The use of microdialysis for the study of drug kinetics: some methodological considerations illustrated with antipyrine in rat frontal cortex.

1. The neuropharmacokinetics of antipyrine, a readily dialysable drug, in rat frontal cortex were studied and the effect of sampling time and contribution of period sampling and dialysate dead volume investigated in relation to tmax, Cmax, AUC and t1/2 values. 2. After i.p. administration, antipyrine (35 mg kg-1, n = 5) concentrations rose rapidly in rat frontal cortex (tmax, 12 min) and then declined exponentially tmax, Cmax, AUC and t1/2 values were determined after 2 min dialysate sampling and compared to values obtained from simulated sampling times of 4, 6, 8, 10 and 20 min. 3. Antipyrine tmax and Cmax values were directly dependent on sampling frequency. Thus, mean 2 min sampling tmax and Cmax values were 63% lower and 27% higher, respectively, compared to 20 min sampling values. AUC and t1/2 values were unaffected. 4. Adjustment for dialysate dead volume (the volume of dialysate within the dialysis probe and sampling tube) reduced tmax values significantly but did not affect the other neuropharmacokinetic parameters. 5. Contribution of period sampling on neuropharmacokinetic parameters were investigated by comparing plots of antipyrine concentration data at midpoint and at endpoint of sampling time interval. Only tmax values were affected with values decreasing with increasing sampling time interval. 6. In conclusion, although microdialysis is a useful method for monitoring events at the extracellular level and for kinetic studies, it is important to understand its inherent characteristics so that data can be interpreted appropriately. Sampling frequency, particularly during monitoring of periods of rapid change, is very important since Cmax and tmax values will be significantly underestimated and overestimated respectively, if sampling time is longer rather than shorter. These considerations are particularly important in relation to microdialysis studies of pharmacokinetic-pharmacodynamic interrelationships and modelling.

Alterations of lidocaine and pentylenetetrazol-induced convulsions by manipulation of brain monoamines.

The thresholds for pentylenetetrazol and lidocaine-induced clonic convulsions were significantly influenced by manipulation of brain biogenic amines. Pretreatment with inhibitors of monoamine synthesis, alpha-methyl-p-tyrosine and p-chlorophenylalanine, caused significant decreases in brain monoamine contents and pentylenetetrazol seizure threshold, while the threshold for lidocaine-induced convulsions was significantly increased by either treatment. Moreover, the inhibitor of dopamine-beta-hydroxylase, disulfiram, caused significant decrease in brain noradrenaline (NA) and significant increase in brain dopamine (DA) contents. The threshold for pentylenetetrazol-induced convulsions was decreased by treatment with disulfiram, while that of lidocaine was increased by the same treatment. Furthermore, treatment with L-dihydroxyphenylalanine (L-DOPA) caused significant increase in brain DA contents, while 5-hydroxytryptophan (5-HTP) treatment caused significant increase in brain 5-hydroxytryptamine (5-HT) contents, but the thresholds for lidocaine and pentylenetetrazol-induced convulsions were not influenced by either treatment. These results may suggest that the brain monoaminergic systems, different from their ability to inhibit control of pentylenetetrazol seizures, act to potentiate lidocaine-induced convulsions.

An evaluation of the epileptogenic properties of a rifampicin/clindamycin-impregnated shunt catheter.

A process has been developed by which ventriculoperitoneal hydrocephalus shunts, which are prone to bacterial colonisation, can be impregnated with antimicrobials in order to confer antibacterial activity. Concern that their use might be associated with an increased risk of postoperative seizures has been addressed here. Using two rat models, namely pentylenetetrazole (PTZ) and maximal electroconvulsive seizure (ECS) thresholds, the possible epileptogenic characteristics of the shunt catheters were determined. Animals implanted with impregnated catheters exhibited no significant difference in PTZ seizure threshold compared with controls. In contrast, the ECS threshold test showed an enhancement in seizure susceptibility in the non-impregnated catheter group, in accordance with that found in human subjects, but a significant reduction in the impregnated catheter group at 2 and 28 days, postoperatively. These data suggest that the use in human subjects of shunts impregnated with these antimicrobials will not increase the risk of postoperative seizures.

Anticonvulsant activity of di-n-propylacetate and brain monoamine metabolism in the rat.

1. Sodium di-n-propylacetate (DPA) treatment induced significant increases in brain contents of gamma-aminobutyric acid (GABA), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA). Furthermore, the threshold for pentylenetetrazol (PTZ) clonic convulsions was also increased in response to DPA administration. 2. Pretreatment with inhibitors of monoamine synthesis alpha-methyl-p-tyrosine (AMPT) and p-chlorophenylalanine (PCPA) did not alter the anticonvulsant activity of DPA, but when given alone, both AMPT and PCPA caused significant decreases in brain monoamine contents and PTZ threshold seizures. 3. Experiments using probenecid suggest that the increases in 5-HIAA and HVA seen after DPA treatment could have resulted from inhibition of their active transport out of the brain. These data indicate that the anticonvulsant action of DPA is not dependent on changes in monoamine metabolism in the brain.

The effect of monoamine depletors on metrazol induced convulsions and brain gamma-aminobutyric acid (GABA) contents in rats.

The thresholds for metrazol (pentylenetetrazol) clonic convulsions and brain gamma-aminobutyric acid contents were significantly reduced after treatment with the monoamine depletors reserpine, tetrabenazine and p-chlorophenylalanine. Moreover, alpha-methyltyrosine, and alpha-methyl-m-tyrosine also lowered metrazol threshold seizures, but had no effect on brain alpha-aminobutyric acid contents. Furthermore, neither 5-hydroxytryptophan nor tranylcypromine had a significant effect on metrazol threshold seizures or brain alpha-aminobutyric acid contents, but blocked the changes previously induced by p-chlorophenyl alanine and reserpine.

A possible role for spinal noradrenaline in the mechanisms of 6-hydroxydopamine against pentylenetetrazol induced convulsions in rats.

The threshold of the generalized clonic convulsions induced by intravenous infusion of pentylenetetrazol (PTZ) was significantly increased by the intraperitoneal administration of noradrenaline (NA) neurotoxin, 6-hydroxydopamine, which produced no changes in the levels of catecholamines in discrete areas of rat brain, but the effect was accompanied by spinal depletion of NA. Moreover, the anticonvulsant effects of phenobarbitone (PB) and diphenylhydantoin (DPH) against PTZ convulsions were also significantly increased in the animals pretreated with 6-OHDA. These results suggest that the observed elevation of PTZ convulsive threshold and the potentiation of anticonvulsant activity of PB and DPH in 6-OHDA treated rats were possibly mediated through spinal cord depletion of NA.

Differential effects of alpha-methyl-p-tyrosine and 6-hydroxydopamine on pentylenetetrazol seizures in mice.

An intraperitoneal injection of the tyrosine hydroxylase inhibitor, alpha-methyl-p-tyrosine, did not alter the incidence of seizures induced by pentylenetetrazol, but increased the severity and duration of the tonic and clonic phases which resulted in death of some animals. By contrast, pentylenetetrazol seizures' characteristics were significantly changed in response to the intraperitoneal administration of the norepinephrine antagonist, 6-hydroxydopamine, by abolishing the tonic and clonic phases of the seizure. Moreover, alpha-methyl-p-tyrosine slightly attenuated the protective effect of 6-hydroxydopamine against pentylenetetrazol-induced seizures. Neurochemically, alpha-methyl-p-tyrosine significantly lowered the brain contents of both norepinephrine and dopamine while 6-hydroxydopamine caused no changes in the brain contents of these amines.