Nerea Leal(1), Monica Rodriguez(1), Rosario Calvo(1), Fatima Agrad(1), Leire de la Fuente(2), Elena Suarez(1), John C Lukas(3)
(1)Department of Pharmacology, School of Medicine, University of the Basque Country, Leioa, Spain; (2)PharmaDatum, Edificio BEAZ, Sangroniz, Sondika; (3)Department of Pharmacy, Laboratory of Pharmacokinetics and Biopharmaceutics, University of Athens, Athens, Greece.
Background: Propofol shows large variability in the hypnotic dose that may be due to pharmacokinetic and/or pharmacodynamic alterations caused by pathologies, so possibly also by diabetes mellitus (DM). The authors tested the influence of iatrogenic DM in the animal model in the induction dose and the time to the same endpoint (hypnosis) was lower in DM but the observed weight loss and alterations in the binding ratio explained the difference only partially. The pathology of the disease is known to include physiological changes in membrane permeability and metabolism among others and this remains undetermined.
Purpose: The pharmacokinetics and pharmacodynamics of propofol were studied in the DM rat model in order to elucidate the observed differences at induction of the hypnotic effect.
Methods: Diabetes was induced in rats (n = 10) by 60 mg/kg i.p. streptozotocin. Control rats (n = 8) received vehicle i.p. Glucose, cholesterol, triglycerides and albumin levels were determined in all animals. To study the pharmacokinetics, propofol was administered at 6 mg/kg/min for 2 minutes and 11 to 12 arterial blood samples were taken between 2.5 and 540 min and assayed for total propofol by HPLC. Bi and tricompartmental models were used with the FOCE method in NONMEM to analyze the observations. The –2LLD objective function difference at the 7.5 (p < 0.005) level, the SE estimates and residual plots were the criteria for model development.
Results: The pharmacokinetics differed structurally between control and DM rat groups. A bicompartmental description optimally explained kinetics under DM while a tricompartmental model described the observations in controls. In DM, central clearance was (mean [intercompartmental CV%]) CL = 0.024 L/min (61%), central volume, Vc = 0.2 L (45%), intercompartmental clearance, Q = 0.01 L/min (42%) and peripheral volume, Vt = 0.83 L (no CV estimate). In controls, CL = 0.028 L/min (28%), Vc = 0.24 L (11%), Q1 = 0.045 L/min (56%), V2 = 0.26 L (8%), Q2 = 0.034 L/min (31%), V3 = 5.49 L (no CV estimate).
Conclusions: The kinetics of propofol in rats is altered by diabetic disease hence the initial distribution and elimination phases, of primary interest in anesthesia, differ. It may be of interest to perform studies in humans. We are in the process of analyzing the pharmacodynamics and covariate relationships in rats. The population distributions can be utilized to explore dosing protocols via simulation.
Reference: PAGE 12 (2003) Abstr 420 [www.page-meeting.org/?abstract=420]
Poster: poster