Pharmacokinetics of oral

absorption
 Introduction

• Pharmacokinetic models after extravascular drug administration must consider drug absorption from
the site of administration, for example, the gut, the lung, etc

One compartment open model:

First order…… passive diffusion
Gradual absorption….rate
Rapid, instant, uniform distribution…. No rate
• Definitions of absorption:

1. absorption occurs when drug reaches the systemic circulation

2. absorption occurs when drug reaches the portal vein

3. drug is assumed to be absorbed when it leaves the lumen and crosses the apical membrane of
the enterocytes lining the intestine
• Drug absorption from the gastrointestinal (GI) tract or any other extravascular site is dependent on:

1. the physicochemical properties of the drug and the environment in the small intestine

2. The dosage form used Order of the process • PH

• Degree of ionization
3. The anatomy and physiology of the absorption site, such as:

• surface area of the GI tract pH affect degree of ionization …. Affect extent of

transport…affect the order of the process
• stomach emptying rate

• GI mobility: low abs. is done

• blood flow to the absorption site

• Two methodologies to study the kinetics of absorption

1. top-down approach (observed clinical data)…… take samples of disease then find fitting
model
2. Bottom up approach (broader understanding of the human body and its mechanisms)….take
samples from clinical diseased patients
 Absorption kinetics (the top-down approach)
• Drug absorption may be described as either a first-order or a zero-order input process

• The rate of change in the amount of drug in the body, dDB/dt, is dependent on the

relative rates of drug absorption and elimination (Fig. 8-3).

The net rate of drug accumulation in the body at any time is equal to the rate of drug absorption less the
rate of drug elimination, regardless of whether absorption rate is zero-order or first-order
first order
Amount of drug in GI Amount of eliminated drug Zero order

rate of drug accumulation= rate of drug absorption - rate of drug elimination

regardless of whether absorption rate is zero-order or first-order

 Ka=Ke
Ka= Ke Ka -Ke=zero

Cmax

Ka > Ke

Ke > Ka

Ke
Ka=0
• Factors influencing the elimination rate constants (Ke):

1. A small elimination rate constant, k may be caused by reduced renal drug excretion

2. A small k may also be due to reduced hepatic clearance caused by relatively inactive metabolic
enzymes such as CYPs for some patients

• Rate of systemic drug absorption from an orally administered solid dosage form encompasses many
individual rate processes, including:

• dissolution of the drug

• GI motility

• blood flow

• transport of the drug across the capillary membranes and into the systemic circulation

• The calculation of ka is useful in designing a multiple-dosage regimen.

• Knowledge of the ka and k values allows for the prediction of peak and trough plasma drug
concentrations following multiple dosing
• In bioequivalence studies:

drug products are given in chemically equivalent (ie, pharmaceutical equivalents) doses, and the
respective rates of systemic absorption may not differ markedly.

Therefore, for these studies, tmax, or time of peak drug concentration, can be very useful in
comparing the respective rates of absorption of a drug from chemically equivalent drug products
Zero-order absorption model
• Zero-order drug absorption from the dosing site into the plasma usually occurs when either:

1. The drug is absorbed by a saturable process ….. Need transporters and channels

2. A zero-order controlled-release delivery system is used…extended, prolonged

Zero order drug input (absorption)

• In this model, drug in the gastrointestinal tract, DGI, is absorbed systemically at a constant rate, k0.
Drug is simultaneously and immediately eliminated from the body by a first-order rate process
defined by a first-order rate constant, k. This model is analogous to that of the administration of a drug
by intravenous infusion
• The rate of first-order elimination at any time is equal to DBk. The rate of input is simply k0
Therefore, the net change per unit time in the body can be expressed as

dD/dtB = ka – ke.DB DB= D0.𝒆−𝒌𝒆.𝒕

Zero 0rder First order
∫ Integration then /Vd

• The rate of drug absorption is constant until the amount of drug in the gut, DGI, is depleted. The
time for complete drug absorption to occur is equal to DGI/k0. After this time, the drug is no longer
available

