Biopharmaceutics

Rate constants and order of reaction

One- compartment open model: intravenous bolus
administration

Dr. Kawther Khalid Ahmed

University of Baghdad College of Pharmacy
Rate constants and order of reaction
Pharmacokinetics is mathematical analysis of processes of ADME.
A→B - d A/ dt d
d C/dt = - k Cn

Zero order kinetics

The rate of a zero-order process is one that proceeds over time (t) independent from the concentration of the
drug .
−dC/dt = k0
C = C0 − k0 t
where C0 is the initial concentration of the drug at t = 0 and k0 is the zero-order rate constant.
The units for k0 are concentration per unit time (e.g, [mg/mL]/h)
Y= b ± m X

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Rate constants and order of reaction
C = C0 − k0 t
where C0 is the initial concentration of the drug at t = 0 and k0 is the zero-order rate constant.
The units for k0 are concentration per unit time (e.g, [mg/mL]/h)
Y= b ± m X

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Zero order kinetics
Example: calculate the zero-order rate constant ([ng/mL]/min) if the initial
concentration of the drug is 200 ng/mL and that at t = 30 minutes is 35 ng/mL.

C= C0 − k0 t
35 = 200 − k0 (30)
k0 = 5.5 (ng/mL)/min

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Zero order kinetics
In pharmacokinetics, the time required for the drug concentration to decrease or disappear
by one-half is known as Half-life ( t½)
t½ = (0.5 C0)/k0

Example: When does the concentration of drug equal to 100 ng/mL?

100 = 200 − 5.5 t
( 100 − 200)/5.5 = −t
t = 18.2 min

OR t½ = (0.5 C0)/k0
t½ = (0.5)(200)/5.5
= 18.2 minutes
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Zero order kinetics
Examples of zero-order processes are:

✓ Metabolism/ protein-drug binding /enzyme or carrier-mediated transport under

saturated conditions

✓ Administration of drug as a constant rate iv infusion

✓ Controlled drug delivery system such as that from SC implants or osmotic

pumps

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First-order kinetics
The rate of a first-order process is dependent upon the concentration of the drug:

-dC/dt= k1C zero order −dC/dt = k0

C=C0. e –kt
ln Ct= ln C0- kt or log Ct=log C0 – kt /2.303
At t1/2: Ct = 0.5C0
ln 0.5C0 = lnC0 - k1t½ ln 0.5+ lnC0 = lnC0 - k1t½
ln 0.5 = - k1t½ t½ = −0.693 / −k1
t½ = 0.693 / k1

Most pharmacokinetic processes (absorption, distribution and elimination) follow first-order

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• a. Does the decrease in the amount of drug A appear to be a zero-
order or a first-order process? b. What is the rate constant k? c. What
is the half-life t1/2? d. Does the amount of drug A extrapolate to
zero on the x axis? e. What is the equation for the line produced on
the graph?
a. linear conc vs t plot: zero order kinetics
b. Rate constant can be calculated from slope
= (10 – 89)/(120 – 20) = 0.78mg/min

c. t½ = (0.5 C0)/k0 C = C0 − k0 t
C0 = C + k0 t = 57 + (0.78 X 60) = 103.8 mg (note it should be higher than the
first measured conc)
t½ = (0.5 X 103.8)/0.78 = 66.5 min

d. The amount of drug, A, does extrapolate to zero on the x axis.

e. C = C0 − k0 t , C = 10.3.8 − 0.78 t
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If the half-life for decomposition of a drug is 12 hours, how long will it take for 125 mg
of the drug to decompose by 30%? Assume first-order kinetics and constant
temperature.

log Ct=log C0 – kt /2.303

kt /2.303 =(log C0 - log Ct)
t =2.303 (log C0 - log Ct) / k t½ = −0.693 / −k1 , k1= 0.693/t1/2 = 0.058 h-1
= 2.303 (log C0 - log 0.7C0) / k or Ct = 0.7 X 125 = 87.5 mg
= 2.303 (log C0 – (log 0.7 + log C0) / k
t= 6.17 hours

Please refer to practice problems in chapter 2 for more examples

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One- compartment open model:
intravenous bolus administration

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intravenous bolus administration
The simplest drug administration is when the entire drug is given in a rapid IV
injection, also known as an IV bolus.
The one-compartment open model with IV bolus administration is the simplest
pharmacokinetic model.

