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Plasma protein binding of drugs has important implications for drug disposition and action since it is the first, and controlling, step in drug distribution. Physiological changes in pregnancy include significant changes in plasma composition which affect drug binding and subsequent drug response; the extent of these changes depends on the stage of gestation. Both albumin and alpha 1-acid glycoprotein fractions are reduced, and consequently the binding of both acidic and basic drugs may be affected. This may lead to difficulties in maintaining adequate plasma concentrations of highly protein-bound drugs, since the measurement of total drug concentration in plasma may no longer be a valid indicator for dose adjustment. The newborn infant displays a continually changing plasma profile. The presence of fetal proteins and endogenous substrates known to interfere with drug binding can lead to unexpected complications due to a higher than expected 'free' drug fraction. Furthermore, a decrease in the affinity of albumin for bilirubin during this period may lead to bilirubin displacement by drugs such as diazepam, sulphonamides and salicylate, resulting in clinical jaundice which would not occur beyond the neonatal period. Plasma composition and its effect on drug binding should be taken into account when prescribing highly protein bound drugs with narrow therapeutic: toxic ratios.

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1 Paracetamol was administered to nursing mothers. The drug passed rapidly into milk and the milk:plasma concentration ratio was approximately unity. 2 The estimated maximum dose to the neonate was 1.85% of the weight-adjusted maternal oral dose of paracetamol 1.0 g. Recovery of paracetamol was greater from the breast from which samples were taken frequently than from the breast which was sampled only once. 3 Paracetamol, its glucuronide, sulphate, cysteine and mercapturate conjugates were found in the urine of the neonates although only the parent drug was detected in breast milk.4 The neonates excreted significantly greater proportions of unchanged paracetamol (P < 0.01) and significantly lesser proportions of paracetamol sulphate (P < 0.001) than did healthy volunteers aged 11-80 years who received a therapeutic dose of paracetamol. 5 The findings are compatible with a deficiency of sulphate conjugation by the neonate.Keywords paracetamol neonate metabolism breast milk biotransformation

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