[Pharmacokinetics and disposition of silodosin (KMD-3213)].
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.
Matsubara
Yasuhito
Y
Pharmacokinetics Research Laboratory, R&D, Kissei Pharmaceutical Co., Ltd., Matsumoto City, Japan. yasuhito_matsubara@pharm.kissei.co.jp
Kanazawa
Toru
T
Kojima
Yasunari
Y
Abe
Yoshikazu
Y
Kobayashi
Kaoru
K
Kanbe
Hiroki
H
Harada
Hiroshi
H
Momose
Yasunori
Y
Terakado
Sakae
S
Adachi
Yasuhisa
Y
Midgley
Ian
I
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
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