• The drug concentration in the plasma subsequently declines in accordance with a first-order
elimination rate process Similar to Iv infusion

a
 First-order absorption model
• This model assumes a first-order input across the gut wall and first-order elimination from the body
• This model applies mostly to the oral absorption of drugs in:
1. solution
2. rapidly dissolving dosage (immediate release) forms such as tablets, capsules, and suppositories
3. intramuscular or subcutaneous aqueous injections may also be described using a first-order
process

• DGI is the amount of drug in solution in the GI tract at any time t

• D0 is the dose of the drug
• where ka is the first-order absorption rate constant from the GI tract
• F is the fraction absorbed
First-order absorption model

D0= dose
DGI= D0.𝒆−𝒌𝒂.𝒕 DB= D0.𝒆−𝒌𝒆.𝒕

We have fraction absorbed (F):

Bcz. fraction of drug is absorbed
and Fraction of drug is remaining

∫ ∫ ∫
∫Integration then /Vd
• The maximum plasma concentration after oral dosing is Cmax, and the time needed to reach
maximum concentration is tmax.

• The tmax is :

• independent of dose

• dependent on the rate constants for absorption (ka) and elimination (k)

• Therefore, the net rate of concentration change is equal to zero

• Cmax is: directly proportional to:

• the dose of drug given (D0)

• the fraction of drug absorbed (F)

• At later time intervals, when drug absorption has been completed, that is, e−kat ≈ 0

During only elimination

Completed absorption
Pharmacokinetics of oral absorption
 Determination of absorption rate constant from oral absorption data
Ka
1- The method of residuals Fitting method

Assumptions:

1. Ka is larger than Kel

2. Drug absorption and elimination follow first-order kinetics

3. The drug pharmacokinetics follow one compartment model

2- Determination of ka by Plotting Percent of Drug Unabsorbed (%unabsorbed)

Versus Time (Wagner–Nelson ) Method
 Determination of absorption rate constant from oral absorption data:
1- method of residuals
• The method of residuals (also known as feathering, peeling, or curve stripping) is a commonly

employed technique for resolving a curve into various exponential terms.

• This method allows the separation of the monoexponential constituents of a biexponential plot of

plasma concentration against time.

• Therefore, it is a useful procedure for fitting a curve to the experimental data of a drug when the drug

does not clearly follow a one-compartment model

• Assuming ka >> k in the previous equation

 Constant= A

Cp= A. [𝒆−𝒌𝒆.𝒕 − 𝒆−𝒌𝒂.𝒕 ]

• the value for the second exponential will become insignificantly small with time (ie, e-kat = 0) and can
therefore be omitted. When this is the case, drug absorption is virtually complete

• Then the equation could be reduced to:

−𝒌𝒆.𝒕
Cp= A. 𝒆

This equation, which represents first-order drug elimination, will yield a linear plot on semi log paper.
The slope is equal to - k/2.303.
The value for ka can be obtained by using the method of residuals or a feathering technique
1. Plasma concentration vs. time on a semi-logarithmic scale

2. The slope of the line representing the elimination phase is calculated (-kel/2.303).

3. Then, this line is back extrapolated to the y-axis

4. Three points at the extrapolated line (residual line) are taken at three different time points
and within the absorption phase.

5. Vertical line is dropped from these three points and the corresponding plasma concentration
(time points are determined) is calculated

6. The differences between the y-coordinate values of the points on the extrapolated curve and
the y-coordinate values on the plasma concentration time curve are calculated.

