PHARMACOKINETICS OF ELTANOLONE FOLLOWING BOLUS INJECTION AND CONSTANTRATE INFUSION

Disposition of intravenous anaesthetic eltanolone was studied when adm inister ed as a bolus injection (B) of 0.75 mg/kg and constant rate in travenous infusion at 2 mg/kg/hr (I2) and 3.5 mg/kg/hr (I3.5) for 2 hr in healthy male volunteers. Venous blood samples were collected for 1 hr and 20 hr following bolus injection and intravenous infusion, resp ectively. Serum eltanolone concentrations were determined by a specifi c gas chromatographic mass spectrometric assay. Using a nonlinear regr ession analysis, the individual data sets were best fitted by a three- compartment mamillary model with central elimination. Derived pharmaco kinetic parameters expressed as median and 95% confidence intervals in dicated an initial fast distribution with a half-life of 1.80 (0.23-5. 47) min (B), 1.44 (0.97-2.06) min (I2) and 1.44 (0.95-2.39) min (I3.5) , an intermediate phase with a half-life of 35.4 (28.7-45.2) min (B), 39.6 (31.0-47.9) min. (13.5 and 35.4) (33.3-44.9) min (I3.5) and a mod erately short terminal phase with a half-life of 3.8 (2.7-5.9) hr (B), 5.0 (4.2-6.1) hr (I2) and 4.6 (4.0-4.8) hr (I3.5). The serum clearanc e after bolus injection was 1.37 (1.23-1.67) L/hr/kg and after infusio n was 1.36 (1.25-1.52) L/hr/kg (I2) and 1.17 (1.11-1.31) L/hr/kg (I3.5 ). The pharmacokinetics of eltanolone appear to be linear over the dos age range studied. Pharmacokinetic parameters obtained after bolus inj ection were very, much similar to the parameters obtained after infusi on with the exception of t(1/2)beta which was longer after the infusio n (significant) and the volume of central compartment which was longer after infusion (not significant). Context sensitive times were estima ted for a 30%, 50% and 80%, drop in the concentration of eltanolone af ter different infusion times. A 30% drop in concentration is estimated to take about 2 to 3 min. A 50% drop in concentration is estimated to rake about 8 min when duration of infusion is 3 hr and reaches a valu e of about 10 min by a duration of infusion of 10 hr. A 80% drop in co ncentration is estimated to take about 55 min following an infusion of 1 hr and it reaches a value of 70-80 min following an infusion of 10 hr.