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 ‰ow, but that in human was low (20％), demonstrating a large species diŠerence 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 a 1 -acid glycoprotein (AGP) contributing to the binding proˆle. 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.

Silodosin in the treatment of benign prostatic hyperplasia

“…This glucuronide conjugate has been found to have a half-life of about 24 hours as compared with 13.3 hours for silodosin and an AUC three- or four fold higher than for the parent compound. Therefore, silodosin and its active metabolite have an extended half-life that makes once-daily dosing possible 28–30. Silodosin is excreted in the urine (33.5%) and feces (54.9%) 16…”

Computational Design and Application of Molecularly Imprinted/MWCNT Based Electrochemical Sensor for the Determination of Silodosin

“…Blocking 1 A-adrenoreceptors allows smooth muscle in these tissues to relax, lowering bladder outlet resistance, while leaving detrusor smooth muscle contractility unaffected. This improves both storing (irritative) and voiding (obstructive) symptoms associated with benign prostatic hyperplasia [1]. The reported allergic reaction and side effects of SLD (drug hypersensitivity) may include: swelling of face, lips or tongue, problems with breathing or swallowing, skin rash, itching, skin or mouth blisters.…”