DISPOSITION OF 2 TETRAMETHYLCYCLOPROPANE ANALOGS OF VALPROMIDE IN THEBRAIN, LIVER, PLASMA AND URINE OF RATS

2,2,3,3-Tetramethylcyclopropane carboxamide (TMCD) and N-methyl TMCD ( M-TMCD) are analogues of valpromide (VPD) or amide derivatives of valp roic acid (VPA), one of the major antiepileptic drugs (AEDs). In roden t models both TMCD and M-TMCD are more potent as anticonvulsants than VPA. The present study investigates the pharmacokinetics (PK) of TMCD and M-TMCD in rats by monitoring the levels of these two amides in the brain, liver, plasma and urine of rats. The disposition of TMCD and M -TMCD was analyzed in a comparative manner with that of VPD and VPA, p reviously studied by us. The following similar PK parameters were obta ined for TMCD and M-TMCD, respectively: clearance, 5 and 5.6 ml/min/kg ; volume of distribution (V-ss), 0.72 and 0.96 l/kg; half-life (t(1/2) ), 1.1 and 1.2 h; and mean residence time (MRT), 2.41 and 2.8 h. The r atio of AUCs of TMCD of liver to plasma and brain to plasma were 1.67 and 1.13, respectively. The ratios of the AUCs of M-TMCD of liver to p lasma and brain to plasma were 1.43 and 0.99, respectively. Thus, both compounds distribute evenly between plasma and brain, but their distr ibution into the liver is 50% larger than that in the plasma. Therefor e, PK analysis of TMCD and M-TMCD brain levels gave major PK parameter s similar to those obtained from the plasma data. The fraction metabol ized of M-TMCD to TMCD was 32%. The brain was not found to be a metabo lic site for the M-TMCD to TMCD biotransformation which occurred prima rily in the liver as indicated by the high liver concentrations of TMC D as a metabolite of M-TMCD. Unlike VPD, TMCD and M-TMCD did not under go amide-acid biotransformation to their corresponding inactive acid, 2,2,3,3-tetramethylcyclopropane carboxylic acid (TMCA). Both M-TMCD an d TMCD distribute better into the brain than VPA, a fact that may cont ribute to their better anticonvulsant activity. (C) 1998 Elsevier Scie nce B.V.