title: [Pharmacokinetics and disposition of silodosin (KMD-3213)].
abstract: After a single oral dose of silodosin in male rats, male dogs and healthy human male volunteers, C(max) occurred within about 2 h, indicating rapid absorption. The elimination half-life was about 2 h in rat and dog, but 4.7 h (fasted) and 6.0 h (non-fasted) in humans. Absolute bioavailability values in rat, dog and human were about 9, 25 and 32%, respectively. In rat and dog, total blood clearance was almost equivalent to the hepatic blood flow, but that in human was low (20%), demonstrating a large species difference in hepatic clearance. In each species, the apparent volume of distribution exceeded the volume of total body water. After an oral dose of (14)C-silodosin to male rats, radioactivity was rapidly and widely distributed to most tissues. The highest concentrations outside the gastrointestinal tract were found in liver and kidney, with only low concentrations in brain tissues. The in vitro plasma protein binding of silodosin was about 80% in rat and dog, and 95.6% in humans, with alpha(1)-acid glycoprotein (AGP) contributing to the binding profile. Silodosin was found to be a dual substrate for CYP3A4 and p-glycoprotein. In human plasma, two major metabolites generated by UDP-glucuronosyltransferase (UGT; UGT2B7) and alcohol/aldehyde dehydrogenase (ADH/ALDH) were found, but no glucuronide conjugates were detected in rat or dog plasma. After a single oral dose of (14)C-silodosin in rat, dog and human, the urinary excretion of radioactivity was 15-34%, with that of unchanged silodosin being less than 4%. The radioactivity was predominantly excreted via the feces.
authors.affiliation: Pharmacokinetics Research Laboratory, R&D, Kissei Pharmaceutical Co., Ltd., Matsumoto City, Japan. yasuhito_matsubara@pharm.kissei.co.jp
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Matsubara
authors.forename: Toru
authors.initials: T
authors.lastname: Kanazawa
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Kojima
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Abe
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kanbe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Harada
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Momose
authors.forename: Sakae
authors.initials: S
authors.lastname: Terakado
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Adachi
authors.forename: Ian
authors.initials: I
authors.lastname: Midgley
mesh_terms: D000284:Administration, Oral; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D018938:Caco-2 Cells / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D041981:Gastrointestinal Tract / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D008297:Male; D011485:Protein Binding; D051381:Rats; D013045:Species Specificity; D014018:Tissue Distribution
chemical_list: D000317:Adrenergic alpha-Antagonists; D001798:Blood Proteins; D007211:Indoles; D003577:Cytochrome P-450 Enzyme System; C095285:silodosin; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human