KINETICS OF DRUG-ACTION IN DISEASE STATES .1. EFFECT OF INFUSION RATE ON PHENOBARBITAL CONCENTRATIONS IN SERUM, BRAIN AND CEREBROSPINAL-FLUID OF NORMAL RATS AT ONSET OF LOSS OF RIGHTING REFLEX

  • 1 January 1984
    • journal article
    • research article
    • Vol. 229  (1) , 44-50
Abstract
The purpose of this investigation was to develop a method to determine the effect of various diseases on the concentration-pharmacologic activity relationship of phenobarbital (PB) in a manner that excludes or accounts for pharmacokinetic variables affecting drug disposition. Adult female rats (.simeq. 180 g) received an i.v. infusion of PB at one of 5 different rates (0.412-4.12 mg/min) until the animals lost their righting reflex (after 8.0 .+-. 0.4 to 62 .+-. 10 min of infusion). The total dose, the serum concentration (both total and unbound drug) and the brain concentration of PB at onset of loss of righting reflex (LRR) increases with increasing infusion rate. The PB concentration in cerebrospinal fluid at onset of LRR (mean .+-. S.D.: 108 .+-. 19 .mu.g/ml, n [no.] = 29) was not affected by the infusion rate. Concomitant infusion of PB and its p-hydroxy metabolite had no apparent effect on the concentrations of PB at onset of LRR even though the serum concentration of p-hydroxy PB was higher than upon infusion of PB only. CSF, unlike some regions of the brain, evidently equilibrates very rapidly with the biophase of the receptors for PB-induced LRR. Determination of PB concentrations in the CSF at the onset (rather than offset) of action facilitates assessement of the effect of diseases on the PB concentration-pharmacologic activity relationship by avoiding development of acute tolerance and excluding or minimizing effects due to disease-associated pharmacokinetic variables such as altered plasma protein binding and body distribution of the drug. The use of a barbiturate with a relatively long biologic half-life, and of onset rather than offset of LRR as the pharmacodynamic endpoint, also minimizes effects due to known or unknown drug metabolite(s). The method should therefore be generally useful for assessing the effects of diseases and other variables on the pharmacodynamics of many drugs with CNS activity.

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