PT  - JOURNAL ARTICLE
AU  - Shizuo Yamada
AU  - Takashi Okura
AU  - Ryohei Kimura
AU  - Yoshiharu Deguchi
AU  - Yasunori Suzuki
AU  - Takuo Kobayashi
AU  - Kazuo Aisaka
TI  - Disposition and α<sub>1</sub>-Adrenoceptor Binding Characteristics of JTH-601 and Its Metabolites in Rat Tissues
DP  - 2000 Dec 01
TA  - Drug Metabolism and Disposition
PG  - 1487--1492
VI  - 28
IP  - 12
4099  - http://dmd.aspetjournals.org/content/28/12/1487.short
4100  - http://dmd.aspetjournals.org/content/28/12/1487.full
SO  - Drug Metab Dispos2000 Dec 01; 28
AB  - The present study was performed to characterize the disposition and α1-adrenoceptor binding of JTH-601, a novel α1L-adrenoceptor antagonist, and its metabolites (β-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 α1-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 α1-adrenoceptors in rat tissues in vivo and that JTH-601-G1 retains the prostatic α1-adrenoceptor subtype selectivity of its parent compound. The American Society for Pharmacology and Experimental Therapeutics