Assumptions
✓ The drug is administered instantly into the body
✓ The drug is instantaneously and rapidly distributed throughout the body
✓ The drug elimination occurs immediately upon entering the body.

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 intravenous bolus administration
Elimination starts
immediately

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 Elimination rate constant
o The rate of elimination for most drugs from a tissue or from the body is a first-order process, in
which the rate of elimination is dependent on the amount or concentration of drug present.

o The elimination rate constant, k, is a first-order elimination rate constant with units of time-1
(e.g., hr-1 or 1/hr)

o Generally, the parent or active drug is measured in the vascular compartment. Total removal or
elimination of the parent drug from this compartment is affected by metabolism
(biotransformation) and excretion.

o The elimination rate constant represents the sum of each of these processes: k = km + ke + ……
Where km = first-order rate process of metabolism and ke = first-order rate process of excretion.
k= overall elimination rate constant
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Rate expression dC/dt= kC

Y= mX +b
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Volume of distribution
The volume of this single compartment is termed the apparent volume of
distribution (VD).

It is not an actual volume in the body, but is a theoretical volume that the drug
uniformly distributes to immediately after being injected into the body.

The apparent volume of distribution is a proportion between the amount of drug

administered (IV bolus dose) and the plasma drug concentration, Cp0, at that time
immediately after being injected.
VD= Dose / Cp0

The apparent volume of distribution for any given drug is generally a constant.
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Example: Exactly 1 g of drug is dissolved in an unknown volume of water. Upon assay,
the concentration of this solution is 1mg/ml. What is the original volume of this solution?

The original volume of the solution may be obtained by the following proportion,

x = 1000mL or 1 L

If, in the above example, the volume of solution is known to be 1 L, and the concentration
of the solution is 1 mg/ml, then, to calculate the total amount of drug present, X mg / 1000
mL = 1 mg / mL x = 1000 mg

Therefore, the total amount of drug in the solution is 1000mg, or 1 g.

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 Calculation of Volume of Distribution
In a one-compartment model (IV administration), both D (or DB0) and Cp0 are known
DB0 [The dose of drug given by IV bolus (rapid IV injection) represents the amount of
drug in the body]
Cp0 [determined by extrapolation, Cp0 represents the instantaneous drug concentration
after drug equilibration in the body at t = 0]

Then the apparent volume of distribution, VD, may be calculated from the
following equation

The apparent VD is a volume term that can be expressed as a simple volume ( Liter L) or in
terms of percent of body weight. 18
 The apparent volume of distribution is not a true physiologic volume

Most drugs have an apparent volume of distribution smaller than, or equal to, the body
mass.

If a drug is highly bound to plasma proteins or the molecule is too large to leave the
vascular compartment, then Cp0 will be higher, resulting in a smaller apparent VD.

For example, the apparent volume of distribution of warfarin is small, approximately 0.14
L/kg, much less than the total body mass. This is because warfarin is highly bound to
plasma proteins, making it hard to leave the vascular compartment.

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 The apparent volume of distribution is not a true physiologic volume

• For some drugs, the volume of distribution may be several times the body mass.

• In this case, a very small Cp0 may occur in the body due to concentration of the drug in
peripheral tissues and organs, resulting in a large VD.

• Drugs with a large apparent VD are more concentrated in extravascular tissues and less
concentrated intravascularly.

• For example, the apparent volume of distribution of digoxin is very high, 7.0 L/kg, much
greater than the body mass. This is because digoxin binds extensively to tissues, especially
muscle tissues.

