Comparison of Toxicity and Toxicokinetics/Pharmacokinetics of an α1L-Adrenoceptor Agonist in Rats and Rhesus Monkeys

Abstract

Abstract. We have investigated the toxicity of an a 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 a 1L -adrenoceptor subtypes between rats and monkeys, which would be closely related with the effect on blood pressure by a 1L -adrenoceptor agonist.

Agonist pharmacology at recombinant α1A‐ and α1L‐adrenoceptors and in lower urinary tract α1‐adrenoceptors

“…We have hypothesized that this may be due to the expression of distinct α 1 ‐adrenoceptor phenotypes (α 1A and α 1L ) from a single α 1A ‐adrenoceptor gene. Therefore, in the present study, we first examined the agonist profiles of recombinant α 1A ‐ and α 1L ‐adrenoceptor phenotypes using various drugs, A61603, NS‐49, Ro 115–1240 and ESR1150 (Figure ), which have been developed for SUI therapy (Knepper et al ., ; Obika et al ., ; Blue et al ., ; Musselman et al ., ; Matsumaru et al ., ; Nishimune et al ., ). Other than noradrenaline and phenylephrine, these drugs showed high specificity for α 1A ‐ and α 1L ‐adrenoceptor phenotypes and were essentially inactive at the α 1B ‐ and α 1D ‐adrenoceptors.…”

“…Therefore, α 1 ‐adrenoceptor agonists may be useful clinically to treat women with stress urinary incontinence (SUI; Taki et al ., ; Andersson and Wein, ). As shown in Figure , many α 1 ‐adrenoceptor agonists, such as A61603 (Knepper et al ., ), Ro 115–1240 (Blue et al ., ; Musselman et al ., ), NS‐49 (Obika et al ., ), MK017 (Nishimune et al ., ) and ESR1150 (Matsumaru et al ., ), have been tested for this purpose, but to date no successful clinical application has been achieved. This may be due to a moderate/poor efficacy of these agonists in the LUT and problems associated with their toxic side effects, which includes their propensity to increase BP.…”