Distribution in female rats of an anaesthetic intravenous dose of 14C-propofol.
1. Bolus i.v. doses of 14C-propofol (9 mg/kg) were administered to female rats for measurement of tissue levels of total 14C and propofol from 2 min to 24 h post-dose; whole-body autoradiography was studied at 6 min, 2 h and 24 h post-dose, and also involved 15-day pregnant rats. 2. The blood propofol concentration-time profile was fitted by a tri-exponential function corresponding to a three-compartment open model. Data show rapid distribution during the mixing period into highly perfused tissues and muscle, comprising the central compartment, and slower uptake into less well-perfused skin and adipose tissues comprising the deeper compartments. 3. The initial decline in blood propofol concentration was associated with redistribution (t1/2 4 min), the second decline (15-240 min post-dose) was associated with metabolism (t1/2 33 min) and the third decline reflected slow depletion of drug from deep tissue compartments (t1/2 6.4 h). 4. Blood and brain propofol concentrations on waking (at 7 min post-dose) were 4 micrograms/ml and 9 micrograms/g respectively; the model shows that, at this time, 30% of the dose was lost from the central compartment by redistribution and a similar amount by metabolism. 5. Tissue profiles of total 14C and propofol diverged for highly perfused tissues (other than brain) because of slow clearance of metabolites, accentuated by enterohepatic recirculation.
Simons
P J
PJ
Safety of Medicines Department, ICI Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, UK.
Cockshott
I D
ID
Douglas
E J
EJ
Gordon
E A
EA
Knott
S
S
Ruane
R J
RJ
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D005260:Female; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009132:Muscles / Q000378:metabolism; D015742:Propofol / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D015742:Propofol