Absorption, disposition, metabolism and excretion of [14C]mizagliflozin, a novel selective SGLT1 inhibitor, in rats.

The pharmacokinetic and metabolite profiles of mizagliflozin, a novel selective sodium glucose co-transporter 1 inhibitor designed to act only in the intestine, were investigated in rats. Mizagliflozin administrated intravenously (0.3 mg/kg) and orally (3 mg/kg) declined with a short half-life (0.23 and 1.14 h, respectively). The absolute bioavailability was only 0.02%. Following intravenous administration of [14 C]mizagliflozin (0.3 mg/kg), radioactivity in plasma was also rapidly declined. Up to 24 h after oral administration of [14 C]mizagliflozin (1 mg/kg), radioactivity was recovered in the faeces (98.4%) and in the urine (0.8%). No remarkable accumulation of radioactivity in tissues was observed using tissue dissection technique and whole body autoradiography. Orally dosed [14 C]mizagliflozin was mostly metabolised to its aglycone, KP232, in the intestine. In the plasma, KP232 and its glucuronide were predominant. KP232 glucuronide was also prominent in the bile and was recovered as KP232 in the faeces possibly because of the deconjugation by gut microflora. Mizagliflozin was observed neither in the urine nor the faeces. These findings suggest that orally administered mizagliflozin is poorly absorbed, contributing to low systemic exposure; if absorbed, mizagliflozin is rapidly cleared from circulation.

[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.