Mass Balance of the Indoleamine 2,3-Dioxygenase Inhibitor Navoximod (GDC-0919) in Rats and Dogs: Unexpected Cyanide Release from Imidazo[5,1- a ]isoindole and Species Differences in Glucuronidation.

Autor:	Wang S; Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (S.W., E.C., J.W., H.L., W.L., S.C.K., L.S.); Pliant Therapeutics, South San Francisco, California (S.M.); and Process Chemistry & Catalysis, F. Hoffmann-La Roche Ltd, Basel, Switzerland (S.P.H., M.B.)., Ma S; Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (S.W., E.C., J.W., H.L., W.L., S.C.K., L.S.); Pliant Therapeutics, South San Francisco, California (S.M.); and Process Chemistry & Catalysis, F. Hoffmann-La Roche Ltd, Basel, Switzerland (S.P.H., M.B.)., Chen E; Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (S.W., E.C., J.W., H.L., W.L., S.C.K., L.S.); Pliant Therapeutics, South San Francisco, California (S.M.); and Process Chemistry & Catalysis, F. Hoffmann-La Roche Ltd, Basel, Switzerland (S.P.H., M.B.)., Wang J; Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (S.W., E.C., J.W., H.L., W.L., S.C.K., L.S.); Pliant Therapeutics, South San Francisco, California (S.M.); and Process Chemistry & Catalysis, F. Hoffmann-La Roche Ltd, Basel, Switzerland (S.P.H., M.B.)., Le H; Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (S.W., E.C., J.W., H.L., W.L., S.C.K., L.S.); Pliant Therapeutics, South San Francisco, California (S.M.); and Process Chemistry & Catalysis, F. Hoffmann-La Roche Ltd, Basel, Switzerland (S.P.H., M.B.)., Hanlon SP; Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (S.W., E.C., J.W., H.L., W.L., S.C.K., L.S.); Pliant Therapeutics, South San Francisco, California (S.M.); and Process Chemistry & Catalysis, F. Hoffmann-La Roche Ltd, Basel, Switzerland (S.P.H., M.B.)., Binder M; Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (S.W., E.C., J.W., H.L., W.L., S.C.K., L.S.); Pliant Therapeutics, South San Francisco, California (S.M.); and Process Chemistry & Catalysis, F. Hoffmann-La Roche Ltd, Basel, Switzerland (S.P.H., M.B.)., Lee W; Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (S.W., E.C., J.W., H.L., W.L., S.C.K., L.S.); Pliant Therapeutics, South San Francisco, California (S.M.); and Process Chemistry & Catalysis, F. Hoffmann-La Roche Ltd, Basel, Switzerland (S.P.H., M.B.)., Khojasteh SC; Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (S.W., E.C., J.W., H.L., W.L., S.C.K., L.S.); Pliant Therapeutics, South San Francisco, California (S.M.); and Process Chemistry & Catalysis, F. Hoffmann-La Roche Ltd, Basel, Switzerland (S.P.H., M.B.)., Salphati L; Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (S.W., E.C., J.W., H.L., W.L., S.C.K., L.S.); Pliant Therapeutics, South San Francisco, California (S.M.); and Process Chemistry & Catalysis, F. Hoffmann-La Roche Ltd, Basel, Switzerland (S.P.H., M.B.) salphati.laurent@gene.com.
Jazyk:	angličtina
Zdroj:	Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2023 Jul; Vol. 51 (7), pp. 862-872. Date of Electronic Publication: 2023 Apr 14.
DOI:	10.1124/dmd.123.001289
Abstrakt:	Navoximod (GDC-0919) is a small molecule inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1) developed to reduce T cell immunosuppression associated with cancer. This study describes the absorption, metabolism, and excretion (AME) of navoximod in rats and dogs after a single oral dose of [ 14 C]-navoximod. An unexpected thiocyanate metabolite M1 and a chiral inversion metabolite M51 were captured as the major circulating metabolites in rats, accounting for 30% and 18% of 0-24 hours exposure, respectively. These two metabolites combined had much lower systemic exposure in dogs and humans (<6% and <1%). The novel cyanide release is proposed to occur via 4,5-epoxidation on the fused imidazole ring, leading to ring opening and rearrangement along with the release of cyanide. The decyanated metabolites were identified and confirmed by synthetic standards, which supported the proposed mechanism. In dogs, glucuronidation to M19 was the major clearance mechanism, representing 59% of the dose in the bile of bile duct-cannulated (BDC) dogs and 19% of the dose in the urine of intact dogs. Additionally, M19 also represented 52% of drug related exposure in circulation in dogs. In comparison, in humans, navoximod was mainly cleared through glucuronidation to M28 and excreted in urine (60% of the dose). The differences in the metabolism and elimination observed in vivo were qualitatively recapitulated in vitro with liver microsomes, suspended hepatocytes, and cocultured primary hepatocytes. The striking species differences in regioselective glucuronidation is likely explained by the species differences in UGT1A9, which was mainly responsible for M28 formation in humans. SIGNIFICANCE STATEMENT: The results from this study demonstrated significant species differences in metabolism (especially glucuronidation) and elimination of navoximod among rats, dogs, and humans. The study also illustrated the mechanism of a novel cyanide release metabolism from the fused imidazo[5,1-a]isoindole ring. Such biotransformation should be kept in mind when working with imidazole-containing new chemical entities in drug discovery and development. (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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