Kinetics of drug action in disease states. XIV. Effect of infusion rate on pentylenetetrazol concentrations in serum, brain and cerebrospinal fluid of rats at onset of convulsions.

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 (approximately 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 brain 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 min and the apparent volume of distribution was 896 +/- 134 ml/kg (all values are mean +/- S.D.). Serum protein binding was negligible (less than 10%).(ABSTRACT TRUNCATED AT 250 WORDS)