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Introduction
106
6.2
106
6.3
109
6.4
110
6.5
WagnerNelson method
(one-compartment model) and
LooRiegelman method
(two-compartment model)
111
115
6.6
6.7
116
6.8
116
6.9
117
6.10
118
6.11
120
6.12
121
6.13
Flip-flop kinetics
126
Objectives
Upon completion of this chapter, you will have the ability to:
calculate plasma drug concentration at any given time after the administration of an extravascular
dose of a drug, based on known or estimated pharmacokinetic parameters
interpret the plasma drug concentration versus time curve of a drug administered extravascularly
106
Basic Pharmacokinetics
6.1 Introduction
(6.1)
where dX/dt is the decrease in the amount of absorbable drug present at the site of administration per
unit time (e.g., mg h1 ); Ka is the first-order absorption rate constant (h1 ; min1 ); and (Xa )t is the mass
or amount of absorbable drug at the site of administration (e.g., the gastrointestinal tract) at time t.
Upon integration of Eq. (6.1), we obtain the following:
(Xa )t = (Xa )t=0 eKa t = FX0 eKa t
(6.2)
(6.3)
Figure 6.1
107
Both Eqs (6.2) and (6.3) and Fig. 6.4 clearly indicate that the mass, or amount, of drug that remains
at the absorption site or site of administration (or
remains to be absorbed) declines monoexponentially
with time.
However, since we cannot measure the amount
of drug remaining to be absorbed (Xa ) directly, because of practical difficulty, Eqs (6.2) and (6.3), for
the time being, become virtually useless for the purpose of determining the absorption rate constant;
and, therefore, we go to other alternatives such as
monitoring drug in the blood and/or urine to determine the absorption rate constant and the absorption
characteristics.
(6.4)
108
Basic Pharmacokinetics
Figure 6.2
Passage of drug in the gastrointestinal tract until transport across the membrane.
SCHEME:
Xa
Ka (h1)
(Absorbable
drug at absorption Absorption
site)
X
(drug in
body or
blood)
K (h1)
Xu
Elimination
SETUP:
Xa
Ka
Xu
Figure 6.3 Absorption of a one-compartment drug with first-order elimination, where Xa is the mass or amount of absorbable
drug remaining in the gut, or at the site of administration, at time t (i.e., drug available for absorption at time t); X is the mass or
amount of drug in the blood at time t; Xu is the mass or amount of drug excreted unchanged in the urine at time t; Ka is the
first-order absorption rate constant (h1 or min1 ); and K (or Kel ) is the first-order elimination rate constant (h1 or min1 ).
(b)
Slope =
Xa (mg)
Xa (mg)
(a)
t=0
t=0
Time (h)
109
Ka
2.303
Time (h)
Figure 6.4 Amount of drug remaining at the site of administration against time in a rectilinear plot (a) and a semilogarithmic
plot (b). Xa , amount of absorbable drug at the site of administration; (Xa )0 , amount of absorbable drug at the site of
administration at time t = 0; F, fraction of administered dose that is available to reach the general circulation.
(X)t =
(6.5)
Ka FX0
(eKt eKa t )
V(Ka K)
(6.6)
Ka FX0
(eKt ).
V(Ka K)
(6.7)
110
Basic Pharmacokinetics
X (mg)
KaXa = KX
Elimination phase
(KX >> KaXa)
Absorption phase
(KaXa >> KX)
t=0
Time (h)
Figure 6.5 A typical rectilinear profile illustrating amount of drug (X ) in blood or body against time. Xa , amount of absorbable
drug at the absorption site at time t; Ka and K , first-order absorption and elimination rate constants, respectively; Ka Xa and KX ,
first-order rates of absorption and elimination, respectively.
