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 saturable phenomenon for some drug dispositions, either during their absorption 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 technique has been used to compare brain and blood concentrations of a potential analgesic, UP 26-91 (3-¿[2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl]thio¿ -1,2,4-triazolo[4,3-a]pyrioline, citrate salt, CAS 115762-17-9 for the base), at different intravenous doses. Microdialysis probes were surgically implanted in the cerebral 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 unlabelled drug was injected into the animal's tail vein. Three doses of drug (2.5, 12.5 and 22.5 mg.kg-1) were tested, with three rats for each dose. All the doses consisted of the same amount of radiolabelled product, used as a tracer, supplemented by the amount of non-radiolabelled UP 26-91 necessary to reach the desired concentration. The rats were conscious, freely moving and had free access to food and water. Microdialysis samples were collected at the rate of 1 microliter.min-1, and sampled every 15 min for 16-17 h. The two highest doses were in the range of those used for toxicological studies. Blood UP 26-91 radioactivity concentrations were superimposable independent of the dose. Thus, it can be concluded that there was a linear relationship between blood concentrations and administered doses. By contrast, the brain concentration for the highest administered dose was statistically higher than the two others (p < 0.05), which demonstrated that UP 26-91 exhibited a non-linear pharmacokinetics in the brain. It is therefore likely that a saturable transport mechanism occurs across the blood-brain barrier. This study demonstrates that blood toxicokinetics may not correctly reflect tissue exposure to a drug.
Bouër
R
R
Laboratoire Cinétique des Xénobiotiques, Faculté des Sciences Pharmaceutiques, Toulouse, France.
Saivin
S
S
Malmary
M F
MF
Hermann
P
P
Poey
J
J
Houin
G
G
D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000378:metabolism*; D007262:Infusions, Intravenous; D008297:Male; D017551:Microdialysis; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity
D018712:Analgesics, Non-Narcotic; D010879:Piperazines; D014230:Triazoles; C114211:UP 26-91