• Consequently, binding of a drug to peripheral tissues or to plasma proteins will

significantly affect the VD. 20
The apparent volume of distribution is not a true physiologic volume

• The apparent VD is a useful parameter in considering the relative amounts of drug in the vascular
and in the extravascular tissues.
• For each drug, the apparent VD is a constant.
• In certain pathologic cases, the apparent VD for the drug
may be altered if the distribution of the drug is
changed.
• For example, in edematous conditions, the
total body water and total extracellular water
increases; this is reflected in a larger apparent VD
value for a drug that is highly water soluble.
• Similarly, changes in total body weight and lean body mass
(which normally occur with age, less lean mass, and
more fat) may also affect the apparent VD. 21
• Note:

Relates plasma conc at any Relates amount of the drug in the

time to initial plasma conc body at any time to initial dose
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The IV single dose equation;
ln Cp = ln Cp0 –kt
may be modified to calculate the elimination rate constant or half-life of a drug in a
patient when two plasma samples and their time of collection are known:
Or
log Cp = log Cp0 - kt/2.3
If the first plasma sample is taken at t1 instead of zero and corresponds to plasma drug
concentration C1, then C2 is the concentration at time t2 and t is set to (t2-t1).
C2 = C1 e-k (t2-t1)
ln C2 = ln C1 – k (t2-t1)
k = (ln C1 -ln C2) / (t2-t1) ,
t1/2 = 0.693/k
t1/2 = 0.693 (t2-t1)/ ln C1 –lnC2

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A 50-kg woman was given a single IV dose of an antibacterial drug at a dose of 6 mg/kg.
Blood samples were taken at various time intervals. The concentration of the drug (Cp) was
determined in the plasma fraction of each blood sample and the following data were obtained
a. What are the values for VD, k, and t1/2 for this drug?
VD= dose/Cp0
Dose = 50 kg X 6 mg/kg = 500 mg
log Cp = log Cp0 - kt/2.303 (use any Cp, t data point)
k = - 2.303 X ∆y/ ∆ x = 0.17 hr-1
logCp0 = log(7.23) – (0.17*1)/2.303
= 0.93, you can also solve it using (lnC)
Cp0 = 8.5 ug/ml
VD= 500 mg/ 8.5 mg/L = 5.8 L
t1/2 = 0.693/k= 4 hr you plot data and determine t1/2 from the plot
Note that answer will differ slightly depending on which point you use, or if you
calculated Cp0 by extrapolation 24
b. This antibacterial agent is not effective at a plasma concentration of less than 2 mg/mL.
What is the duration of activity for this drug?
Time to reach 3 mg/ml
log Cp = log Cp0 - kt/2.303
t = 2.303 (log Cp0 – log (2))/k = 8.5 hr

c. How long would it take for 99.9% of this drug to be eliminated?

Time required for drug to reach 0.1% Cp0 , Ct = 0.001* 8.5 = 0.0085 ug/ml, calculate t as
before
Or about 10 t1/2 = 40 hr
d. If the dose of the antibiotic was doubled exactly, what would be the increase in duration
of activity?
First order kinetics, t1/2 is constant, calculate new Cp0 from VD and new dose, and
calculate time required to reach 2 ug/ml as in b

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A new drug was given in a single intravenous dose of 200 mg to an 80-kg adult male
patient. After 6 hours, the plasma drug concentration of drug was 1.5 mg/100 mL of
plasma. Assuming that the apparent VD is 10% of body weight, compute the total
amount of drug in the body fluids after 6 hours. What is the half-life of this drug?

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A drug has an elimination half-life of 8 hours and follows first-order elimination kinetics.
If a single 600-mg dose is given to an adult female patient (62 kg) by rapid IV injection,
what percent of the dose is eliminated (lost) in 24 hours assuming the apparent VD is 400
mL/ kg? What is the expected plasma drug concentration (Cp) at 24 hours post dose?

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Clearance
Clearance is a measure of drug elimination from the body without identifying the
mechanism or process.

Clearance (drug clearance, systemic clearance, total body clearance, ClT) considers
the entire body or compartment as a drug-eliminating system from which many
elimination processes may occur

Drug clearance refers to the volume of plasma fluid that is cleared of drug per unit
time.
Clearance may also be considered as the fraction of drug removed per unit time
multiplied by VD.
Rate of elimination is the amount of drug eliminated per unit time
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Drug clearance in the one-compartment model

The rate of drug elimination may be

expressed in several ways, each of which
essentially describes the same process, but
with different levels of insight and
application in pharmacokinetics.

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Mathematically, the rate of drug elimination is first order rate
dDB/dt= - k DB
dDB/dt= - k VD Cp

Clearance, Cl, is expressed as volume/time.

