BLOOD-TO-BRAIN TRANSFER OF VARIOUS OXICAMS - EFFECTS OF PLASMA-BINDING ON THEIR BRAIN DELIVERY

Purpose. The objective of this work was to assess the influence of bin ding to plasma proteins and to serum on the brain extraction of four a ntiinflammatory oxicams. Methods. The brain extraction of isoxicam, te noxicam, meloxicam and piroxicam was investigated in rats using the ca rotid injection technique. Blood protein binding parameters were deter mined by equilibrium dialysis using human serum, human serum albumin ( HSA) and alpha-1-acid glycoprotein (AAG) solutions at various concentr ations. Results. All oxicams had low values of brain extraction, betwe en 19% and 39% when dissolved in serum, i.e. under physiological condi tions. Brain efflux rate constants calculated from the wash-out curves were the same in the absence or presence of serum. Brain efflux was i nversely related to the polarity of the oxicams, such that the higher their H-bonding capacity, the lower their brain efflux. The free dialy zable drug fraction was inversely related to protein concentration. Ho wever, rat brain extraction was always higher than expected from in vi tro measurements of the dialyzable fraction. Conclusions. Except for p iroxicam whose brain extraction was partially decreased in the presenc e of proteins, the serum unbound and initially bound fractions of oxic ams both seem available for transfer into the brain. Modest affinities for AAG rule out any related effect. More surprising is the apparent lack of effect on brain transfer of the high-affinity binding to HSA a nd serum. The enhanced brain uptake of meloxicam in the presence of AA G could be a result of interactions between this globular protein and the endothelial wall.