No abstract

The concentration of 6-phosphogluconate in the brain increased from 0-24 nmol/g in the controls to 1430 and 1506 nmol/g in rats treated with 50 mg of 6-aminonicotinamide/kg of body weight. A dose-dependent increase in the concentrations of glucose and glucose 6-phosphate as well as of 6-phosphogluconate was found in the brains of 6-aminonicotinamide-treated rats. The biochemical changes and symptoms of neurological disorder in 6-aminonicotinamide-treated rats were not due to hypothermia. The rate of utilization of glucose via the hexosemonophosphate shunt was determined by isolation of gluconate from 6-phosphogluconate and measurement of its [14C]content at short time intervals after injection of [U-14C]glucose into 6-aminonicotinamide-treated rats; it was 16.5 nmol of glucose utilized/min per g of brain, and represented approximately 2.3% of the overall utilization of glucose in the brain. A highly significant correlation was observed between the concentration of 6-phosphogluconate and the concentration of glucose 6-phosphate and free glucose. The validity of this correlation was supported by the results of previous investigations involving several other treatments.

A major limitation of conventional carbamazepine (CBZ) formulations is their pharmacokinetics, which typically require q.i.d. dosing. Two extended-release formulations of CBZ have been developed recently to support b.i.d. dosing. One, Carbatrol (CBTL) uses immediate-, extended-, and enteric-release beads in a capsule. The other, Tegretol-XR (TXR), uses an osmotic pump (Oros tablet). To our knowledge, this is the first head-to-head comparison of the multidose pharmacokinetics of these two new formulations. The objective of the study was to evaluate the pharmacokinetics of carbamazepine (CBZ) and CBZ-10,11-expoxide (CBZ-E) after multidose b.i.d. dosing with CBTL or TXR. In this randomized, crossover study, 15 normal healthy adults received 400 mg of each formulation b.i.d. for 5 days. Blood samples for CBZ and CBZ-E analysis were obtained prior to morning doses on all days and hourly for 12 h after the Day 5 dose. There was a minimum interperiod washout of 9 days. For CBTL and TXR, the key CBZ pharmacokinetic measures of area under the curve of concentration versus time (AUC(0-tau)), maximum concentration (Cmax), and minimum concentration (Cmin) were bioequivalent. The ratio for CBTL-to-TXR was 98% (90% confidence intervals, 92-104%), 107% (96-118%), and 96% (89-104%), respectively. Similar ratios were also observed for CBZ-E: 102% (97-107%), 99% (92-107%), and 93% (83-109%), respectively. In conclusion, CBTL b.i.d. and TXR b.i.d. were bioequivalent in their pharmacokinetic parameters for CBZ and CBZ-E after 5 days of dosing.

Abstract— To obtain evidence of the site of conversion of [U‐14C]glucose into glutamate and related amino acids of the brain, a mixture of [U‐14C]glucose and [3H]glutamate was injected subcutaneously into rats. [3H]Glutamate gave rise to several 3H‐labelled amino acids in rat liver and blood; only 3H‐labelled glutamate, glutamine or γ‐aminobutyrate were found in the brain. The specific radioactivity of [3H]glutamine in the brain was higher than that of [3H]glutamate indicating the entry of [3H]glutamate mainly in the ‘small glutamate compartment’. The 14C‐labelling pattern of amino acids in the brain and liver after injection of [U‐14C]glucose was similar to that previously reported (Gaitondeet al., 1965). The specific radioactivity of [14C]glutamine in the blood and liver after injection of both precursors was greater than that of glutamate between 10 and 60 min after the injection of the precursors. The extent of labelling of alanine and aspartate was greater than that of other amino acids in the blood after injection of [U‐14C]glucose. There was no labelling of brain protein with [3H]glutamate during the 10 min period, but significant label was found at 30 and 60 min. The highest relative incorporation of [14C]glutamate and [14C]aspartate in rat brain protein was observed at 5 min after the injection of [U‐14C]glucose. The results have been discussed in the context of transport of glutamine synthesized in the brain and the site of metabolism of [U‐14C]glucose in the brain.