Law of Mass Action

     The rate of an elementary reaction (defined by reduction of reactant or

formation of product) is proportional to the concentration of each individual
species involved in the elementary reaction.

Multiple-Dosing Regimens (Repetitive Dosing)

Graph 1:

Cmax and Cmin are defined as:

where the maximum and minimum plasma concentrations of a repetitive
intravenous dosing regimen can be determined if the dosing interval (T), the
overall elimination rate constant(kel), and the initial plasma concentration are
known.  R is the fraction of the initial plasma concentration that remains at the
end of any dosing interval. 

Repetitive Intravenous Dosing

In repetitive dosing, the plasma concentration at the end of the first dosing
interval is given by:

(1)     CP1T = CP1Oexp(-kelT)

Immediately after the second dose is injected, the plasma [ ] will be,

(2)     CP2O = CP1T + CP1O = CP1Oexp(-kelT) + CP1O   and so on.

We then need to define a certain parameter R, which is the fraction of the initial
plasma concentration that remains at the end of any dosing interval.  R is given
as

(3)     R = exp(-kelT) = 10-(kelT /2.30)

Equations (1) and (2) are simplified into

CP1T = CP1OR

for the plasma concentration at the end of the first dosing interval, and

CP2O = CP1OR + CP1O

for the plasma concentration at the beginning and end of the nth dosing interval.
 Repetitive Intravenous Dosing
The series can be carried further for more doses:

CP2T = (CP1OR + CP1O)R

CP3O = (CP1OR + CP1O)R + CP1O

CP3T = [(CP1OR + CP1O)R + CP1O]R,...,etc.

The nth dosing interval has plasma concentrations at the beginning and end
equalling:

Beginning = CP1O + CP1OR + CP1OR2 +...+CP1ORn-1

End = CP1OR + CP1OR2 + CP1OR3 +...+CP1ORn

R is always smaller than 1 and so Rn becomes smaller as n increases.  High power

terms therefore become neglible as n increases.  Additional doses to the system
will not change the value of CPnO or CPnT significantly and so is why the plasma
concentrations reach a plateau instead of continuing to rise as more doses are
given.  Hence, we define Cmax and Cmin as the plasma concentrations at the
beginning and end, respectively, of the nth dosing interval after the plateau has
been reached.  When n = infinity,

Repetitive Extravascular Dosing

Cmin and Cmax can also be calculated if the drug is administered via an
extravascular route.  The equations however become more complex.  From an
equation describing the plasma concentration versus time curve after one
extravascular administration(@), our new equation may be written as follows:
where D is the dose administered and F is the fraction of the dosage absorbed.
[FD = DGO]

At certain fixed intervals(T), n doses of the drug are administered and so the
plasma concentrations following the nth dose are obtained by

where t' is the time elapsed after the nth dose.  When n is large (as when the
plasma [ ] reach a plateau), the terms exp(-nkelT) and exp(-nkaT) become neglibly
small and so the equation simplifies to

Repetitive Extravascular Dosing

This then can be used to calculate Cmin and Cmax values on the plasma
concentration plateau as we substitite values in for t' that corresponds to the
peaks and valleys in the Cp vs. t curve.  Thus if t'=tmax,

Cmax is:

and Cmin is: