Disposition and metabolism of semagacestat, a γ-secretase inhibitor, in humans

Drug Metabolism and Disposition

Volumn 38, Issue 4, 2010, Pages 554-565

  Yi, Ping ^a   Hadden, Chad ^a   Kulanthaivel, Palaniappan ^a   Calvert, Nathan ^a   Annes, William ^a   Brown, Thomas ^a   Barbuch, Robert J ^a   Chaudhary, Archana ^a   Ayan Oshodi, Mosun A ^a   Ring, Barbara J ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CARBON 14; CYTOCHROME P450 1A2; CYTOCHROME P450 2B6; CYTOCHROME P450 2C19; CYTOCHROME P450 2C8; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 3A4; CYTOCHROME P450 3A5; DRUG METABOLITE; GAMMA SECRETASE INHIBITOR; SEMAGACESTAT;

ADULT; AGED; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DRUG ABSORPTION; DRUG CLEARANCE; DRUG DISPOSITION; DRUG DISTRIBUTION; DRUG ELIMINATION; DRUG EXCRETION; DRUG HALF LIFE; DRUG METABOLISM; DRUG STRUCTURE; HUMAN; HUMAN EXPERIMENT; MALE; MAXIMUM PLASMA CONCENTRATION; NORMAL HUMAN; PRIORITY JOURNAL; RADIATION DOSE; RADIOACTIVITY; RADIOCHROMATOGRAPHY; SINGLE DRUG DOSE; TANDEM MASS SPECTROMETRY; TIME TO MAXIMUM PLASMA CONCENTRATION; URINARY EXCRETION;

ADULT; AGED; ALANINE; AMYLOID PRECURSOR PROTEIN SECRETASES; AREA UNDER CURVE; AZEPINES; BIOTRANSFORMATION; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; CYTOCHROME P-450 CYP3A; FECES; HALF-LIFE; HUMANS; HYDROXYLATION; MAGNETIC RESONANCE SPECTROSCOPY; MALE; MIDDLE AGED; PROTEASE INHIBITORS; TISSUE DISTRIBUTION;

EID: 77950196208     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.109.030841     Document Type: Article

References (27)

