Disposition of two tetramethylcyclopropane analogues of valpromide in the brain, 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 valproic acid (VPA), one of the major antiepileptic drugs (AEDs). In rodent 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, previously studied by us. The following similar PK parameters were obtained for TMCD and M-TMCD, respectively: clearance, 5 and 5.6 ml/min/kg; volume of distribution (V(3s)), 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 ratio 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 plasma and brain to plasma were 1.43 and 0.99, respectively. Thus, both compounds distribute evenly between plasma and brain, but their distribution into the liver is 50% larger than that in the plasma. Therefore, PK analysis of TMCD and M-TMCD brain levels gave major PK parameters similar to those obtained from the plasma data. The fraction metabolized of M-TMCD to TMCD was 32%. The brain was not found to be a metabolic site for the M-TMCD to TMCD biotransformation which occurred primarily in the liver as indicated by the high liver concentrations of TMCD as a metabolite of M-TMCD. Unlike VPD, TMCD and M-TMCD did not undergo amide- acid biotransformation to their corresponding inactive acid, 2,2,3,3- tetramethylcyclopropane carboxylic acid (TMCA). Both M-TMCD and TMCD distribute better into the brain than VPA, a fact that may contribute to their better anticonvulsant activity.