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Measurement of plasma drug concentrations can provide useful information. It enables doctors to make treatment decisions toward achieving therapeutic concentrations and managing patients suffering an overdose. Concentration measurements enable new formulations of drugs to be registered with regulatory authorities on the basis of bioequivalence. These measures are a prerequisite in the development of new drugs, as the pharmacokinetic information obtained contributes substantially to the determination of dose and dosing interval. If sufficient information is available about relationships between plasma or serum concentrations and therapeutic effect, then determination of speed of onset and comparisons of different drugs become easier. However, interpretation of plasma or serum drug concentrations is not always straightforward. The objective of this review is to examine some of the issues and make some observations with specific reference to one of the most widely available and commonly used antipyretic and analgesic drugs, paracetamol (acetaminophen).
Paracetamol is said to be an effective antipyretic at plasma concentrations of 10-20 mg/l. 1 However, the paper by Rumack, 1 which is often cited as the source of these antipyretic plasma concentrations, provides no data and only refers to an unpublished source. Several papers have documented a time delay of 1-2 h between maximum plasma concentrations (Cmax) and maximum temperature reduction. 2 3 It is reasonable that a time delay should occur, given that the effect site for antipyresis is the hypothalamus, which must induce physiological body change to cause temperature reduction. Fever associated with prostaglandin E-like activity in the cerebrospinal fluid (CSF) has been shown to be abolished by paracetamol, but the drug had no effect on fever that was not mediated by prostaglandins. 4 As the plasma time-concentration profile of paracetamol administered orally is a semi-bell shaped, or rising and falling, curve, a single concentration or range of observed concentrations can be obtained from either side of the curve. To make sense of this, additional information is necessary: when was the sample obtained in relation to dosing and how long after dosing does Cmax occur (Tmax)? A concentration of 10 mg/l, for example, may be found both before and after Cmax. This spot concentration of 10 mg/l after Tmax may be associated with greater fever reduction than the same concentration before Tmax. Conversely, a spot concentration of...