Metabolism and disposition of GTS-21, a novel drug for Alzheimer's disease

1. GTS-21, a novel drug for Alzheimer's disease, is currently under clinica l development, In the current study the metabolism and disposition of GTS-2 1 have been evaluated in rat and dog after single oral and intravenous admi nistration. 2. Following oral administration of [C-14]GTS-21 to rat, radioactivity was primarily excreted in the faeces (67 %;) via the bile with possible enteroh epatic circulation. Urinary excretion of radioactivity in rat and dog was 2 0 and 19 % respectively. 3. GTS-21 was rapidly and extensively absorbed after oral administration an d rapidly cleared from plasma. The maximum concentration ratio of GTS-21 to total radioactivity in plasma was low, indicating first-pass or pre-system ic biotransformation. 4. In rat, GTS-21 showed linear pharmacokinetics over doses ranging from 1 to 10 mg/kg with an absolute bioavailability of 23 %. In dog, the absolute bioavailability was 27 % at an oral dose of 3 mg/kg. 5. GTS-21 was O-demethylated to yield compounds that were then subject to g lucuronidation. Three of the metabolites in rat urine were isolated and cha racterized as 4-OH-GTS-21, 4-OH-GTS-21 glucuronide and 2-OH-GTS-21 glucuron ide. The major urinary metabolites were 4-OH-GTS-21 glucuronide and 2-OH-GT S-21 glucuronide. 6. In vitro chemical inhibition of cytochrome P450 in human liver microsome s indicated that CYP1A2 and CYP2E1 were the isoforms primarily responsible for the O-demethylation of GTS-21, with some contribution from CYP3A.