Abstracts

Pharmacokinetics may be a limiting factor in the antiepileptic effect of ketone bodies [italic]in vivo[/italic] due to their short half-life. To evaluate this issue, we studied the time course of acute and chronic administration of [beta]-hydroxybutyrate (BHB) isomers in young adult rats. Male Wistar rats, age 5-9 weeks, received either regular water or water containing 3 gm/L racemic sodium [beta]-Hydroxybutyrate (rBHB, n=18) or 2 gm/L (D)[ndash]sodium [beta]-Hydroxybutyrate (dBHB, n=19) for periods ranging from 3 to 14 days before being given an acute convulsant. Blood BHB and glucose levels were obtained throughout the course of ketone administration via standard retro-orbital bleeding techniques and measured using hand held Precision Xtra monitor (Medisense), and/or Ketosite machine (Stanbio Labs). Most of the measurements were taken between the hours of 9 a.m. and 12 noon. Acute kinetics were measured after IP injections of dBHB (300 mg/kg) at 5, 15, 30, 60, and 120 minute intervals. Daily water consumption varied with the weight of the rats. Rats weighing [lt]200 gm averaged 20-30 ml H[sub]2[/sub]O/day, while rats weighing 250-350 consumed 30-50 ml H[sub]2[/sub]O/day. Calculated daily BHB ingestion was 360 mg/kg/day for dBHB-fed rats, and 600 mg/kg/day for rBHB-fed rats. Despite these high doses, BHB levels rarely rose significantly above control levels, even after prolonged administration. With the Medisense monitor, BHB levels did not increase markedly after 1-6 days of ketone water ingestion. Even increasing the dBHB water concentration by 50% did not significantly raise blood BHB levels after 3 days. In later trials, the Ketosite meter was used because more precise and less variable BHB measurements were obtained. After 7 to 14 days of ketone water, BHB levels were still no different than controls (control: 0.14 mM (n=11), rBHB group: 0.16 mM (n=12), dBHB group: 0.15 mM (n=10)). In acute kinetic trials (n=8), an IP injection of 300 mg/kg dBHB attained a peak value at 5 min (1.54 mM) with a rapid decline of BHB blood levels in the first hour. BHB levels were still elevated at 60 minutes after injection (0.29 mM) compared to baseline. The calculated half life was 16.9 min. Glucose levels were taken concurrently with BHB levels and were consistently in the normal to high range (119-205 mg/dL). There was no difference between glucose levels in control and experimental groups (control: 168 mg/dL (n=25), dBHB group: 167 mg/dL (n=24), rBHB group: 149 mg/dL (n=18)). Chronic feeding of two BHB isomers to young adult rats did not achieve ketone levels that were different than controls. This may be explained, in part, by the rapid serum half-life of BHB. The consistency of glucose levels between control and ketone fed rats indicates that glucose did not have a role in the anti-seizure effect of BHB. (Supported by private donations.)