Studies on the pharmacokinetics and metabolism of a gamma-secretase inhibitor BMS-299897, and exploratory investigation of CYP enzyme induction.
BMS-299897 is a gamma-secretase inhibitor that was effective in reducing amyloid beta-peptide (A beta) in transgenic mice and guinea pigs. Therefore, pharmacokinetic and drug metabolism studies were conducted in animals to support its clinical development. The compound appeared to have low to intermediate total body clearance and was orally bioavailable (24-100%). The oral absorption of BMS-299897 from solid dosage forms appeared to be dissolution rate-limited. BMS-299897 was distributed into extravascular space (V(ss) >or= 1.3 l kg(-1)), including brain (brain-to-plasma ratio = 0.13-0.50). BMS-299897 appeared to be a P-glycoprotein (P-gp) substrate as the brain-to-plasma ratio was two-fold higher in the mdr1a knockout mouse as compared with the wild-type. Apparent autoinduction by BMS-299897 was observed in murine and rat efficacy and toxicity studies. In vitro, BMS-299897 was a weaker inducer of cytochrome P450 3A4 (CYP3A4) and a weaker transactivator of human pregnane X receptor (hPXR) as compared with rifampicin. Induction of human UGT1A and UGT2B was evaluated in primary human hepatocytes, but the results were inconclusive. A low potential for autoinduction in humans was predicted at a clinical dose of 250 mg and the prediction was consistent with the findings from a clinical multiple-dose study with BMS-299897 in probable Alzheimer's patients.
Zheng
M
M
Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research and Development, Wallingford, CT, USA. Ming.Zheng@bms.com
Wang
J
J
Lubinski
J
J
Flint
O P
OP
Krishna
R
R
Yao
M
M
Pursley
J M
JM
Thakur
A
A
Boulton
D W
DW
Santone
K S
KS
Barten
D M
DM
Anderson
J J
JJ
Felsenstein
K M
KM
Hansel
S B
SB
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000328:Adult; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000904:Antibiotics, Antitubercular / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001921:Brain / Q000201:enzymology; D002087:Butyrates / Q000493:pharmacokinetics* / Q000494:pharmacology; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004285:Dogs; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000077297:Pregnane X Receptor; D051381:Rats; D017207:Rats, Sprague-Dawley; D011987:Receptors, Steroid / Q000378:metabolism; D012293:Rifampin / Q000493:pharmacokinetics / Q000494:pharmacology; D013045:Species Specificity
C497115:4-(2-((1R)-1-(((4-chlorophenyl)sulfonyl)-2,5-difluoroanilino)ethyl)-5-fluorophenyl)butanoic acid; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D000904:Antibiotics, Antitubercular; D002087:Butyrates; D006846:Hydrocarbons, Halogenated; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D003577:Cytochrome P-450 Enzyme System; C408695:Cyp3a41a protein, mouse; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D053829:Amyloid Precursor Protein Secretases; D012293:Rifampin