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

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Azuma R, Komuro M, Korsch BH, Andre JC, Onnagawa O, Black SR, Mathews JM

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

Xenobiotica. 1999 Jul;29(7):747-62.

PubMed ID

10456692 [ View in PubMed

]

Abstract

1. GTS-21, a novel drug for Alzheimer's disease, is currently under clinical development. In the current study, the metabolism and disposition of GTS-21 have been evaluated in rat and dog after single oral and intravenous administration. 2. Following oral administration of [14C]GTS-21 to rat, radioactivity was primarily excreted in the faeces (67%) via the bile with possible enterohepatic circulation. Urinary excretion of radioactivity in rat and dog was 20 and 19% respectively. 3. GTS-21 was rapidly and extensively absorbed after oral administration and rapidly cleared from plasma. The maximum concentration ratio of GTS-21 to total radioactivity in plasma was low, indicating first-pass or pre-systemic 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 glucuronidation. Three of the metabolites in rat urine were isolated and characterized as 4-OH-GTS-21, 4-OH-GTS-21 glucuronide and 2-OH-GTS-21 glucuronide. The major urinary metabolites were 4-OH-GTS-21 glucuronide and 2-OH-GTS-21 glucuronide. 6. In vitro chemical inhibition of cytochrome P450 in human liver microsomes indicated that CYPIA2 and CYP2E1 were the isoforms primarily responsible for the O-demethylation of GTS-21, with some contribution from CYP3A.

DrugBank Data that Cites this Article

Drugs

GTS-21

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
GTS-21	Cytochrome P450 1A2	Protein	Humans	Unknown	Substrate	Details
GTS-21	Cytochrome P450 2E1	Protein	Humans	Unknown	Substrate	Details