Application of 4-hydroxyantipyrine and acetaminophen O-sulfate as biodistribution promoter

The effects of 4-hydroxyantipyrine (4-OH), a major metabolite of antipyrine and its sulfate, 4-hydroxyan-tipyrine O-sulfate (4-S), on the pharmacokine tics of citicoline and thiopental sodium were investigated in rats. The con comitant use of 4-OH increased significantly the tissue-to-plasma concentra tion ratio (K-p) of citicoline in the brain and liver and that of thiopenta l sodium in the brain, liver, and heart, while 4-S did not affect them. The permeability clearance of blood-brain barrier (BBB) (K-in) and the total d istribution volume (V-dbr) of citicoline were not affected by either 4-OH o r 4-S. However, those of thiopental sodium were significantly increased by not only 4-OH but also by 4-S. On the other hand, the plasma concentration of antipyrine Nas significantly decreased by the intravenous bolus coadmini stration of V-acetyl-p-aminophenyl O-sulfate (ARAPS) at steady-state plasma concentration of antipyrine. A similar reduction Nas not observed with the intravenous coadministration of acetaminophen (ARAP). The K-p value of ant ipyrine was significantly increased in the brain by the coadministration of APAPS, but was not affected by APAP The increment in the drug distribution to the brain with the concomitant use of 4-OH (or APAPS) observed in this study is useful information for the application of drug combinations as bio distribution promoters.