M.J. Garrido1, M van den Haak, M Danhof and P-H van der Graaf2
Leiden/Amsterdam Center for Drug Research, Division of Pharmacology. Box 9503, 2300 RA Leiden (The Netherlands). Current address: 1)Department of Pharmacy, Faculty of Pharmacy, University of Navarra, 31080 Pamplona (Spain). 2)Pfizer Central Research (UK).
Aim: The aim of this study was to investigate the in vivo pharmacokinetics (pk) of low-efficacy -opioid receptor agonists, butorphanol and nalbuphine using a population approach.
Methods: Male Wistar rats (250-300g) randomly divided into four groups, were used to study the pk of butorphanol (n=3groups) and nalbuphine (n=1group). Butorphanol was administered in 10 min i.v. infusion of 2.5, 5 and 10mg/kg, respectively; and nalbuphine was also infused in 10 min i.v. infusion of 5mg/kg. The total volume infused for all groups was 0.4ml. Several blood samples were collected during and after infusions for both compounds, which were directly hemolyzed and measured by an HPLC assay developed in our group. The respiratory parameters, pH, pCO2 and pO2 were also measured at different times during the experiments to monitor the respiratory effect and the body temperature was kept between 37 and 38ºC using an electrical thermopad. To prevent undesired convulsions, the animals received a steady-state continuous infusion of midazolam during the experiments. Pk analysis was performed by NONMEM program (version V).
Results: The pharmacokinetics of butorphanol and nalbuphine were adequately described by a two compartment model with first order rate elimination from the central compartment. In the case of butorphanol, pk was not dose-dependent, since no significant (P>0.05) differences were found between parameters. The interindividual variability was associated to volume of distribution at the steady-state (Vss) and total clearance (Cl); and the intraindividual variability was described using a proportional error model. No changes in the respiratory parameters were observed for any of the groups, only a slight decrease in pH could be found for butorphanol as well as nalbuphine, however, that decrease was not statistically different from the pH control value in rats. The average midazolam concentrations measured at three different times during the experiment were the same in all animals.
Reference: PAGE 9 (2000) Abstr 110 [www.page-meeting.org/?abstract=110]
Poster: poster