1. Blennow K, de Leon MJ, and Zetterberg H (2006) Alzheimer's disease. Lancet 368:387-403.
2. Burk O and Schwab M (2007) The limited impact of CYP3A5 genotype for the pharmacokinetics of CYP3A substrates. Eur J Clin Pharmacol 63:1097-1098.
3. Dai Y, Hebert MF, Isoherranen N, Davis CL, Marsh C, Shen DD, and Thummel KE (2006) Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro. Drug Metab Dispos 34:836-847.
4. Dennison JB, Jones DR, Renbarger JL, and Hall SD (2007) Effect of CYP3A5 expression on vincristine metabolism with human liver microsomes. J Pharmacol Exp Ther 321:553-563.
5. Desai AK and Grossberg GT (2005) Diagnosis and treatment of Alzheimer's disease. Neurology 64:S34-S39.
6. Fleisher AS, Raman R, Siemers ER, Becerra L, Clark CM, Dean RA, Farlow MR, Galvin JE, Peskind ER, Quinn JF, et al. (2008) Phase 2 safety trial targeting amyloid β production with a γ-secretase inhibitor in Alzheimer disease. Arch Neurol 65:1031-1038.
7. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, and Gillespie F (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373:523-527.
8. Gitter B, Czilli D, Li W, Dieckman D, Bender M, Nissen J, Mabry T, Yin T, Boggs L, McClure D, et al. (2004) Stereoselective inhibition of amyloid beta peptide secretion by LY450139, a novel functional gamma secretase inhibitor. Neurobiol Aging 25 (Suppl 2):S571.
9. Hyslop P, May P, Audia J, Calligaro D, McMillian C, Garner C, Cramer J, Gitter B, Porter W, and Nissen J (2004) Reduction in Aβ(1- 40) and Aβ(1-42) in CSF and plasma in the beagle dog following acute oral dosing of the γ secretase inhibitor, LY450139. Neurobiol Aging 25 (Suppl 2):S147.
10. Imbimbo BP (2008) Therapeutic potential of γ-secretase inhibitors and modulators. Curr Top Med Chem 8:54-61.
11. Joyce AT, Zhao Y, Bowman L, Flynn JA, Carter CT, and Ollendorf DA (2007) Burden of illness among commercially insured patients with Alzheimer's disease. Alzheimers Dement 3:204-210.
12. Kharasch ED, Walker A, Isoherranen N, Hoffer C, Sheffels P, Thummel K, Whittington D, and Ensign D (2007) Influence of CYP3A5 genotype on the pharmacokinetics and pharmacodynamics of the cytochrome P4503A probes alfentanil and midazolam. Clin Pharmacol Ther 82:410-426.
13. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, Hall SD, et al. (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nature Genetics 27:383-391.
14. Lanz TA, Karmilowicz MJ, Wood KM, Pozdnyakov N, Du P, Piotrowski MA, Brown TM, Nolan CE, Richter KE, Finley JE, et al. (2006) Concentration-dependent modulation of amyloid-β in vivo and in vitro using the γ-secretase inhibitor, LY-450139. J Pharmacol Exp Ther 319: 924-933.
15. May P, Yang Z, Li W-Y, Hyslop P, Siemers E, and Boggs L (2004) Multi-compartmental pharmacodynamic assessment of the functional γ-secretase inhibitor LY450139 in PDAPP transgenic and nontransgenic mice. Neurobiol Aging 25 (Suppl 2):S65.
16. Ness D, Boggs L, Hepburn DL, Gitter B, Long G, May P, Piroozi K, Schafer K, and Yang Z (2004) Reduced β-amyloid burden, increased C-99 concentrations and evaluation of neuropathology in the brains of PDAPP mice given LY450139 dihydrate daily by gavage for 5 months. Neurobiol Aging 25 (Suppl 2):S238-S239.
17. Olson RE and Albright CF (2008) Recent progress in the medicinal chemistry of γ-secretase inhibitors. Curr Top Med Chem 8:17-33.
18. Perrett HF, Barter ZE, Jones BC, Yamazaki H, Tucker GT, and Rostami-Hodjegan A (2007) Disparity in holoprotein/apoprotein ratios of different standards used for immunoquantification of hepatic cytochrome P450 enzymes. Drug Metab Dispos 35:1733-1736.
19. Rice DP, Fillit HM, Max W, Knopman DS, Lloyd JR, and Duttagupta S (2001) Prevalence, costs, and treatment of Alzheimer's disease and related dementia: a managed care perspective. Am J Manag Care 7:809-818.
20. Selkoe DJ (2001) Alzheimer's disease: genes, proteins, and therapy. Physiol Rev 81:741-766.
21. Shimada T, Yamazaki H, Mimura M, Inui Y, and Guengerich FP (1994) Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270:414-423.
22. Siemers E, Skinner M, Dean RA, Gonzales C, Satterwhite J, Farlow M, Ness D, and May PC (2005) Safety, tolerability, and changes in amyloid β concentrations after administration of a γ-secretase inhibitor in volunteers. Clin Neuropharmacol 28:126-132.
23. Siemers ER, Dean RA, Friedrich S, Ferguson-Sells L, Gonzales C, Farlow MR, and May PC (2007) Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-β after inhibition of γ-secretase. Clin Neuropharmacol 30:317-325.
24. Siemers ER, Quinn JF, Kaye J, Farlow MR, Porsteinsson A, Tariot P, Zoulnouni P, Galvin JE, Holtzman DM, Knopman DS, et al. (2006) Effects of a γ-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 66:602-604.
25. Thervet E, Anglicheau D, King B, Schlageter MH, Cassinat B, Beaune P, Legendre C, and Daly AK (2003) Impact of cytochrome P450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation 76:1233-1235.
26. Totah RA and Rettie AE (2005) Cytochrome P450 2C8: substrates, inhibitors, pharmacogenetics, and clinical relevance. Clin Pharmacol Ther 77:341-352.
27. Xie HG, Wood AJ, Kim RB, Stein CM, and Wilkinson GR (2004) Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics 5:243-272.