Pethidine binding in whole blood: methodology and clinical significance

A three-compartment equilibrium dialysis method was developed for the simultaneous and direct determination of drug binding in whole blood and in plasma and of the blood to plasma concentration ratio (b/p). The unbound fraction of pethidine in the blood of six healthy volunteers (0.63, s.d. 0.09, n = 23 determinations) was significantly different from that in the blood of six patients (0.72, s.d. 0.08, n = 24 determinations). There was no significant difference in the b/p of six patients (0.84, s.d. 0.09, n = 24 determinations) and six volunteers (0.90, s.d. 0.14, n = 23 determinations). The observed unbound fraction of pethidine in blood (0.6 to 0.7) was considerably lower than previously reported. As this value for the unbound fraction (0.6 to 0.7) is similar to the reported estimated hepatic extraction ratio of the drug in man, it is proposed that pethidine elimination should be described as 'capacity limited, binding sensitive' rather than 'flow-limited'.