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
-Diclofenac (DCF), a nonsteroidal anti-inflammatory drug, is well known to induce idiosyncratic hepatotoxicity. Although there remains much to be elucidated about its onset mechanism, it is widely accepted as a hypothesis that idiosyncratic hepatotoxicity arises from a specific immune response to a hapten formed by covalent binding of drugs or their reactive metabolites to hepatic tissues. In this study, we investigated the effects of covalent binding of DCF reactive metabolites to hepatic tissues using a rat model of liver injury induced by co-treatment with lipopolysaccharide (LPS) at a non-hepatotoxic dose. In studies done in vitro using hepatic microsomes prepared from rats treated with LPS alone, 4'-and 5-hydroxylation activities on DCF metabolism and adducts of reactive metabolites to dansyl glutathione (dGSH) were markedly decreased associated with a decrease in total P450 content. However, in studies done in vivo, the LPS/DCF co-treatment significantly increased adducts of 5-hydroxydiclofenac (5-OH-DCF) to rat hepatic tissues and delayed the elimination of 5-OH-DCF from plasma. Furthermore, we investigated the effects of co-treatment on hepatic GSH level in rats. A decrease of hepatic GSH was observed with the LPS/DCF co-treatment but not with LPS or DCF alone. The results suggest that covalent binding of reactive metabolites via 5-OH-DCF to hepatic tissues may play an important role in the onset of DCF-induced idiosyncratic hepatotoxicity, especially under decreased GSH conditions.
We evaluated the effects of probenecid, a potent organic anion transporter 1 (OAT1) and OAT3 inhibitor, on the pharmacokinetics and safety of ritobegron, a selective β3 -adrenoceptor agonist, in healthy men. Twelve healthy men were administered a single oral dose of ritobegron (20 mg) alone or in combination with probenecid 2 hours before administration of ritobegron. In the combination sequence, additional doses of probenecid were administered 4 and 10 hours after the administration of ritobegron. Probenecid increased the Cmax of KUC-7322, an active form of ritobegron, and the AUC0-48 h by 1.39 and 2.93 times, respectively. Probenecid prolonged the t1/2 of KUC-7322 from 1.6 to 3.4 hours and decreased the renal clearance and cumulative fraction of KUC-7322 excreted in urine from 18.5 to 4.9 L/h and from 64.7% to 49.7%, respectively. Coadministration of probenecid did not influence adverse events, blood pressure, pulse rate, or heart rate relative to ritobegron alone. Although probenecid inhibited renal tubule secretion of KUC-7322 via OAT3 and increased KUC-7322 exposure, it did not influence adverse effects or vital signs. Therefore, clinically significant drug-drug interactions are unlikely to occur when probenecid is administered in combination with OAT3 inhibitors or substrates.
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.
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