Clearance is a constant because VD and k are both constants.

where DB is the amount of drug in the body, dDB/dt is the rate of drug elimination from
the body (mg/h), Cp is the plasma drug concentration (mg/L), k is a first-order rate
constant (h–1 or 1/h), and VD is the apparent volume of distribution (L).
The negative sign refers to the drug exiting from the body.

Clearance unit: L/hr or ml/min

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 Consider a compartment volume, containing VD
liters. If Cl is expressed in liters per minute (L/min),
then the fraction of drug cleared per minute in the
body is equal to Cl/VD

For drugs that follow first-order elimination, the rate of drug elimination is dependent on the amount
of drug remaining in the body.

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Today, pharmacokineticists regard drug clearance and the volume of distribution as
independent (primary) parameters that are necessary to describe the time course of
drug elimination.
While, k and half-life are secondary parameters that come about as a result of Cl and
VD
The clearance concept may also be applied a biologic system in physiologic modeling
without the need of a theoretical compartment
Cp = Cp0 e-kt
Cp = D0/VD e-(Cl/VD)t
Above equation is applied directly in clinical pharmacy to determine clearance and
volume of distribution in patients.
When only one sample is available, i.e., Cp is known at one sample time point, t after a
given dose, the equation cannot be determined unambiguously because two unknown
parameters must be solved, i.e., Cl and VD.

In practice, the mean values for Cl and VD of a drug are obtained from the population
values in the literature
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Clearance from drug-eliminating tissues
Clearance may be applied to any organ that is involved in drug elimination from the
body. As long as first-order elimination process are involved, clearance represents
the sum of the clearances for each drug-eliminating organ as shown
ClT = ClR + ClNR
Where ClR is renal clearance or drug clearance through the kidney, and ClNR is
nonrenal clearance through other organs.

ClNR is assumed to be due primarily to hepatic clearance (ClH) in the absence of

other significant drug clearances, such as elimination through the lung or the bile

ClT = ClR + ClH

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For some drugs, the elimination rate process is more complex and a
noncompartment method may be used to calculate certain pharmacokinetic
parameters such as clearance. In this case, clearance can be determined directly from
the plasma drug concentration-versus-time curve by

AUC is calculated from the plasma drug

concentration–time curve from 0 to infinity
(∞) using the trapezoidal rule

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The classical one-compartment model is described by two model parameters: (1)
elimination constant, k, and (2) volume of distribution, VD.

• Cl calculation needs full PK study

• Cl estimation needs only 2 Cp
measurement
• Not practical in clinical settings
• Clinically feasible: preferred by clinical
pharmacists • Preferred by pharmacokineticists
• Depends on k which is a secondary
parameters dependent on Cl
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Calculation of k from urinary excretion data
The elimination rate constant k may be calculated from urinary excretion data
For rapid intravenous administration, DB0 is equal to the dose D0. Therefore,
if DB0 is known, the renal excretion rate constant (ke) can be obtained from the intercept.

Note that the slope of

the log excretion rate
constant is a function of
the elimination rate
constant k and not of
the urinary excretion
rate constant ke

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• In practice, urine is collected over a specified time interval, and the urine specimen
is analyzed for drug.
• An average urinary excretion rate is then calculated for that collection period.
Therefore, the average rate of urinary drug excretion, Du/t, is plotted against the time
corresponding to the midpoint of the collection interval, t*, for the collection of the
urine sample on a semilogarithmic paper.

•Construct a graph on a semilogarithmic

scale of Du/t versus t*. The slope of this
line should equal –k/2.3.

•The amount of unchanged drug in the

urine can be expressed as a function of
time through the following equation

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Criteria for obtaining valid urinary excretion data:

1. A significant fraction of the unchanged drug must be excreted in the urine.

2. The assay technique must be specific for the unchanged drug and must not
include interference due to drug metabolites that have similar chemical
structures.
3. Frequent sampling is necessary for a good curve description.
4. Urine samples should be collected periodically until almost all of the drug is
excreted. In practice, approximately seven elimination half-lives are needed for
99% of the drug to be eliminated.
5. Variations in urinary pH and volume may cause significant variation in urinary
excretion rates.
6. Subjects should be carefully instructed as to the necessity of giving a complete
urine specimen (ie, completely emptying the bladder).

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Please take a look at
practice problems in
chapter form more
examples

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