FURTHER READING
Rowland M, Tozer TN. Therapeutic regimens. In: Clinical pharmacoki-
netics: concepts and applications, 3rd edn. Baltimore, MD: Williams
and Wilkins, 1995: 53–105.
Birkett DJ. Pharmacokinetics made easy (revised), 2nd edn. Sydney:
McGraw-Hill, 2002. (Lives up to the promise of its title!)begins slowly and accelerates as plasma concentration
falls (Figure 3.7).
2.The time required to eliminate 50% of a dose increases
with increasing dose, so half-life is not constant.
3.A modest increase in dose of such a drug disproportionately
increases the amount of drug in the body once the drug-
elimination process is saturated (Figure 3.8). This is very
important clinically when using plasma concentrations of,
for example, phenytoinas a guide to dosing.
16 PHARMACOKINETICS
Case history
A young man develops idiopathic epilepsy and treatment
is started with phenytoin, 200 mg daily, given as a single
dose last thing at night. After a week, the patient’s serum
phenytoin concentration is 25μmol/L. (Therapeutic range is
40–80μmol/L.) The dose is increased to 300 mg/day. One
week later he is complaining of unsteadiness, there is nys-
tagmus and the serum concentration is 125μmol/L. The
dose is reduced to 250 mg/day. The patient’s symptoms
slowly improve and the serum phenytoin concentration
falls to 60μmol/L (within the therapeutic range).
Comment
Phenytoin shows dose-dependent kinetics; the serum con-
centration at the lower dose was below the therapeutic
range, so the dose was increased. Despite the apparently
modest increase (to 150% of the original dose), the plasma
concentration rose disproportionately, causing symptoms
and signs of toxicity (see Chapter 22).Key points- Two-compartment model. Following a bolus dose the
plasma concentration falls bi-exponentially, instead
of a single exponential as in the one-compartment
model. The first ( ) phase mainly represents
distribution; the second () phase mainly represents
elimination. - Non-linear (‘dose-dependent’) kinetics. If the
elimination process (e.g. drug-metabolizing enzyme)
becomes saturated, the clearance rate falls.
Consequently, increasing the dose causes a
disproportionate increase in plasma concentration.
Drugs which exhibit such properties (e.g. phenytoin)
are often difficult to use in clinical practice.