m2 X
dt
sX – Xo = – k u X – k m1 X – k m2 X
sX + k u X + k m1 X + km2 X = Xo
Xo
X = 

(s + K)
K = ( k u + k m1 + k m2 ) and K1 = k mu1
dXm1

 = k m1 X – K1X m1
dt
sX m1 – Xm1o = k m1 X – K1X m1
X m1o = 0
k m1 Xo
sX m1 + K1X m1 = 

(s + K)
Q
simplified yields: C = 

KVd
dX
a = Q – k a X a
dt
Q
sX a – Xao =  – k a Xa
s
X a0 = 0
sX a + k a Xa = ( Q ⁄ s )
X a ( s + ka ) = ( Q ⁄ s )
Q
X a = 
s(s + ka)
– kat
Q( 1 – e )
X a = 
ka
dX
 = k a X a – KX
dt
sX – Xo = k a Xa – KX
Xo= 0
ka Q
sX + KX = 
s ( s + ka )
ka Q
X ( s + K ) = 

s ( s + ka )
ka Q
X = 

s ( s + ka ) ( s + K )
dX
 = – KX
dt
Dose
sX – Xo = – KX
Q sX + KX = X o
X
X ( s + K )= Xo
km
Xo
X = 

s+K
Xm kmu Xmu
dX m
 = k m X – K1X m
dt
dX sX m – Xo = k m X – K1X m
 = Q – KX
dt
Q sX m + K1X m = k m X
sX – Xo =  – KX
s
km X o
X m ( s + K1 ) = 
Q s+K
sX + KX = 
s
km Xo
Q X m = 
X ( s + K ) =  ( s + K1 ) ( s + K )
s
km Xo – Kt – K 1t
Q (e – e
X m =  )
X =  ( K1 – K )
s( s + K )
Thus,
dX
m = k m X – K1X m km X o
X m =  ( e – e
dt – Kt – K 1t
) + …
( K1 – K )
sX m – Xo = k m X – K1Xm
k m Q ( 1 – e –Kt ) ( 1 – e –K1t )
sX m + K1X m = k m X   – 
K1 – K K K1
km Q
X m ( s + K1 ) = 

s( s + K )
km Q
X m = 

s ( s + K1 ) ( s + K )
ku Xu dX mu k mu k m Xo –K1t – Kt
X {e
 = k mu Xm =  –e }
dt ( K – K1 )
dX dX mu k mu k m X o
 = k u ( X o e ) + 
 { e – e }
– Kt –K1t – Kt
km u + 
dt dt ( K – K1 )
Xm kmu Xmu
dX
 = – k u X – k m X
dt
sX – Xo = – k u X – k m X
sX + k u X + k m X = X o
X ( s + ku + km ) = Xo
( ku + km ) = K
Xo
X = 
(s + K)
– Kt
X = Xo e
dX
u = k m X = k u ( Xo e –Kt )
dt
dX
m = k m X – K1X m
dt
sX m – Xo = k m X – k1Xm
km Xo
sX m + K1X m = 

(s + K)