(b)
Cp (ng mL1)
t=0
Intercept =
Cp (ng mL1)
(a)
Time (h)
t=0
KaFX0
V (Ka K )
Slope =
K
2.303
Time (h)
Figure 6.6 A plot of plasma concentration (Cp ) against time on rectilinear (a) and semilogarithmic (b) paper. (Xa )0 , amount of
absorbable drug at the site of administration at time t = 0; F, fraction of administered dose that is available to reach the general
circulation; Ka and K, first-order absorption and elimination rate constants, respectively; V, apparent volume of distribution.
The elimination half life and elimination rate constant can be obtained by methods described earlier
and illustrated in Fig. 6.7.
111
Table 6.1 Illustration of the table created for determination of the first-order absorption rate constant Ka
Time (h)
Extrapolated plasma
concentration (Cp )extrap
Differences between
extrapolated and observed
values for each time in the
absorption phase (units, e.g.,
g mL1 )
V (Ka K )
Cp (mg L1)
Intercept =
KaFX0
Slope =
K
2.303
t 1/2
Time (h)
Ka FX0
(eKa t )
V(Ka K)
(6.8)
the first-order absorption rate constants, using the equation Ka = 0.693/(t1/2 )abs , or Ka =
(Slope) 2.303.
XA = X + XE
(6.10)
(6.11)
Since X = VCp ,
dCp
dXA
=V
+ KVCp .
dt
dt
(6.12)
= VCp + KV(AUC)t0
(6.13)
112
Basic Pharmacokinetics
Intercept =
KaFX0
V (Ka K )
Extrapolated concentration
values
Cp (mg mL1)
Absorption
phase
t=0
Time (h)
Figure 6.8 Semilogarithmic plot of plasma concentration (Cp ) versus time of an extravascular dosage form, showing the
method of residuals. Other abbreviations as in Fig. 6.6.
Intercept =
KaFX0
V(Ka K )
Slope =
Ka
2.303
or Ka =
0.693
(t1/2)abs
t1/2
Absorption
Time (h)
Figure 6.9 Semilogarithmic plot of plasma concentration (Cp )diff . between calculated residual concentrations and measured
ones versus time, allowing the calculation of the absorption rate constant. (t1/2 )abs , absorption half life; other abbreviations as in
Fig. 6.6.
Z
(XA ) = (VCp )
+
KV
Cp dt
0
0
= V Cp 0 V(Cp ) + KV(AUC)
0
= KV(AUC)
0
(6.14)
since (Cp )0 and (Cp ) both equal zero for an extravascular dose.
In order to obtain the ratio of mass of drug absorbed at a given time t to the maximum amount
VCp + KV(AUC)t0
.
KV(AUC)
0
(6.15)
(6.16)
(6.17)
113
(6.12)
(6.18)
(6.19)
dXu /dt
.
Ku V
(6.20)
d Ku V
dXu /dt
dXA
=V
+ KV
.
dt
dt
Ku V
60
1
(100) = 33.3%
90
which is in agreement with our previous result.
For first-order absorption, drug remaining to be
absorbed expressed as a fraction of absorbable drug
dXu
dt
+
K dXu
.
Ku dt
(6.21)
114
Basic Pharmacokinetics
120
Drug remaining
to be absorbed
Cumulative drug
absorbed
100
Cumulative drug
eliminated
80
60
Cumulative drug
excreted unchanged
40
Drug in the body
20
0
Figure 6.10
versus time.
6
Time (h)
10
12
Rectilinear (RL) plot of disposition of extravascularly administered drug, showing the fraction of drug unabsorbed
100
Cumulative drug
eliminated
Cumulative drug
excreted unchanged
Drug in the body
10
Drug remaining
to be absorbed
0.1
0
10
12
Time (h)
Figure 6.11 Semilogarithmic (SL) plot of disposition of extravascularly administered drug, showing the fraction of drug
unabsorbed versus time.
