Prostate selectivity of JTH-601-G1, an active metabolite of JTH-601, in dogs

Objective To evaluate the effect of JTH-601-G1, an active metabolite and gl ucuronide conjugate of JTH-601 (an alpha(1)-adrenoceptor antagonist), on sm ooth muscle contraction in canine prostate and artery, and to examine the e ffect of JTH-601-G1 on prostatic urethral pressure and blood pressure in an aesthetized dogs. Materials and methods Male beagle dogs were used in both an in vitro and an in vivo study, In the former, the prostate and right common carotid artery were isolated, and smooth muscle strips from the prostate and open-ring st rips from the carotid artery prepared, The effects of JTH-601-G1 on phenyle phrine- and noradrenaline-induced contraction were assessed in these tissue s, In the in vivo study, four dogs were anaesthetized and the change in ure thral pressure, blood pressure and heart rate measured continuously. Vehicl e (saline) and JTH-601-G1 were then infused intravenously in increasing dos es (0.33-3.3 mu g/kg/min for 30 min). In three other dogs, the effect of JT H-601-G1 infusion at a higher rate (25 mu g/kg/min for 3 h) on blood pressu re was evaluated, and the plasma concentration of JTH-601-G1 measured using highperformance liquid chromatography-mass spectrometry. Results Of the distinct metabolites of JTH-601, JTH-601-G1 had the most pot ent alpha(1)-adrenoceptor antagonistic effect in isolated canine prostate. JTH-601-G1 also antagonized alpha(1)-adrenoceptor agonist-induced contracti on in common carotid artery, but the pA(2) value in the artery was approxim ate to 25 times higher than that in the prostate. In anaesthetized dogs, JT H-601-G1 decreased urethral pressure in a dose-dependent manner: at the hig hest dose, urethral pressure decreased by 24.5% and blood pressure by 7.0%. However, there was no significant change in heart rate at any dose, The pl asma concentration of JTH-601-G1 increased with the dose of JTH-601-G1, but the concentration of both JTH-601 and other metabolites was below the dete ction limit. The higher JTH-601-G1 infusion rate caused blood pressure to d ecrease by only 6-10% even at JTH-601-G1 plasma concentrations of approxima te to 1500 ng/mL during the infusion, Although there was a negative correla tion between mean blood pressure and plasma JTH-601-G1 concentration, the d ecrease in blood pressure was small compared with the reduction in urethral pressure, Conclusion JTH-601-G1 appears to be a major active metabolite of JTH-601 bu t with a higher selectivity for canine prostate than artery. The results al so indicate that in addition to the alpha(1)-adrenoceptor, the alpha(1)-adr enoceptor plays an important prostatic selective role in smooth muscle cont raction via the alpha(1)-adrenoceptor.