Tolerability and pharmacokinetics of oxaloacetate 100 mg capsules in Alzheimer's subjects

Russell H Swerdlow, Rebecca Bothwell, Lewis Hutfles, Jeffrey M Burns, Gregory A Reed, Russell H Swerdlow, Rebecca Bothwell, Lewis Hutfles, Jeffrey M Burns, Gregory A Reed

Abstract

Bioenergetics and bioenergetic-related functions are altered in Alzheimer's disease (AD) subjects. These alterations represent therapeutic targets and provide an underlying rationale for modifying brain bioenergetics in AD-affected persons. Preclinical studies in cultured cells and mice found that administering oxaloacetate (OAA), a Krebs cycle and gluconeogenesis intermediate, enhanced bioenergetic fluxes and upregulated some brain bioenergetic infrastructure-related parameters. We therefore conducted a study to provide initial data on the tolerability and pharmacokinetics of OAA in AD subjects. Six AD subjects received OAA 100 mg capsules twice a day for one month. The intervention was well-tolerated. Blood level measurements following ingestion of a 100 mg OAA capsule showed modest increases in OAA concentrations, but pharmacokinetic analyses were complicated by relatively high amounts of endogenous OAA. We conclude that OAA 100 mg capsules twice per day for one month are safe in AD subjects but do not result in a consistent and clear increase in the OAA blood level, thus necessitating future clinical studies to evaluate higher doses.

Keywords: AD, Alzheimer's disease; ADASCog, Alzheimer's Disease Assessment Scale-Cognitive subset; AUC, area under the curve; Alzheimer's disease; CBC, complete blood count; CDR, Clinical Dementia Rating; COX, cytochrome oxidase; Clinical trial; FDG PET, fluoro-deoxyglucose positron emission tomography; HOMA-IR, homeostatic model assessment of insulin resistance; IP, intraperitoneal; KU ADC, University of Kansas Alzheimer's Disease Center; LC–MS/MS, liquid chromatography–tandem mass spectrometry; LFT, liver function tests; MMSE, mini-mental state exam; Mitochondria; OAA, oxaloacetate; Oxaloacetate; PGC1α, peroxisome proliferator-activated receptor gamma coactivator; PK, pharmacokinetic; Pharmacokinetics; mtDNA, mitochondrial DNA.

Figures

Fig. 1
Fig. 1
Pharmacokinetics of Oxaloacetate (POX) study organization.
Fig. 2
Fig. 2
OAA plasma concentration versus time. Results are shown for the analysis of plasma samples from subject 3.

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