Pharmacokinetics and Disposition of Silodosin (KMD-3213)

• Published in: YAKUGAKU ZASSHI Vol. 126; no. Special_Issue; pp. 237 - 245
• Main Authors: MATSUBARA, Yasuhito, KANAZAWA, Toru, KOJIMA, Yasunari, ABE, Yoshikazu, KOBAYASHI, Kaoru, KANBE, Hiroki, HARADA, Hiroshi, MOMOSE, Yasunori, TERAKADO, Sakae, ADACHI, Yasuhisa, MIDGLEY, Ian
• Format: Journal Article
• Language: Japanese
• Published: Japan The Pharmaceutical Society of Japan 2006
• Subjects: Administration, Oral; Adrenergic alpha-Antagonists - administration & dosage; Adrenergic alpha-Antagonists - metabolism; Adrenergic alpha-Antagonists - pharmacokinetics; Animals; Biological Availability; Blood Proteins - metabolism; Caco-2 Cells - metabolism; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - metabolism; Dogs; Gastrointestinal Tract - metabolism; Half-Life; Humans; Indoles - administration & dosage; Indoles - metabolism; Indoles - pharmacokinetics; Intestinal Absorption; Male; metabolism; pharmacokinetics; Protein Binding; Rats; silodosin (KMD-3213); species differences; Species Specificity; Tissue Distribution; α1A-adrenoceptor antagonist
• ISSN: 0031-6903; 1347-5231
• DOI: 10.1248/yakushi.126.237

After a single oral dose of silodosin in male rats, male dogs and healthy human male volunteers, Cmax 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 14C-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 α1-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 14C-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.