BIOPHARMACEUTICS AND
PHARMACOKINETICS
613-T
MISS NIMRA WAHEED
1
Learning Objectives
• In two compartment extravascular model the drug is taken orally
how is absorbed , distributed first in the central compartment and
than goes in the peripheral tissue compartment and eliminated from
the body occurs from the central compartment.
• We will know how to draw the graph and calculate the
pharmacokinetic parameters.
• The pharmacokinetic parameters helps in calculating the
methamethical formula for the calculation of rate constants
,biological half life , volume of distribution and area under the curve.
2
Previous Lecture
• In the last lecture we the studied about the solved example of
One compartment EV Model with lag time .
• We have studied how to draw graph and calculate
pharmacokinetic model of one compartment EV model.
3
TWO COMPARTMENT
EXTRAVASCULAR
TWO-COMPARTMENT EXTRAVASCULAR MODEL
A schematic representation of a two-compartment pharmacokinetic model following
extravascular administration is shown in Fig. 12-11. This schematic consists of two
rectangular boxes to represent two- compartments: central compartment and tissue
compartment reversibly connected to each other by first- order rate constants of
transfer of drug from central compartment into the tissue compartment, and from
tissue compartment into the central compartment. Drug input takes place in the
central compartment and drug elimination also takes place from central
compartment.
PLASMA PROFILE
After first-order absorption, the drug appears in the central compartment,
followed by first-order distribution into the tissue compartment and first-order
elimination from the central compartment. It is assumed that the rate of
absorption of drug is greater than its elimination rate. The plasma profile of
the two-compartment pharmacokinetic model following extravascular
administration differs from the plasma profile seen in two-compartment model
after intravenous administration, in that the extravascular profile shows an
absorption phase. Also, the post-absorptive phase is not linear (as was seen in
extravascular one-compartment model), but it is biphasic. was seen in two-
compartment intravenous model.
Fig. 12-12 is a typical plasma profile of a two-compartment model following
extravascular administration. This profile consists of the following four segments:
(a) the initial portion of the graph reflects absorption, beginning of distribution, and
elimination. This is followed by distribution of drug between the central and tissue
compartments,
(b) the peak reflects distribution equilibrium, elimination, and beginning of decline
of absorption,
(c) the middle portion of the biphasic curve represents distribution, predominance
of elimination, and for all practical purposes, termination of absorption, and
(d) the terminal portion of the plasma profile represents essentially elimination.
This plasma profile therefore consists of the following first-order processes:
(i)first-order absorption of drug,
(ii) first-order elimination of drug, and
(iii) first-order distribution of drug between the central and the tissue compartment.
The plasma profile of a drug, which confers the characteristics of a two-
compartment model upon the body, is described by the following tri-exponential
equation:
where,
C = plasma drug concentration,
• B = the y-intercept of the back extrapolated terminal phase of plasma concentration
data,
• β= the hybrid micro-consant obtained from the slope of the linear segment having
the y-intercept = B,
• P = the y-intercept of back extrapolated terminal phase of linear segment obtained
after first feathering,
• = the hybrid micro-constant obtained from the slope of the linear segment having
the y-intercept =P,
• A = the y-intercept of back extrapolated terminal phase of linear segment
obtained after second feathering,
• α = the hybrid micro-constant obtained from the slope of the linear segment having
the y-intercept = A, and
• t = time.
In this equation, α > > β. The hybrid micro- constant α represents the rate constant of
absorption (Ka), and the hybrid micro-constant β represents the rate constants of
elimination of drug from the body.
FEATHERING
A series of residual concentration-time values are obtained when one subtracts
concentration-time values on the back-extrapolated line from the corresponding true
plasma concentration-time values (data points). Some residual concentration values
obtained by subtraction will have a negative value. These are from the data points
which fall below the back-extrapolated straight line. The data points which fall above
the back-extrapolated straight line yield positive values.
The y-intercepts B, P, and A, are complex functions of the following.
(a) the administered dose (D).
(b) fraction of the administered dose absorbed (F).
(c) the three hybrid micro-constants (α,, , and β)
(d) rate constant of transfer of drug from tissue compartment into the central
compartment (K21), and
(e) the apparent volume of central compartment (Vc).
The three y-intercepts B, P, and A are defined as follows:
PHARMACOKINETIC PARAMETERS
Several equations have been proposed to calculate the pharmacokinetic parameters
associated with a two-compartment model. Some of these are given here.
RATE CONSTANTS:
There are four first-order rate constants associated with a two-compartment
extravascular pharmacokinetic model, These are
(i) rate constant of absorption (Ka = α),
(ii) rate constant of elimination of drug from the central compartment (K10),
(iii) rate constant of transfer of drug from the central compartment into the tissue
compartment (K12), and
(iv) rate constant of transfer of drug from the tissue compartment into the central
compartment (K21).
These rate constants are determined using the following equations:
BIOLOGICAL HALF-LIFE:
VOLUMES OF DISTRIBUTION:
The apparent volumes of distribution in a two-compartiment model are
(i)the apparent volume of central compartment and
(ii) the apparent volume of tissue compartment.
The total volume of distribution is the sum total of apparent volumes of distrībution of drug in
the central and tissue compartments.
The apparent volume of central compartment and the apparent volume (total) of distribution
of the drug are calculated using the following equations, and the apparent volume of the tissue
compartment is determined by difference:
AREA UNDER THE CURVE:
The total area under the curve is determined using the equation:
Summary:
• We have studied the two compartment extravascular model.
• We have studied how to draw the graph and calculate the
pharmacokinetic parameters in which we have calculated the rate
constants, biological half life , volume of distribution and area under
the curve.
Further Reading and References
• Book: Biopharmaceutics and
pharmacokinetics by PL Madan
• Chapter 12
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