Comparison of toxicity and toxicokinetics/pharmacokinetics of an alpha 1L-adrenoceptor agonist in rats and rhesus monkeys.
We have investigated the toxicity of an alpha(1L)-adrenoceptor agonist, ESR 1150 CL, and compared the toxicokinetics and pharmacokinetics in rats and monkeys. In rats, this compound induced death with remarkable sacculated aneurysms of the aorta in groups given more than 3 mg/kg per day in a 4-week repeated oral administration study. On the other hand, these findings were not observed in monkeys during a 2-week repeated oral administration study at doses up to 30 mg/kg per day. Orally administered ESR 1150 CL raised blood pressure transiently and dose-dependently during the 4-week repeated study in rats, whereas no increase of blood pressure was observed during the 2-week oral toxicity study in monkeys. Contrary to our expectation, the exposure level of ESR 1150 CL in rats was not higher than that in monkeys in the toxicokinetic evaluation. Pharmacokinetic evaluation indicated good absorption of the compound, but the bioavailability was very low in both rats and monkeys. These findings suggest that the potent species difference in toxicity of ESR 1150 CL between rats and monkeys does not depend on differences of toxicokinetics/pharmacokinetics. Rather, we suggest that the reason is likely to be species difference in the biological susceptibility of the alpha(1L)-adrenoceptor subtypes between rats and monkeys, which would be closely related with the effect on blood pressure by alpha(1L)-adrenoceptor agonist.
Matsumaru
Takehisa
T
Division of Molecular Pharmacology and Pharmacogenomics, Department of Genome Sciences, Kobe University Graduate School of Medicine, Hyogo, Japan.
Sugiura
Reiko
R
Sakai
Kenji
K
Igarashi
Takashi
T
Kuno
Takayoshi
T
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005263:Femoral Artery / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008253:Macaca mulatta; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D013045:Species Specificity
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D018340:Receptors, Adrenergic, alpha-1