C-14-NAVP AND C-14-PEV REPEATED DOSE STUDY IN RAT PHARMACOKINETIC STUDY IN RATS AFTER REPEATED ORAL ADMINISTRATIONS OF C-14-VALPROIC ACID SODIUM-SALT AND C-14-VALPROIC ACID PIVALOYL OXYMETHYL ESTER

The absorption, excretion and tissue distribution of radioactivity aft er repeated oral equimolar doses of C-14-valproic acid sodium salt (Na VP) or C-14-valproic acid pivaloyl oxymethyl ester (PEV) was investiga ted in male rats treated once a day for 14 consecutive days. The 14th day plasma time-course of radioactivity after PEV administrations was characterised by a slow absorption rate with a delayed peak (tmax 2 h, Cmax 7.52 +/- 1.35 mu g eq./ml), followed by a plateau lasting up to 8 h. After NaVP treatment, the main peak of radioactivity was observed 0.5 h after administration (Cmax 8.30 +/- 1.26 mu g eq./ml) followed by a secondary peak due to biliary enterohepatic recycling. Starting f rom 4 h onwards, radioactivity levels after PEV treatment were higher than those af ter NaVP (AUC tau = 113.3 h.mu g eq./ml after PEV vs 71. 9 h.mu g eq./ml after NaVP), but concentrations declined with similar terminal half-lives (52.8 h for PEV and 49.7 h for NaVP). Radioactivit y recovered (0-432 h interval) in urine accounted for 79.3 % (PEV) and 56.1 % (NaVP) while, in faeces accounted for 9.1 % (PEV) and 26.1 % ( NaVP) of total administered dose (14 days). The difference is attribut able to a higher excretion of radioactivity in the bile for NaVP. The missing fraction in the total radioactivity balance is probably excret ed in expired air, as observed in single dose studies. Radioactivity e xcreted in bile (0-8 h interval of the last 14th day) accounted for 5. 1% (NaVP) and 0.23% (PEV) of the total administered dose (14 days). A possible explanation of this difference may be a different metabolism pattern for the two compounds. The negligible biliary excretion observ ed after PEV administration is probably due to an inhibition of the gl ucuronation of valproic acid (or other metabolites) caused by the piva lic acid. Due to the presence of the enterohepatic recycle, the radioa ctivity levels in intestine, 0.5 and 2 h after administration, were hi gher after NaVP administration. According to higher plasma levels, the radioactivity concentrations in liver, kidneys an d some fat tissues were found to be slightly higher after PEV administration. At 120 h af ter the last treatment of both compounds, relevant tissue concentratio ns were observed in mesenteric lymphnodes, perirenal and brown fat. Th e tissue-plasma radio activity ratio appeared quite similar for the tw o compounds.