K
(Xu )
Ku
(6.23)
The ratio (XA )t /(XA ) is the fraction of absorbable drug that has been absorbed at time t. It is
obtained by dividing Eq. (6.22) by Eq. (6.23):
(XA )t
=
(XA )
1
Ku
=
dXu
dt
time t is
Ft =
Cp dt + (Xperi )t /Vc
R
K10 0 Cp dt
(Cp )t + K10
(6.25)
dXu
+ KKu (Xu )t
dt
K
Ku (Xu )
+ K(Xu )t
K(Xu )
(6.24)
In practice this ratio approaches 1 when the absorption process is virtually complete (i.e., in about 5
absorption half lives); so one does not have to collect
urine samples until all drug has been eliminated from
the body. If absorption is first order, the semilogarithmic plot of 1[(XA )t /(XA ) ], i.e., the fraction of drug
remaining to be absorbed, versus time will result in a
straight line whose slope is Ka /2.303, as we have
seen in the case where plasma drug level data was
collected.
3. LooRiegelman method
(two-compartment model)
This method is relevant for a drug displaying
two-compartment pharmacokinetics. We will not describe the entire method. Use of this method requires
a separate intravenous administration of drug in each
subject who will be tested for absorption of oral
drug. In this method the fraction drug absorbed at
where (Xperi )t is the amount of drug in the peripheral (tissue) compartment at time t after oral
administration and Vc is the apparent volume of
distribution of the central compartment. K10 , the
first-order elimination rate constant of drug from
the central compartment, is estimated from an intravenous study in the same subject. The quantity
(Xperi )t /Vc can be estimated by a rather complicated
approximation procedure requiring both oral and
intravenous data.
Intercept of
feathered line and
extrapolated line
Cp (mg L1)
Cp (mg L1)
Theoretical
intercept
t=0
Time (h)
Time (h)
Log time (t0)
Figure 6.12
115
Semilogarithmic plots of the extrapolated plasma concentration (Cp ) versus time showing the lag time (t0 ).
Basic Pharmacokinetics
incomplete wetting of drug particles (large contact angle may result in a smaller effective
surface area) owing to the hydrophobic nature
of the drug or the agglomeration of smaller insoluble drug particles
poor formulation, affecting any of the above
a delayed release formulation.
Intercept of
feathered and
extrapolated lines
Cp (mg L1)
116
Feathered line
Time (h)
constant (K), we need to employ a different pharmacokinetic model to fit the data.
Note that the absorption rate constant for a given
drug can change as a result of changing the formulation, the dosage form (tablet, suspension, capsule) or
the extravascular route of drug administration (oral,
intramuscular, subcutaneous, etc.). Administration of
a drug with or without food will also influence the
absorption rate constant for the same drug administered orally through the same formulation of the same
dosage form.
Ka FX0
.
V(Ka K)
(6.26)
Ka >>> K
117
MTC
Therapeutic
range
Ka >> K
MEC
Cp (g L1)
Ka > K
Ka K
Problems ?
Time (h)
Figure 6.14 Rectilinear plot of plasma concentration (Cp ) versus time for various magnitudes of absorption (Ka ) and elimination
(K ) rate constants. MTC, minimum toxic concentration; MEC, minimum effective concentration.
In the absence of data for the fraction of administered dose that reaches the general circulation, the
best one can do is to obtain the ratio of V/F:
Ka X0
1
V
=
.
(6.27)
F
(Ka K) Intercept
Ka FX0 Kt
(e
eKa t )
Ka K
and
(Xa )t = FX0 eKa t .
(6.29)
(6.30)
(6.31)
ln Ka Ka tmax = ln K Ktmax
ln Ka ln K = Ka tmax Ktmax
ln(Ka /K) = tmax (Ka /K)
or
tmax =
dX
= Ka (Xa )tmax K(X)tmax = 0
dt
or
Ka (Xa )tmax = K(X)tmax .
Ka FX0 Ktmax
(e
eKa tmax )
Ka K
(6.28)
ln(Ka /K)
.
