Disposition and Metabolism of Semagacestat, a γ-Secretase Inhibitor, in Humans

Abstract

ABSTRACT:Semagacestat is a functional ␥-secretase inhibitor that has been shown to reduce the rate of formation of amyloid-␤ in vitro and in vivo. This study was conducted to characterize the disposition of semagacestat in humans. After a single 140-mg dose of [ 14 C]semagacestat administered as an oral solution to six healthy male subjects, semagacestat was rapidly absorbed (T max ϳ0.5 h) and eliminated from the systemic circulation (terminal t 1/2 ϳ2.4 h). The major circulating metabolites of semagacestat, M2 (hydrolysis of the amide bond proximal to the benzazepine ring) and M3 (benzylic hydroxylation of the benzazepine ring), accounted for approximately 27 and 10% of total radioactivity exposure, respectively, as calculated from relative area under the plasma concentration versus time curve from 0 to 24 h derived from the plasma radiochro- Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by cognitive impairment. The prevalence rate is approximately 6% among those aged more than 65 years. Currently more than 4 million Americans suffer from AD, and this number is expected to quadruple by year 2050 as average lifespan increases (Rice et al., 2001;Joyce et al., 2007). AD has a substantial impact on patients, caregivers, and the healthcare system. Average total medical costs for AD patients are more than 5-fold higher than those for control populations. Development of pharmaceuticals for the treatment of AD would greatly benefit AD patients and society. The cause of AD is not yet clear. Pathological studies revealed the existence of neuritic plaques in the brains of AD patients (Desai and Grossberg, 2005;Blennow et al., 2006). The plaques are mainly composed of amyloid-␤ (A␤) peptides that are formed by the sequential cleavage of the amyloid precursor protein (APP). APP is first cleaved by the ␤-site APP-cleaving enzyme to form the N terminus of A␤, which is further cleaved by ␥-secretase at multiple sites to form A␤ isoforms ranging from 37 (A␤37) to 43 (A␤43) residues (Olson and Albright, 2008). Mutations in APP near cleavage sites resulting in the A␤ formation have been linked to AD in several families (Selkoe, 2001;Imbimbo, 2008). This observation suggests that a reduction in A␤ synthesis could slow the disease progression in patients with AD.Semagacestat, an azepine class ␥-secretase inhibitor, is one of a very few ␥-secretase inhibitors that have been advanced into clinical trials as potential disease-modifying agents for the treatment of AD (Olson and Albright, 2008). Semagacestat reduces the rate of formation of A␤ in whole cell assays, as well as in transgenic and nontransgenic mice, beagle dogs, and guinea pigs Hyslop et al., 2004;May et al., 2004;Lanz et al., 2006). A transgenic mouse model of AD was generated using a platelet-derived growth factor ␤ promoter driving a human APP minigene encoding the APP V171F mutation (PDAPP mouse). These mice express high levels of human mutant APP and progressively develop many of the pathologArticle, publication date, and citation ...

Metabolism of (2S)-Pterosin A: Identification of the Phase I and Phase II Metabolites in Rat Urine

“…Our study reveals the amounts of 3␣-hydroxylated metabolites to be much more than those of 3␤-hydroxylated ones, similar to what was observed in dicentrine metabolites (Lai et al, 2010) and implying the regioselectivity of hydroxylation at C-3. The regioselectivity of benzylic hydroxylation also occurred in semagacestat metabolites, which were primarily formed by CYP3A4 and CYP3A5 (Yi et al, 2010). The metabolites may be responsible for in vivo toxicological and pharmacological effects.…”

The Effects on Metabolic Clearance when Administering a Potent CYP3A Autoinducer with the Prototypic CYP3A Inhibitor, Ketoconazole

“…This observation is consistent with high bioavailability and a modest contribution, approximately 23%, of CYP3A to the overall semagacestat CL/F and of a 4-to 5-fold increase in CYP3A activity in response to multiple doses of semagacestat. The formation of the M3 metabolite of semagacestat is catalyzed by CYP3A4 and CYP3A5, and as expected, the AUC of this metabolite increased by approximately 50% after autoinduction (Table 3); exposure to M2, a non-CYP3A metabolite, was unchanged between single and multiple dosing with semagacestat (Yi et al, 2010).…”

“…1B) (Yi et al, 2010). The formation of M3 was investigated using recombinant enzymes coexpressed with cytochrome b 5 and was found to be primarily CYP3A-dependent, with the intrinsic clearance of CYP3A5 being approximately 2 times greater than that of CYP3A4 when catalyzing the formation of M3 (Yi et al, 2010).…”

“…In humans, semagacestat has two major circulating metabolites: M2 (formed by hydrolysis of the amide bond proximal to the benzazepine ring) and M3 (formed by benzylic hydroxylation of the benzazepine ring) (Fig. 1B) (Yi et al, 2010). The formation of M3 was investigated using recombinant enzymes coexpressed with cytochrome b 5 and was found to be primarily CYP3A-dependent, with the intrinsic clearance of CYP3A5 being approximately 2 times greater than that of CYP3A4 when catalyzing the formation of M3 (Yi et al, 2010).…”

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

“…In addition, different GSIs enjoy quite inequivalent pharmacokinetics. LY900009 is cleared by oxidation and amide hydrolysis, and its renal clearance is low, while semagacestat, an analogue of LY900009, mostly depends on renal clearance (89,90). RO4929097 is cleared by autoinduction of cytochrome P450 family 3 subfamily A polypeptide 4 (CYP3A4), indicating that combination RO4929097 therapy with antitumor agents metabolized by CYP3A4 might show limit clinical utility (91) Supplementary Figs.…”