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 glucuronide conjugate of JTH-601 (an alpha1-adrenoceptor antagonist), on smooth muscle contraction in canine prostate and artery, and to examine the effect of JTH-601-G1 on prostatic urethral pressure and blood pressure in anaesthetized 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 strips from the carotid artery prepared. The effects of JTH-601-G1 on phenylephrine- and noradrenaline-induced contraction were assessed in these tissues. In the in vivo study, four dogs were anaesthetized and the change in urethral pressure, blood pressure and heart rate measured continuously. Vehicle (saline) and JTH-601-G1 were then infused intravenously in increasing doses (0.33-3.3 microg/kg/min for 30 min). In three other dogs, the effect of JTH-601-G1 infusion at a higher rate (25 microg/kg/min for 3 h) on blood pressure was evaluated, and the plasma concentration of JTH-601-G1 measured using high-performance liquid chromatography-mass spectrometry. RESULTS: Of the distinct metabolites of JTH-601, JTH-601-G1 had the most potent alpha1-adrenoceptor antagonistic effect in isolated canine prostate. JTH-601-G1 also antagonized alpha1-adrenoceptor agonist-induced contraction in common carotid artery, but the pA2 value in the artery was approximately 25 times higher than that in the prostate. In anaesthetized dogs, JTH-601-G1 decreased urethral pressure in a dose-dependent manner; at the highest 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 plasma 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 detection limit. The higher JTH-601-G1 infusion rate caused blood pressure to decrease by only 6-10% even at JTH-601-G1 plasma concentrations of approximately 1500 ng/mL during the infusion. Although there was a negative correlation between mean blood pressure and plasma JTH-601-G1 concentration, the decrease 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 but with a higher selectivity for canine prostate than artery. The results also indicate that in addition to the alpha1A-adrenoceptor, the alpha1L-adrenoceptor plays an important prostatic selective role in smooth muscle contraction via the alpha1-adrenoceptor.