Ka K
(6.32)
Cp (mg L1)
Basic Pharmacokinetics
Cp (mg L1)
118
tmax estimated
from graph
tmax
Time (h)
Real tmax
Time (h)
Figure 6.15 Dependency of estimate of the peak time (tmax ) on the numberof data points. Ka , absorption rate constant; K ,
elimination rate constant; Xa , absorbable mass or amount of drug at the absorption site; X , mass or amount of drug in the blood
or body; Cp , plasma concentration.
Differences in onset and peak time may be observed as a result of administration of the same
drug in different dosage forms (tablet, suspension,
capsules, etc.) or the administration of the same
drug in same dosage forms but different formulations
(Fig. 6.16). Please note that this is due to changes in
Ka and not in K (elimination rate constant).
119
MTC
Cp (mg mL1)
Onset of action
for IM route
MEC
Oral route
IM route
Time (h)
tmax for oral route
tmax for IM route
Figure 6.16 Rectilinear plots of plasma concentration (Cp ) against time following the administration of an identical dose of a
drug via the oral or intramuscular (IM) extravascular routes to show variation in time to peak concentration (tmax ) and in onset of
action. MTC, minimum toxic concentration; MEC, minimum effective concentration.
Cp (mg mL1)
(Cp )t =
Time (h)
by
Ka FX0
(eKt eKa t ).
V(Ka K)
I=
MEC
t=0
MTC
Ka FX0
.
V(Ka K)
Ka FX0
(eKtmax eKa tmax ).
V(Ka K)
(6.33)
We also know from Eqs (6.6) and (6.7) that the intercept (I) of the plasma concentrationtime plot is given
(6.34)
120
Basic Pharmacokinetics
(Cp)max
(Cp)max
Cp (mg mL1)
Cp (mg mL1)
tmax
t=0
t=0
Time (h)
Time (h)
Figure 6.18 Rectilinear plots of plasma concentration (Cp ) against time following the administration of a drug via extravascular
route. The accuracy of the estimation of the peak plasma concentration (Cp )max depends upon having sufficient data points (full
points) to identify the time of peak concentration (tmax ).
I=
KaFX0
Cp (ng mL1)
V (Ka K )
Elimination phase
tmax
Absorption
phase
Time (h)
Figure 6.19 Semilogarithmic plot of plasma concentration (Cp ) against time following the administration of a drug via the
extravascular route, showing the intercept (I) and the time of peak concentration (tmax ). Other abbreviations as in Fig. 6.6.
FX0 Ktmax
e
V
(6.35)
where
FX0
=
V
Ka K
Ka
(I)
121
Ka FX0
V(Ka K)
Ka FX0
Intercept(Ka K)
123 500 g h1
67 g mL1 (0.177 h1 )
123 500
= 10 372.92 mL or 10.37 L.
11.906
ln(Ka /K)
.
Ka K
122
Basic Pharmacokinetics
Table 6.2 Lincomycin, an antibiotic used when patient is allergic to penicillin or when penicillin is inappropriate
Route of administration
Fraction absorbed
Orala
0.30
2.6
2 to 4
Intramuscular
Not available
9.5
0.5
Intravenous
1.00
19.0
0.0
Table 6.3 Haloperidol (Haldol), a drug used for psychotic disorder management
Route of administration
Percentage absorbed
Oral
60
2 to 6
24 (1238)
Intramuscular
75
0.33
21 (1336)
Intravenous
100
Immediate
14 (1019)
Fraction absorbed
0.50.6
440545
13
0.91.0
576
0.25
KaFX0
Oral route
V (Ka K )
Cp (ng mL1)
IV route
Slope =
K
2.303
t1/2 =
0.693
K
Time (h)
Figure 6.20 Administration of a drug by intravascular (IV) and extravascular (oral) routes (one-compartment model). Even for
administration of the same dose, the value of plasma concentration (Cp ) at time zero [(Cp )0 ] for the intravenous bolus may be
higher than the intercept for the extravascular dose. This will be determined by the relative magnitudes of the elimination rate
constant (K ) and the absorption rate constant (Ka ) and by the size of fraction absorbed (F) for the extravascular dosage form. X0 ,
oral dose of drug; X0 , IV bolus dose of drug.
