BLOOD AND CEREBRAL CONCENTRATIONS OF THE NEW POTENTIAL ANALGESIC UP-26-91 MEASURED IN-VIVO BY MICRODIALYSIS AFTER TOXIC DOSES

The concept of proportionality between the pharmacological effects of drugs and their dosage has been questioned since the discovery of satu rable phenomenon for some drug dispositions, either during their absor ption or their elimination. Such saturation may also occur during the distribution phase in the tissues. This phenomenon, however. is often difficult to demonstrate and microdialysis is a powerful technique to assess precise changes in drug concentrations in tissue. This techniqu e has been used to compare brain and blood concentrations of a potenti al analgesic, UP 26-91 n-1-yl]ethyl]thio}-1,2,4-triazolo[4,3-a]pyrioli ne, citrate salt, CAS 115762-17-9 for the base), at different intraven ous doses. Microdialysis probes were surgically implanted in the cereb ral cortex and the jugular vein of male Sprague-Dawley rats (about 350 g). A single dose of radiolabelled (14)(C) UP 26-91 mixed with unlabe lled drug was injected into the animal's tail vein. Three doses of dru g (2.5, 12.5 and 22.5 mg . kg(-1)) were tested, with three rats for ea ch dose. All the doses consisted of the same amount of radiolabelled p roduct, used as a tracer, supplemented by the amount of non-radiolabel led UP 26-91 necessary to reach the desired concentration. The rats we re conscious, freely moving and had free access to food and water. Mic rodialysis samples were collected at the rate of 1 mu l . min(-1), and sampled every 15 min for 16-17 h. The two highest doses were in the r ange of those used for toxicological studies. Blood UP 26-91 radioacti vity concentrations were superimposable independent of the dose. Thus, it can be concluded that there was a linear relationship between bloo d concentrations and administered doses. By contrast, the brain concen tration for the highest administered dose was statistically higher tha n the two others (p < 0.05), which demonstrated that UP 26-91 exhibite d a non-linear pharmacokinetics in the brain. It is therefore likely t hat a saturable transport mechanism occurs across the blood-brain barr ier. This study demonstrates that blood toxicokinetics may not correct ly reflect tissue exposure to a drug.