7. The difference between these points is the residual (Cr = C – Cp) Cr

 S. L
A=

Mono exponentia
straight line
Only Ke
Bi exponential:
not a straight line
Ka + Ke

You can determine the straight line

of elimination when the Cp values
become close to each other
 C1
C2

Cr

Cp2

T1 T2 T3
5. The values of the residuals are plotted against their corresponding time points on the same
graph.
6. A straight line should be obtained with a slope of -Ka/2.303

7. The extrapolated line representing the elimination phase and the residual line should have
the same y-intercept …. (A)
3- Estimate the absorption rate constant from the slope of the residual line

Residual line

slope = -Ka/2.303

9
 Determination of the Model Parameters
• Tmax, Cmax and AUC

• These three parameter are important for evaluation of an extravascular dosage form and evaluation of
bioequivalence of drugs. dose, doses intervals

• Tmax: indicator of how fast a drug is absorbed, if the rate of absorption is fast, tmax is short

• Cmax: represents the highest plasma concentration that can be achieved with a single dose.

• AUC: a parameter thatcovers the entire period of sampling and it representsthe extent of absorption
and how complete is the absorption How much drug has reached the
systemic circulation

• AUC and Cmax are dependent on the dose, as the dose increases the AUC and Cmax increases

24
Determination of the Model Parameters

• Elimination half life = 0.693/K

• Absorption half life = 0.693/Ka

tmax = (tp)

• Cmax (Conc. at t = tmax)

max max

max
Cl= K*Vd
F XXo o
CCl l == F .
AU C
AU C
Clearance
FFofX.distribution
oX o
VVdd == Volume
K .A U C
K .A U C
FFXXoo
AAUUCC ==
KKVVdd

26
 Normal kinetics vs. Flip-flop kinetics

• In a series of two consecutive, irreversible first-order rate processes such as absorption of a drug
from the intestine and its subsequent systemic elimination, either step can be rate-limiting in the
overall elimination process

• When ka is much greater than k (e.g., ka > k ):

K is rate limiting

after oral administration ……elimination of the drug from the body after oral administration is governed
primarily by how fast it can be removed once it enters the systemic circulation (elimination)

• In this case (e.g., ka > k), a plasma concentration-time profile after oral dosing exhibits:
27
terminal half-life similar to that after intravenous injection
When ka is much smaller than k (e.g., k > ka ) :

• drug disappearance from the body becomes governed by the rate of absorption
rather than by the rate of elimination

• absorption t1/2 becomes longer than elimination t1/2.

Ka is rate limiting
•
Shorter • Elimination half life = 0.693/K As K is bigger

longer • Absorption half life = 0.693/Ka As Ka is smaller

• This phenomenon is called “flip-flop kinetics”

28
 Distinguishing between Normal and Flip-Flop kinetics
IV bolus data is needed to differentiate between Normal and Flip-Flop kinetics
Washing out periods are needed between IV bolus and oral doses
In elimination phase: absorption did not affect In elimination phase: absorption strongly
the elimination delayed (retardation) the elimination

IV bolus
IV bolus

29
 Normal Kinetics example

Difference observed in the absorption phase➔ Normal kinetics…parallel

Theophylline conc-time profile resulting from the

administration of two 130 mg tablets:
Dissolved in 500 mL water and taken on an empty
stomach

The drug is hydrophilic… rapid dissolution then rapid abs.

but the same elimination as normal 1st order absorption

Taken on an empty stomach

Insufficient gastric juices… retarded dissolution

Taken after meal

More gastric juices, Delayed gastric emptying,

30
 Flip-Flop kinetics example
Difference observed in the terminal phase ➔ Flip-flop kinetics… non-parallel

Penicillin G was administered IM as an:

• Aqueous solution (I.M) :

behaved similar to IV bolus… hydrophilic form… rapid absorption

• Procaine penicillin in oil (P I.M):

• drug should transport through a
barrier to reach systemic
circulation….similar to oral route
Oily vehicle… lipophilic form….retardation of drug release…retardation
of drug absorption rate…gradual absorption

• Procaine penicillin in oil with aluminum monostearate (AP-

I.M):
Higher Oily vehicle… more lipophilic form….higher retardation of drug
17
release…more retardation of drug absorption rate….. gradual absorption
Effect of Ka on tmax, Cmax, and AUC

