Concentration-dependent plasma protein binding of flurbiprofen in the rat: an in vivo microdialysis study

The in vivo plasma protein binding and pharmacokinetics of flurbiprofen were studied in awake, unrestrained rats using intravenous microdialysis sampling.

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in both groups sampling was carried out by microdialysis, but in the second group an additional 10 blood samples were withdrawn via a jugular cannula.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.

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.

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.