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 investigate d in relation to t(max), C-max, AUC and t(1/2) values. 2 After i.p. ad ministration, antipyrine (35 mg kg(-1), n=5) concentrations rose rapid ly in rat frontal cortex (t(max), 12 min) and then declined exponentia lly. t(max), C-max, AUC and t(1/2) values were determined after 2 min dialysate sampling and compared to values obtained from simulated samp ling times of 4, 6, 8, 10 and 20 min. 3 Antipyrine t(max) and C-max va lues were directly dependent on sampling frequency. Thus, mean 2 min s ampling t(max) and C-max values were 63% lower and 27% higher, respect ively, compared to 20 min sampling values. AUC and t(1/2) values were unaffected. 4 Adjustment for dialysate dead volume (the volume of dial ysate within the dialysis probe and sampling tube) reduced t(max) valu es significantly but did not affect the other neuropharmacokinetic par ameters. 5 Contribution of period sampling on neuropharmacokinetic par ameters were investigated by comparing plots of antipyrine concentrati on data at midpoint and at endpoint of sampling time interval. Only t( max) values were affected with values decreasing with increasing sampl ing time interval. 6 In conclusion, although microdialysis is a useful method for monitoring events at the extracellular level and for kinet ic studies, it is important to understand its inherent characteristics so that data can be interpreted appropriately. Sampling frequency, pa rticularly during monitoring of periods of rapid change, is very impor tant since C-max and t(max) values will be significantly underestimate d and overestimated respectively, if sampling time is longer rather th an shorter. These considerations are particularly important in relatio n to microdialysis studies of pharmacokinetic-pharmacodynamic interrel ationships and modelling.