[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.

Crystal structure of the alginate (poly alpha-l-guluronate) lyase from Corynebacterium sp. at 1.2 A resolution.

The crystal structure of alginate (poly alpha-l-guluronate) lyase from Corynebacterium sp. (ALY-1) was determined at 1.2A resolution using the MAD method and bromide ions. The structure of ALY-1 is abundant in beta-strands and has a deep cleft, similar to the jellyroll beta-sandwich found in 1,3-1,4-beta-glucanase. The structure suggests that alginate molecules may penetrate into the cleft to interact with the catalytic site of ALY-1. The reported crystal structure of another type of alginate lyase, A1-III, differs from that of ALY-1 in that it consists almost entirely of alpha-helical structure. Nevertheless, the putative catalytic residues in both enzymes are positioned in space in nearly identical arrangements. This finding suggests that both alginate lyases may have evolved through convergent evolution.

The action modes of an extracellular beta-1,3-glucanase isolated from Bacillus clausii NM-1 on beta-1,3-glucooligosaccharides.

The mode of action of an extracellular -1,3-glucanase from Bacillus clausii NM-1 on beta-1,3-3glucooligosaccharides and their alditols was studied. The enzyme could not hydrolyze laminaribiose or laminaritriose. beta-1,3-Glucooligosaccharides higher than laminarihexaose were rapidly hydrolyzed, while laminaritetraose was slowly hydrolyzed. The k(cat)/K(m) ratios for a series of beta-1,3-glucooligosaccharides from laminaritetraose to laminariheptaose showed that the substrate binding site of the enzyme covered a wide range of beta-1,3-glucooligosaccharides having six glucose residues. The action pattern of the enzyme on the alditols corresponding to each laminarioligosaccharide suggested that the catalytic site of the enzyme existed between the third and fourth glucose residue from the non-reducing terminal. The value of k(cat)/K(m) also suggested that the sixth binding position contributed to the catalytic efficiency and stability.