Pharmacokinetics II

The constancy of the process permits
calculation of the plasma volume
that would be cleared of drug, if the remaining
drug were not to assume a homogeneous
distribution in the total volume
(a condition not met in reality).
This notional plasma volume freed of
drug per unit of time is termed the
clearance. Depending on whether plasma
concentration falls as a result of urinary
excretion or metabolic alteration,
clearance is considered to be renal or
hepatic. Renal and hepatic clearances
add up to total clearance (Cltot) in the
case of drugs that are eliminated unchanged
via the kidney and biotransformed
in the liver. Cltot represents the
sum of all processes contributing to
elimination; it is related to the half-life
(t1/2) and the apparent volume of distribution
Vapp (p. 28) by the equation:
Vapp t1/2 = In 2 x ––––
Cltot
The smaller the volume of distribution
or the larger the total clearance, the
shorter is the half-life.
In the case of drugs renally eliminated
in unchanged form, the half-life of
elimination can be calculated from the
cumulative excretion in urine; the final
total amount eliminated corresponds to
the amount absorbed.
Hepatic elimination obeys exponential
kinetics because metabolizing
enzymes operate in the quasilinear region
of their concentration-activity
curve; hence the amount of drug metabolized
per unit of time diminishes
with decreasing blood concentration.
The best-known exception to exponential
kinetics is the elimination of alcohol
(ethanol), which obeys a linear
time course (zero-order kinetics), at
least at blood concentrations > 0.02 %. It
does so because the rate-limiting enzyme,
alcohol dehydrogenase, achieves
half-saturation at very low substrate
concentrations, i.e., at about 80 mg/L
(0.008 %). Thus, reaction velocity reaches
a plateau at blood ethanol concentrations
of about 0.02 %, and the amount of
drug eliminated per unit of time remains
constant at concentrations above
this level.