1. The absorption, metabolism and excretion of teneligliptin were investigated in healthy male subjects after a single oral dose of 20 mg [(14)C]teneligliptin. 2. Total plasma radioactivity reached the peak concentration at 1.33 h after administration and thereafter disappeared in a biphasic manner. By 216 h after administration, ≥90% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 45.4% and 46.5%, respectively. 3. The most abundant metabolite in plasma was a thiazolidine-1-oxide derivative (designated as M1), which accounted for 14.7% of the plasma AUC (area under the plasma concentration versus time curve) of the total radioactivity. The major components excreted in urine were teneligliptin and M1, accounting for 14.8% and 17.7% of the dose, respectively, by 120 h, whereas in faeces, teneligliptin was the major component (26.1% of the dose), followed by M1 (4.0%). 4. CYP3A4 and FMO3 are the major enzymes responsible for the metabolism of teneligliptin in humans. 5. This study indicates the involvement of renal excretion and multiple metabolic pathways in the elimination of teneligliptin from the human body. Teneligliptin is unlikely to cause conspicuous drug interactions or changes in its pharmacokinetics patients with renal or hepatic impairment, due to a balance in the elimination pathways.
Intravenous (IV) edaravone is approved as an amyotrophic lateral sclerosis (ALS) treatment. Because IV administration places a burden on patients, development of orally administered ALS treatments is needed. Therefore, 2 phase 1 studies of oral formulations of edaravone in healthy subjects examined the pharmacokinetics (PK), safety, racial differences, and drug‐drug interactions (DDIs) and investigated the dose of the oral formulation considered to be bioequivalent to the approved dose of the IV formulation. Study 1 was a placebo‐controlled, randomized, single‐blind study of single‐ascending‐dose oral edaravone with the dose range of 30 to 300 mg (n = 56). Study 2 was conducted in 2 cohorts (n = 84); the first assessed DDIs with multiple‐dose edaravone 120 mg/day given over 5 or 8 days (coadministered with single‐dose rosuvastatin, sildenafil, or furosemide), and the second evaluated PK and racial (Japanese/White) differences in PK parameters with doses of 100‐mg edaravone. The oral formulation of edaravone was well absorbed, and plasma concentrations of unchanged edaravone increased more than dose proportionally within the dose range of 30 to 300 mg. No effect of race on oral edaravone PK and no notable DDI effects possibly caused by orally administered edaravone were observed. The oral edaravone formulations were safe and tolerable under the assessed conditions. Mathematical modeling determined that equivalent exposures in plasma with the approved dose of the IV edaravone formulation, as reported previously, could be achieved when the oral edaravone formulation was administered at a dose of ≈100 mg, with an absolute bioavailability of ≈60%.
The mechanosensitive channel with large conductance of Escherichia coli is the first to be cloned among stretchactivated channels. Although its activity was characterized by a patch clamp method, a physiological role of the channel has not been proved. The marine bacterium, Vibrio alginolyticus, is sensitive to osmotic stress and cell lysis occurs under osmotic downshock. We introduced an mscL gene into Vibrio alginolyticus, and the mechanosensitive channel with large conductance functions was found to alleviate cell lysis by osmotic downshock. This is the first report to show a physiological role of the mechanosensitive channel with large conductance.z 1999 Federation of European Biochemical Societies.
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