Clinical Pharmacology and Therapeutics

16 PHARMACOKINETICS
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 drugelimination
process is saturated (Figure 3.8). This is very
important clinically when using plasma concentrations of,
for example, phenytoin as a guide to dosing.
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.
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 25 μmol/L. (Therapeutic range is
40–80 μmol/L.) The dose is increased to 300 mg/day. One
week later he is complaining of unsteadiness, there is nystagmus
and the serum concentration is 125 μmol/L. The
dose is reduced to 250 mg/day. The patient’s symptoms
slowly improve and the serum phenytoin concentration
falls to 60 μmol/L (within the therapeutic range).
Comment
Phenytoin shows dose-dependent kinetics; the serum concentration
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).
FURTHER READING
Rowland M, Tozer TN. Therapeutic regimens. In: Clinical pharmacokinetics:
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!)