123
40
KaXa = KX
32
Cp (g mL1)
8.0
t max
12
24
36
48
60
72
Time (h)
Figure 6.21 Plasma concentration (Cp ) versus time on rectilinear paper for administration of 500 mg dose of drug using values
in Table 6.5. Xa , amount of absorbable drug at the absorption site at time t; Ka and K , first-order absorption and elimination rate
constants, respectively; Ka Xa and KX , first-order rates of absorption and elimination, respectively.
Table 6.5 Plasma concentrationtime data following oral administration of 500 mg dose of a drug
that is excreted unchanged and completely absorbed (F = 1.0); determine all pharmacokinetic
parameters
Table 6.6 Method of residuals to calculate the difference between the extrapolated and observed
plasma concentrations values using the data in
Table 6.5 plotted as in Fig. 6.20
Time (h)
(Cp )extrap
(g mL1 )
(Cp )obs
(g mL1 )
(Cp )diff
(g mL1 )
5.36
0.5
65.0
5.36
59.64
1.0
9.35
1.0
62.0
9.95
52.05
2.0
17.18
2.0
58.0
17.18
40.82
4.0
25.78
4.0
50.0
25.78
24.22
8.0
29.78
8.0
39.0
29.78
9.22
12.0
26.63
18.0
19.40
24.0
13.26
36.0
5.88
48.0
2.56
72.0
0.49
Time (h)
0.5
ln(0.247/0.0693)
ln(3.562)
=
.
(0.247 0.0693)
(0.1777)
124
Basic Pharmacokinetics
100
90
80
70
60
I=
KaFX0
V (Ka K )
50
Feathered
(residual) time
40
30
20
Absorption
phase
10
Slope =
9
8
7
6
Ka
2.303
Elimination phase
Slope =
K
2.303
t 1/2
Cp (g mL1)
t 1/2
10 h
10 h
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
10
20
0.2
30
40
50
60
70
Time (h)
0.1
Figure 6.22 Plasma concentration (Cp ) versus time on semilogarithmic paper for administration of 500 mg dose of drug using
values in Table 6.5. The observed plasma concentrations () are extrapolated back (
) and then the feathered (residual) method
is used to get the residual concentration () plot. Other abbreviations as in Fig. 6.6.
(Cp )max =
Ka FX0
(eKtmax eKa tmax )
V(Ka K)
Ka FX0
= Intercept = 67 mg mL1 .
V(Ka K)
We know that Ka = 0.247 h1 , K = 0.0693 h1
and tmax = 7.148 h. Substituting these values in the
equation gives:
(Cp )max = 67 g mL1
(e0.06937.148 e0.2477.148 )
(Cp )max = 67 g mL1 (e0.495 e1.765 ).
We have
e0.495 = 0.6126 and e1.765 = 0.1720.
Hence, (Cp )max = 67 g mL1 (0.6126 0.1720) =
67 g mL1 (0.4406) = 29.52 g mL1 .
Please note that peak plasma concentration is
always directly proportional to the administered
125
100
90
80
70
Intercept =
KaFX0
V (Ka K )
60
50
40
30
20
Slope =
Ka
2.303
10
9
(t1/2)abs
2.8 h
7
6
5
2.0
4.0
6.0
8.0
Time (h)
2
Figure 6.23 Feathered (residual) plot of the differences [(Cp )diff ] between the observed and the extrapolated plasma
concentrations in Fig. 6.20 (as given in Table 6.6, column 4) plotted against time on semilogarithmic paper. (t1/2 )abs , absorption
half life; other abbreviations as in Fig. 6.6.
Basic Pharmacokinetics
0.6
0.5
0.4
Cp (mg L1)
126
Ka = 5; K = 2
0.3
0.2
Ka = 2; K = 5
0.1
0.0
0
Time (h)