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Metabolism and Pharmacokinetics of SP-8356, a Novel (1S)-(−)-Verbenone Derivative, in Rats and Dogs and Its Implications in Humans

College of pharmacy, Korea University, Sejong 30019, Korea
Research Headquarters, Shin Poong Pharm. Co., Ltd., Ansan, Gyeonggi 15610, Korea
Departments of Biomedical Sciences and Neuroscience, College of Medicine, Korea University, Seoul 02841, Korea
Institute of Inflammation Control, Korea University, Seoul 02841, Korea
Institute of Pharmaceutical Science and Translational Research, Korea University, Sejong 30019, Korea
Biomedical Research Center, Korea University Guro Hospital, Seoul 08308, Korea
Author to whom correspondence should be addressed.
These authors contributed equally to this paper.
Molecules 2020, 25(8), 1775;
Received: 17 March 2020 / Revised: 3 April 2020 / Accepted: 9 April 2020 / Published: 13 April 2020
(1S,5R)-4-((E)-3,4-dihydroxy-5-methoxystryryl)-6,6-dimethylbicylco[3.1.1]hept-3-en-2-one (SP-8356) is a novel (1S)-(−)-verbenone derivative that is currently in preclinical development for the treatment of ischemic stroke and atherosclerosis. This report aimed at characterization of the metabolism and pharmacokinetic properties of SP-8356. Following intravenous dose in rats and dogs, plasma concentrations of SP-8356 declined rapidly with high clearance (CL) and short half-life; after oral administration in both species, its plasma levels were below the quantitation limit. Fourteen circulating metabolites, formed by mono-oxygenation, demethylation, glucuronidation, catechol O-methylation, sulfation and oxidation (bioactivation) followed by glutathione (GSH) conjugation, were tentatively identified in both species. Urinary excretion of SP-8356 appeared to be minimal in rats, compared to its metabolites. GSH conjugate of SP-8356 was also formed during incubation with rat liver S9 fraction consistent with oxidative bioactivation; this bioactivation was almost completely inhibited by the cofactors for glucuronidation, sulfation and methylation, indicating that it may be abolished by competing metabolic reactions in the body. The human pharmacokinetics of SP-8356 was predicted to be similar to that of the animals based on the current in vitro metabolic stability results. In summary, rapid phase II metabolism appears to be mainly responsible for its suboptimal pharmacokinetics, such as high CL and low oral absorption. Because of competing metabolic reactions, potential safety risks related to SP-8356 bioactivation may be low. View Full-Text
Keywords: SP-8356; pharmacokinetics; metabolism; bioactivation; conjugation SP-8356; pharmacokinetics; metabolism; bioactivation; conjugation
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Zhou, Y.; Oh, M.H.; Kim, Y.J.; Kim, E.-Y.; Kang, J.; Chung, S.; Ju, C.; Kim, W.-K.; Lee, K. Metabolism and Pharmacokinetics of SP-8356, a Novel (1S)-(−)-Verbenone Derivative, in Rats and Dogs and Its Implications in Humans. Molecules 2020, 25, 1775.

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