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 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.
Azuma
R
R
Pharmacokinetics Research Laboratory, Taiho Pharmaceutical Co., Ltd, Tokushima, Japan. taihopk@infoweb.ne.jp
Komuro
M
M
Korsch
B H
BH
Andre
J C
JC
Onnagawa
O
O
Black
S R
SR
Mathews
J M
JM
D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D019540:Area Under Curve; D001597:Benzylidene Compounds / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D001646:Bile / Q000737:chemistry; D001682:Biological Availability; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D005243:Feces / Q000737:chemistry; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D018722:Nicotinic Agonists / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014556:Urine / Q000737:chemistry
D001597:Benzylidene Compounds; D002250:Carbon Radioisotopes; D018722:Nicotinic Agonists; D011725:Pyridines; C088936:3-(2,4-dimethoxybenzylidene)anabaseine; D003577:Cytochrome P-450 Enzyme System