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 ， Cmax occurred with − in about 2 h ， indicating rapid absorption ． The elimination half − 1ife was about 2 h in rat and dog， but 4． 7 h (fasted)and 6． Oh (non − fasted)in humans ． Absolute bioavailability values in rat ， dog and human were about 9 ， 25 and 32 ％ ， respec − tive 且 y ， 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 ． ln each species ， the apparent volume of distribu − tion exceeded the vo 【 ume of total body water ． After an oral dose of i4C ・ 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 且 ow 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 α 1 − acid glycoprotein(AGP)contributing to the binding profile ． Silodosin was found to be a dual substrate for CYP3A4 and ρ 一 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 且 4C − 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 ． Key werds − silodosin (KMD − 3213) ；orlA − adrenoceptor antagonist ；pharmacokinetics ；metabolism ；species differences

Safety and Pharmacokinetic Studies of Silodosin, a New .ALPHA.1A-Adrenoceptor Selective Antagonist, in Healthy Chinese Male Subjects

“…This is consistent with previous results indicating that silodosin was mainly metabolized in the liver and excreted through the feces after oral administration. 13) In summary, silodosin is safe and well tolerated in healthy Chinese subjects following single-dosing escalation once daily in the dose range of 2-12 mg, and multiple-dosing twice daily (4 mg per administration). Mild adverse events like headache, dizziness, and TBIL elevation are frequently encountered and are related to dose escalation but reversible after drug discontinuation.…”

“…Results from a study in rats revealed that silodosin underwent biliary excretion and enterohepatic circulation, 13) and these phenomena may cause the re-absorption of silodosin in the intestinal tract. A possible reason could be the powders of silodosin are distributed to different sites after disintegration of the capsules in the gastrointestinal tract, thereby resulting in the delay of absorption and the dual-peaks of absorption.…”

Overlapping Ligand Specificity of P-Glycoprotein and Serum α1-Acid Glycoprotein:Evidences and Potential Implications

“…Accordingly, the reversal of multidrug resistance of microorganisms by inhibiting their ABC transporters is a promising avenue to overcome infectious diseases. [137] N N N O Cl Cl alpidem (hypnotic) [262] S N N thioflavin T (dye) [263] N N aprindine (antiarrhythmic) [264] N N imipramine (antipsychotic) [ [141] NH N N auramine O (dye) [194] NH 2 H 2 N NH 2 pararosaniline (dye) [267] Overlapping Ligand Specificity of P-Glycoprotein [271] O H N OH alprenolol ( -blocker) [175] N N N binedaline (antipsychotic) [162] N N N F OH F 3 C tefludazine (antipsychotic) [102] O H N OH bornaprolol ( -blocker) [43] O H N OH alprenolol ( -blocker) [175] ( [280] N N Cl medazepam (benzodiazepine) [226] [283] O N N COOH rhodamine B [119] Ferenc Zsila ( O N H OH penbutolol ( -blocker) [284] O N H OH propranolol ( -blocker) [177] O O OH phenprocoumon (anticoagulant) [256] O O O OH warfarin (anticoagulant) [137] N NH pipequaline (antipsychotic) [162] S N N N perazine (antipsychotic) [102] [90] S O N H OH tertatolol ( -blocker) [43] O N H OH propranolol ( -blocker) [177] S N N N S thiethylperazine (antiemetic) [291] S N N N Cl prochlorperazine (antipsychotic) [214] S S N HOOC tiagabine (antiepileptic) [292] S S N tipepidine (antitussive) [102] N N OH tolterodine (antimuscarine) [296] N N Cl chlorpheniramine (antihistamine) [43] HN acriflavine (dye) [301] N N N acridine orange (dye) [51] Overlapping Ligand Specificity of P-Glycoprotein N N D-3...…”

In vivometabolic investigation of silodosin using UHPLC-QTOF-MS/MS andin silicotoxicological screening of its metabolites

“…Identification of reactive or toxic metabolites is essential to avoid the toxicity and helps to modify the structure by means of synthetic chemical transformations . Some methods have been reported for the determination of SLD in biological fluids …”