Pharmacokinetics and pharmacodynamics of a new reformulated microemulsion and the long-chain triglyceride emulsion of propofol in beagle dogs.
OBJECTIVE
Microemulsion propofol was developed to eliminate lipid solvent-related adverse events of long-chain triglyceride emulsion (LCT) propofol. We compared dose proportionality, pharmacokinetic and pharmacodynamic characteristics of both formulations.


METHODS
The study was a randomized, two-period and crossover design with 7-day wash-out period. Microemulsion and LCT propofol were administered by zero-order infusion (0.75, 1.00 and 1.25 mg kg(-1) min(-1)) for 20 min in 30 beagle dogs (male/female = 5/5 for each rate). Arterial samples were collected at preset intervals. The electroencephalographic approximate entropy (ApEn) was used as a measure of propofol effect. Dose proportionality, pharmacokinetic and pharmacodynamic bioequivalence were evaluated by non-compartmental analyses. Population analysis was performed using nonlinear mixed effects modelling.


RESULTS
Both formulations showed dose proportionality at the applied dose range. The ratios of geometric means of AUC(last) and AUC(inf) between both formulations were acceptable for bioequivalence, whereas that of C(max) was not. The pharmacodynamic bioequivalence was indicated by the arithmetic means of AAC (areas above the ApEn time curves) and E(0) (baseline ApEn)-E(max) (maximally decreased ApEn) between both formulations. The pharmacokinetics of both formulations were best described by three compartment models. Body weight was a significant covariate for V(1) of both formulations and sex for k(21) of microemulsion propofol. The blood-brain equilibration rate constants (k(e0), min(-1)) were 0.476 and 0.696 for microemulsion and LCT propofol respectively.


CONCLUSIONS
Microemulsion propofol was pharmacodynamically bioequivalent to LCT propofol although pharmacokinetic bioequivalence was incomplete, and demonstrated linear pharmacokinetics at the applied dose ranges.
Lee
S-H
SH
Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Ghim
J-L
JL
Song
M-H
MH
Choi
H-G
HG
Choi
B-M
BM
Lee
H-M
HM
Lee
E-K
EK
Roh
Y-J
YJ
Noh
G-J
GJ
D018686:Anesthetics, Intravenous / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001835:Body Weight; D018592:Cross-Over Studies; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004655:Emulsions; D019277:Entropy; D005260:Female; D008297:Male; D008954:Models, Biological; D017711:Nonlinear Dynamics; D015742:Propofol / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D011897:Random Allocation; D013810:Therapeutic Equivalency; D014018:Tissue Distribution; D014280:Triglycerides / Q000737:chemistry*
D018686:Anesthetics, Intravenous; D004655:Emulsions; D014280:Triglycerides; D015742:Propofol