EARLY PHARMACOKINETICS OF MIDAZOLAM SAMPLING SITE AND SCHEDULE CONSIDERATIONS

The influence of sampling site and sampling schedule on the early pharmacokinetics of a lipophilic drug, midazolam, was studied in 6 anaesthetised patients following an intravenous bolus injection of 0.05 mg/kg. Arterial and venous blood samples were drawn simultaneously over a period of 180 minutes. An extensive sampling procedure was used during the initial distribution phase; specifically, 12 arterial and 4 venous samples within the first 2 minutes. Midazolam concentrations were measured by high-performance liquid chromatography. Compared with peak venous concentrations, peak arterial concentrations were 2-fold greater and were reached 1 minute earlier. Although arterial concentrations exceeded corresponding venous concentrations for up to 90 minutes, a significant arteriovenous difference was observed during the first 2 minutes only. Consequently, noncompartmental pharmacokinetic parameters (mean residence time, volume of distribution at steady-state, total body clearance) obtained from arterial and venous values did not differ significantly. In addition, similar results were obtained for pharmacokinetic parameters using either the complete (continuous sampling over 2 minutes) or limited (assuming 1- and 2-minute samples only) arterial data set. It is concluded that both the sampling site and the sampling schedule altered the initial plasma concentration-time profile of midazolam. Although neither of these factors had a strong influence on the overall pharmacokinetic parameters of midazolam, their potential effect on the pharmacokinetic/pharmacodynamic relationship of midazolam during the onset phase should be considered.