Changing Ka ( K unchanged)

• Increasing the absorption rate constant (Ka)

results in:

• Shorter tmax
• Higher Cmax
• Unchanged AUC

AUC could change in hepatic and renal abnormalities

Ka could change in different delivery systems
32
Effect of K on tmax, Cmax, and AUC

• Increasing the elimination rate constant (K)

Changing K ( Ka unchanged) results in:

• Shorter tmax
• Lower Cmax
• Lower AUC

33
 Bioavailability

• Systemic absorption is often incomplete when given extravascularly

• Knowing the extent of absorption (bioavailability) helps to en-sure that the correct
dose is given extravascularly to achieve a therapeutic systemic exposure

• Although dose is known and area can be determined following an extravascular dose,
clearance is needed to estimate bioavailability

• Oral dose is higher than Iv doses???

• 34 F= 1-ER (extraction ratio due to 1st pass effect)
Bioavailability calculation:
• To determine clearance, a drug must be given intravascularly, as only then is
the amount entering the systemic circulation known (the dose, F =1)
• no interfering absorption process.
DoseIV = Cl  AUCIV

• After an oral dose:

F  Doseoral = Cl  AUCoral

• Given that Clearance is unchanged (for the same drug), F is estimated by:

AUCoral * DoseIV
F =
AUCIV Doseoral
35
If the IV and oral doses were equal, F can be calculated according to:

AUCoral
F=
AUCIV

Remember:
• Ke
• Cl
• Vd
Are the same for the same drug with all different routes of administrations
36
Effect of F on tmax, Cmax, and AUC

300
◼ Increasing the bioavailability F results in:
F=1
250
 Unchanged tmax
 Higher Cmax ……... Related to dose D
Concentration

200

150
 Higher AUC
F = 0.5

100

50 F = 0.25

0
0 20 40 60 80 100
ti m e
37
 Effect of Ka on tmax, Cmax, and AUC

Changing Ka ( K unchanged) Increasing the absorption rate constant (Ka)

results in:

• Shorter tmax
• Higher Cmax
• Unchanged AUC

3
8
 Effect of K on tmax, Cmax, and AUC

Changing K ( Ka unchanged)

Increasing the elimination rate constant (K)

results in:

• Shorter tmax
• Lower Cmax
• Lower AUC

3
9
Effect F on tmax, Cmax, and AUC
◼ Increasing the bioavailability results in:
300
F=1 • Unchanged tmax
250
• Higher Cmax
200
Concentration

• Higher AUC
150
F = 0.5

100

50 F = 0.25

0
0 20 40 60 80 100
time
4
0
 Lag time
• In some individuals, absorption of drug after a single oral dose does not start immediately, due to
such physiologic factors as stomach-emptying time and intestinal motility. The time delay prior to
the commencement of first-order drug absorption is known as lag time

• The lag time for a drug may be observed if the two residual lines obtained by feathering the oral
absorption plasma level–time curve intersect at a point greater than t = 0 on the x axis. The time at the
point of intersection on the x axis is the lag time

Onset time:
• The lag time, t0, represents the beginning of drug absorption and should not be confused with the
pharmacologic term onset time, which represents latency, that is, the time required for the drug to
reach minimum effective concentration (MEC).
41
• where FkaD0/VD(ka - k) is the y-value (A) at the point of intersection of the
residual lines….Y is the same for residual and terminal lines
Shifting in time

No Shifting in time
• The second expression that describes the curve in omits the lag time, as follows:

• where A and B represent the intercepts on the y axis after extrapolation of

the residual lines for absorption and elimination, respectively…..different
Absorption Elimination
intercepts intercept intercept

43
Example 1
A 500-mg dose of the sulfonamide sulfamethoxazole is administered as an oral tablet
to a human subject. Eighty percent of the drug is absorbed, and the balance is
excreted unchanged in feces. The drug distributes into an apparently homogeneous
body volume of 12 L, and has an absorption half-life of 15 min and overall
elimination half- life of 12 h.

