Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles...
-
Upload
clementine-watkins -
Category
Documents
-
view
231 -
download
8
Transcript of Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles...
![Page 1: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/1.jpg)
Two-compartment model
Mohammad Issa Saleh
![Page 2: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/2.jpg)
Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following
intravenous bolus administration
y axis: normal scale y axis: logarithmic scale
![Page 3: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/3.jpg)
A schematic representation of three types of two-compartment models consisting of a central and a peripheral compartment.
Please note the difference in each type is reflected in the placement of an organ responsible for the elimination of the drug from the body. K12, K21, transfer rate constants; K10, K20, elimination rate constants.
X1 X2
X1 X2
X1 X2
![Page 4: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/4.jpg)
Assumptions of the model
• Upon drug absorption there is instantaneous distribution of drug throughout the central compartment (sampling compartment) having a volume V1 (Vc)
• Transfer of drug from the central compartment to the peripheral compartment is by a first-order process
• Transfer of drug from of drug from the peripheral compartment to the central compartment is by a first-order process
![Page 5: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/5.jpg)
One Compartment Two Compartments
Rapid or prompt equilibrium is attained.
Distribution equilibrium is slow (takes finite time).
There is a single disposition phase
Distribution and post-distribution are two distinct phases.
Linear: drug elimination follows first order kinetics
Linear: distribution and
elimination both follow first order
![Page 6: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/6.jpg)
A. We start with virtually no drug in the second compartment, but re-equilibration moves drug in – levels rise
B. A brief equilibrium - no net movement – at the peak of the curve, levels are neither rising nor falling
C. Re-equilibration moves into reverse and drug leaves the second compartment – levels fall
Drug concentrations in the two compartments following a single i.v. bolus injection
![Page 7: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/7.jpg)
X1 X2
K12
K21
K10
1101122211 XKXKXK
dt
dX
2211122 XKXK
dt
dX
Distribution rate from X1 to X2 = 112XK
221XK
110XK
Distribution rate from X2 to X1 =
Elimination rate =
![Page 8: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/8.jpg)
tt eKX
eKX
X
)()( 210210
1
)e(eβ)(α
XoKX αtβt
122
t
C
t
C
eV
KXe
V
KXC
)(
)(
)(
)( 2102101
VC is the volume of the central compartment
Amount in the central compartment
Conc in the central compartment
Amount in the peripheral compartment
tt BeAeC 1
)(
)( 21
Vc
KXoA
)(
)( 21
Vc
KXoB
![Page 9: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/9.jpg)
Determination of the postdistributionrate constant (β) and the
coefficient (B)
• Postdistribution phase to determine:
1. Determine β from the graph by using the slope
2. The y-axis intercept of the extrapolated line is B
![Page 10: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/10.jpg)
Determination of thedistribution rate constant (α) and
the coefficient (A)• Method of residuals: The
difference between measured concentrations and those obtained by extrapolation of the post-distribution line is plotted vs time
1. Determine α from the graph by using the slope
2. The y-axis intercept of the extrapolated line is A
![Page 11: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/11.jpg)
Determination of micro rate constants: the inter-compartmental rate constants (K21 and K12) and
the pure elimination rate constant (K10)
2110 K
αβ K
102112 - Kβ-KαK
B)(A
BαAβK
21
![Page 12: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/12.jpg)
Volume of distribution of the central compartment (VC)
• Volume of distribution of the central compartment (VC). This is a proportionality constant that relates the amount of drug and the plasma concentration immediately (i.e. at t=0) following the administration of a drug.
BA
XoVc
![Page 13: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/13.jpg)
Volume of distribution during the terminal phase (Vb or Vβ)
• This is a proportionality constant that relates the plasma concentration and the amount of drug remaining in the body at a time following the attainment of distribution equilibrium, or at a time on the terminal linear portion of the plasma concentration time data
VcKV
10
![Page 14: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/14.jpg)
Volume of distribution at steady state (Vss)
• This is a proportionality constant that relates the plasma concentration and the amount of drug remaining in the body at a time, following the attainment of practical steady state. This volume of distribution is independent of elimination parameters such as K10 or drug clearance.
VcK
KK
Css
XssVss
21
1221 )(
![Page 15: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/15.jpg)
The area under the plasmaconcentrationtime curve (AUC)
• Model independent: Trapezoid method
• Model dependent:
BAAUC
dtBeAedttCAUC tt
00.).(
![Page 16: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/16.jpg)
Example: The pharmacokinetics of amrinone after a single IV bolus injection (75 mg) in 14 healthy adult male volunteers followed a two-compartment open model and fit the following parameters:A = 4.62 ± 12.0 µg/mLB = 0.64 ± 0.17 µg/mL = 8.94 ± 13 hr–1
= 0.19 ± 0.06 hr–1
From these data, calculate:a. The volume of the central compartmentb. The volume of the tissue compartmentc. The transfer constants k12 and k21
d. The elimination rate constant from the central compartmente. The elimination half-life of amrinone after the drug has equilibrated with the tissue compartment
![Page 17: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/17.jpg)
![Page 18: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/18.jpg)
![Page 19: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/19.jpg)
X1 X2
K12
K21
K10
1101122211 XKXKXKXK
dt
dXaa
2211122 XKXK
dt
dX
Xa
Ka
Two Compartment Extravascular
![Page 20: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/20.jpg)
X1 X2
K12
K21
K10
Xa
Ka
ttt CeBeAeC 1
CBA
Two Compartment Extravascular
![Page 21: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/21.jpg)
![Page 22: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/22.jpg)
![Page 23: Two-compartment model Mohammad Issa Saleh. Typical plasma concentration (Cp) versus time profiles for a drug that obeys a two-compartment model following.](https://reader035.fdocuments.in/reader035/viewer/2022062304/56649d765503460f94a570ae/html5/thumbnails/23.jpg)