KINETICS OF DRUG-ACTION IN DISEASE STATES .14. EFFECT OF INFUSION RATE ON PENTYLENETETRAZOL CONCENTRATIONS IN SERUM, BRAIN AND CEREBROSPINAL-FLUID OF RATS AT ONSET OF CONVULSIONS

  • 1 January 1985
    • journal article
    • research article
    • Vol. 234  (3) , 624-628
Abstract
The purpose of this investigation was to develop a method which can be used to determine the effect of various diseases on the concentration-pharmacologic activity relationship of the central nervous system stimulant pentylenetetrazol (PTZ, Metrazol) in a manner that excludes or accounts for pharmacokinetic variables. Adult female rats (.apprx. 170 g) received an i.v. infusion of PTZ at one of four different rates (0.155-1.53 mg/min) until the animals exhibited the first myoclonic jerk. This occurred after an average of 4.9 to 52 min of infusion. The PTZ concentrations in serum, brain and cerebrospinal fluid at this pharmacologic endpoint were independent of infusion rate. Other groups of rats were infused at three different rates (0.155-1.53 mg/min) to the onset of maximal seizures. Again, the PTZ concentrations in serum, brain and cerebrospinal fluid were not significantly affected by the rate of infusion of the drug. The average (.+-. S.D.) PTZ concentration in cerebrospinal fluid was 46 .+-. 5 mg/l (n = 22) at the onset of the first myoclonic jerk and 109 .+-. 13 mg/l (n = 12) at the onset of maximal seizure. PTZ concentrations in bran and serum were similar to those in cerebrospinal fluid. The total serum clearance of a 20-mg/kg i.v. bolus dose of PTZ was 5.36 .+-. 0.34 ml/min/kg, the terminal half-life was 116 .+-. 25 mn and the apparent volume of distribution was 896 .+-. 134 ml/kg (all values are mean .+-. S.D.). Serum protein binding was negligible (< 10%). The results of this investigation show that PTZ distributes very rapidly from the systemic circulation to the central nervous system, including sites of action, and suggest that PTZ metabolites do not contribute significantly to the pharmacologic action of the drug. The timed-infusion method is therefore suitable for determining the effect of underlying diseases on the pharmacodynamics of PTZ.