1) Calculate the following:

• AUC0→∞
• Tmax
• C max.

2) Recalculate the values in Problem 1 if all parameter values remained unchanged,

but the elimination half-life was
increased to 18 h.
44
Estimate k and ka:

k = 0.693 t1/elimin
2
= 0.693 12 = 0.058 hr −1

ka = 0.6931/t2abs. = 0.693 0.25 = 2.77 hr −1

Estimate AUC:

F Xo 0.8 * 5 0 0
AU C = = = 5 7 5 m g  h r/L
KVd 0.058*12

45
Cl
 Estimate tmax:

2 .3 0 3 Ka
t m ax = (Ka− K)
log
K

46
Estimate Cmax: max
max

max

C max =
12(0.046− 0.058)

0.046* 0.8*500 * −0.058*19.32 −0.046*19.32
e −e 
C max = 10.9 mg/L

47
2- Recalculate the values in Problem 1 if all parameter values remained unchanged, but the
elimination half-life was increased to 18 h

k = 0.039 hr −1
t m ax = 2 3 .5 h r

AU C = 8 5 5 m g  h r /L
C max = 13.3 mg/L

48
Example 2

The presented table gives the plasma drug concentrations that were obtained following
the oral administration of 500 mg dose of drug X. Assuming that drug X follows normal
pharmacokinetics, determine the following:

Time Conc
• Elimination rate constant (hr) (mg/L)
0.25 3.77
• Absorption rate constant 0.5 6.53
• Bioavailability 0.75 8.49
1.5 11.32
• Volume of distribution (normalized for bioavailability) 2 11.7
3 10.92
10 2.96
24 0.18
49 30 0.05
1. Determine elimination phase

1.5

1
Elimination phase
log (Conc) mg/L
0.5

0
0 5 10 15 20 25 30 35

-0.5

-1

-1.5

time (hr)
50
2. Determine K

Terminal line equation:

1.5
y = -0.0883x + 1.359 R2 = 0.9998
K =-slope*2.303 =0.0883*2.303
1
K= 0.2 hr-1
log (Conc) mg/L
0.5

0
0 5 10 15 20 25 30 35

-0.5

-1

-1.5
time (hr)
51
3. Extrapolate the terminal line to cross the y-axis

1.5

y = -0.0883x + 1.359
1 R2 = 0.9998
log (Conc) mg/L

0.5

0
0 5 10 15 20 25 30 35

-0.5

-1

-1.5
time (hr)
4. Draw the residual line

1.5

1
log (Conc) mg/L

0.5

0
0 5 10 15 20 25 30 35

-0.5

-1

-1.5
time (hr)
5. Determine Ka
Residual line equation:

1.5 y = -0.3814x + 1.3372

R2 = 0.9988
1
Ka =-slope*2.303 =0.03814*2.303
log (Conc) mg/L Ka= 0.878 hr-1
0.5

Log Cp not Cp
5 10 15 20 25 30 35
0

-0.5

-1

-1.5

18
• Volume of distribution (normalized for bioavailability): VD/F
From the terminal line best fit line, intercept A =1.359.

Ka  F  D
(A)10 Intercept
=
Vd (Ka − K )
Vd Ka  D 0.878*500
 = Intercept = 1.359 =28.3 L
F 10 (Ka − K ) 10 (0.878− 0.2)
55
Example 3

A patient received a single dose of 500 mg X erythromycin in the form of a tablet that is
known to have 80% bioavailability F.

Calculate:

• the time to reach the maximum concentration tmax (1.7 hr)

• the maximum conc. C max ( 7.11 mg/L)

• AUC (50)

• Clearance (8 L/hr) after this single dose If K is 0.2 hr-1, Ka is 1.3 hr-1, and Vd is 40
liters.

56