P A Evrard1, J Cumps, R K Verbeeck. 1. Pharmacokinetics Laboratory, Catholic University of Louvain, Brussels, Belgium.
Abstract
PURPOSE: The in vivo plasma protein binding and pharmacokinetics of flurbiprofen were studied in awake, unrestrained rats using intravenous microdialysis sampling. METHODS: Flurbiprofen (20 mg/kg) was administered i.v. to 2 groups of 6 rats: in both groups sampling was carried out by microdialysis, but in the second group an additional 10 blood samples were withdrawn via a jugular cannula. In vitro and ex vivo (following i.v. administration of flurbiprofen 20 mg/kg to another group of 13 rats) plasma protein binding of the drug was determined by equilibrium dialysis. RESULTS: The area under the unbound plasma concentration-time profile of flurbiprofen (AUCu), determined by microdialysis sampling was somewhat smaller (-19%, p = 0.666) in the rats undergoing simultaneous serial blood sampling (2.21 +/- 0.36 micrograms.h/ml) as compared to the rats undergoing microdialysis sampling only (2.73 +/- 0.60 micrograms.h/ml). Comparison of total and unbound concentrations of flurbiprofen showed an in vivo plasma binding varying between 99.5% at low and 98.0% at high total flurbiprofen plasma concentrations. Plasma binding of flurbiprofen determined in vitro over the same concentration range was higher (99.5-99.9%) but also concentration-dependent. Plasma binding of flurbiprofen determined ex vivo, on the other hand, corresponded well with the in vivo binding. CONCLUSIONS: Monitoring the fraction of drug unbound in blood of an individual rat throughout a pharmacokinetic experiment has now become possible by using simultaneous sampling of blood and intravenous microdialysates.
PURPOSE: The in vivo plasma protein binding and pharmacokinetics of flurbiprofen were studied in awake, unrestrained rats using intravenous microdialysis sampling. METHODS:Flurbiprofen (20 mg/kg) was administered i.v. to 2 groups of 6 rats: in both groups sampling was carried out by microdialysis, but in the second group an additional 10 blood samples were withdrawn via a jugular cannula. In vitro and ex vivo (following i.v. administration of flurbiprofen 20 mg/kg to another group of 13 rats) plasma protein binding of the drug was determined by equilibrium dialysis. RESULTS: The area under the unbound plasma concentration-time profile of flurbiprofen (AUCu), determined by microdialysis sampling was somewhat smaller (-19%, p = 0.666) in the rats undergoing simultaneous serial blood sampling (2.21 +/- 0.36 micrograms.h/ml) as compared to the rats undergoing microdialysis sampling only (2.73 +/- 0.60 micrograms.h/ml). Comparison of total and unbound concentrations of flurbiprofen showed an in vivo plasma binding varying between 99.5% at low and 98.0% at high total flurbiprofen plasma concentrations. Plasma binding of flurbiprofen determined in vitro over the same concentration range was higher (99.5-99.9%) but also concentration-dependent. Plasma binding of flurbiprofen determined ex vivo, on the other hand, corresponded well with the in vivo binding. CONCLUSIONS: Monitoring the fraction of drug unbound in blood of an individual rat throughout a pharmacokinetic experiment has now become possible by using simultaneous sampling of blood and intravenous microdialysates.