Vol. 28, Issue 12, 1487-1492, December 2000

Disposition and ₁-Adrenoceptor Binding Characteristics of JTH-601 and Its Metabolites in Rat Tissues

Shizuo Yamada, Takashi Okura, Ryohei Kimura, Yoshiharu Deguchi, Yasunori Suzuki, Takuo Kobayashi, and Kazuo Aisaka

Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (S.Y., T.O., R.K.); Department of Biopharmaceutics, Hokkaido College of Pharmacy (Y.D.); and Central Pharmaceutical Research Institute, Japan Tobacco, Inc., Osaka, Japan (Y.S., T.K., K.A.)

The present study was performed to characterize the disposition and ₁-adrenoceptor binding of JTH-601, a novel _1L-adrenoceptor antagonist, and its metabolites (-D-glucopyranosyl uronic acid, JTH-601-G1; hydrogen sulfate, JTH-601-S1) in the rat prostate and other tissues. JTH-601, JTH-601-G1, and JTH-601-S1 inhibited competitively specific [³H]tamsulosin binding in the prostate, submaxillary gland, and spleen of rats in vitro, and the inhibitory effect of JTH-601 was 2.5 to 6.4 times more potent than that of its metabolites. JTH-601 and its metabolites inhibited dose dependently in vivo specific [³H]tamsulosin binding in the particulate fraction of the prostate, aorta, submaxillary gland, and spleen of rats. Compared with that of JTH-601, the in vivo inhibitory effect of JTH-601-G1 was 1.9 to 2.9 times more potent, and the effect of JTH-601-S1 was 1.3 to 3.2 times less potent. Based on the ratios of ID₅₀ values, JTH-601 and JTH-601-G1 appeared to be 4.0 to 6.9 times more selective than prazosin as far as the ₁-adrenoceptors in the prostate and submaxillary gland versus the spleen or aorta were concerned. The total radioactivity in rat tissues after i.v. injection of [³H]JTH-601-G1 was considerably lower than that of [³H]JTH-601. The plasma concentration of [³H]JTH-601-G1 at 10 min after i.v. injection in rats was 3 times higher than that of [³H]JTH-601, and conversely, the concentration in the prostate was 3 times lower. Although in vivo [³H]JTH-601-G1 binding at 10 min was significantly lower than that of [³H]JTH-601 in most rat tissues, there was comparable binding between these radioligands in the prostate and vas deferens. Specific binding of [³H]JTH-601, at 60 min after i.v. injection compared with that at 10 min, was considerably reduced in rat tissues except the prostate and vas deferens, both of which showed relatively sustained binding. In conclusion, the present study has shown that JTH-601 and its metabolites bind to ₁-adrenoceptors in rat tissues in vivo and that JTH-601-G1 retains the prostatic ₁-adrenoceptor subtype selectivity of its parent compound.