DISPOSITION AND a1-ADRENOCEPTOR BINDING CHARACTERISTICS OF JTH-601 AND ITS METABOLITES IN RAT TISSUES

The present study was performed to characterize the disposition and a1-adrenoceptor binding of JTH-601, a novel a1L-adrenoceptor antagonist, and its metabolites (b-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 [H]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 [H]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 a1-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 [H]JTH-601-G1 was considerably lower than that of [H]JTH-601. The plasma concentration of [H]JTH-601-G1 at 10 min after i.v. injection in rats was 3 times higher than that of [H]JTH-601, and conversely, the concentration in the prostate was 3 times lower. Although in vivo [H]JTH-601-G1 binding at 10 min was significantly lower than that of [H]JTH-601 in most rat tissues, there was comparable binding between these radioligands in the prostate and vas deferens. Specific binding of [H]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 a1-adrenoceptors in rat tissues in vivo and that JTH-601-G1 retains the prostatic a1-adrenoceptor subtype selectivity of its parent compound. a1-Adrenoceptor antagonists are effective therapeutic agents for urinary obstruction in patients with benign prostatic hypertrophy (BPH). However, prazosin often produces orthostatic hypotension as a side effect, due to a reduction in peripheral resistance mediated by blockade of the vascular a1-adrenoceptors. Previous studies have shown that the a1A-adrenoceptor subtype mediates the contractile response to noradrenaline in prostatic smooth muscles (Lepor et al., 1993; Price et al., 1993; Forray et al., 1994; Chapple, 1996). In addition, it has been shown that the a1L-adrenoceptor subtype is involved in contraction of the prostate (Muramatsu et al., 1994; Takahashi et al., 1999). On the other hand, the a1B-adrenoceptor subtype mediates the contraction of vascular tissues produced by noradrenaline (Hatano et al., 1994). JTH-601 (3-{N-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]N-methylaminomethyl}-4-methoxy-2,5,6-trimethylphenol hemifumarate) is a novel a1-adrenoceptor antagonist having a relatively higher affinity for both a1Land a1A-adrenoceptors than a1B-adrenoceptors (Muramatsu et al., 1996; Suzuki et al., 1999, 2000a). Among several metabolites of JTH-601, JTH-601-G1 (JTH-601 b-D-glucopyranosyl uronic acid) and JTH-601-S1 (JTH-601 hydrogen sulfate) (Fig. 1) have been shown to be pharmacologically active metabolites mainly by in vitro functional assays (Takahashi et al., 1999; Suzuki et al., 2000b). However, the disposition and in vivo binding characteristics of JTH-601 and its metabolites in the prostate have not been investigated in detail. The in vivo receptor binding characteristics of JTH601 and its metabolites in relation to their pharmacokinetics may be important for a thorough understanding of the pharmacological effects of JTH-601. The aim of the present study was to characterize the disposition and a1-adrenoceptor binding of JTH-601 and its metabolites in the rat prostate and other tissues under in vivo conditions. Materials and Methods Chemicals. [H]Tamsulosin ([H]YM617, 2.08 TBq/mmol), [H]JTH-601 (1.04 TBq/mmol), and [H]JTH-601-G1 (1.37 TBq/mmol) were synthesized by Amersham International PLC (Buckinghamshire, England). JTH-601 and 1 Abbreviations used are: BPH, benign prostatic hypertrophy; JTH-601, 3-{N[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminomethyl}-4methoxy-2,5,6-trimethylphenol hemifumarate; JTH-601-G1, JTH-601 b-Dglucopyranosyl uronic acid; JTH-601-S1, JTH-601 hydrogen sulfate; HPLC, high performance liquid chromatography. Send reprint requests to: Shizuo Yamada, Ph.D., Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan. E-mail: [email protected] 0090-9556/00/2812-1487–1492$03.00/0 DRUG METABOLISM AND DISPOSITION Vol. 28, No. 12 Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics 132/863263 DMD 28:1487–1492, 2000 Printed in U.S.A. 1487 at A PE T Jornals on N ovem er 6, 2017 dm d.aspurnals.org D ow nladed from