R. Bouer et al., BLOOD AND CEREBRAL CONCENTRATIONS OF THE NEW POTENTIAL ANALGESIC UP-26-91 MEASURED IN-VIVO BY MICRODIALYSIS AFTER TOXIC DOSES, Arzneimittel-Forschung, 48(7), 1998, pp. 745-749
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.