title: Novel Mechanism of Decyanation of GDC-0425 by Cytochrome P450.
abstract: GDC-0425 [5-((1-ethylpiperidin-4-yl)oxy)-9H-pyrrolo[2,3-b:5,4-c']dipyridine-6-carbonitrile] is an orally bioavailable small-molecule inhibitor of checkpoint kinase 1 that was investigated as a novel cotherapy to potentiate chemotherapeutic drugs, such as gemcitabine. In a radiolabeled absorption, distribution, metabolism, and excretion study in Sprague-Dawley rats, trace-level but long-lived14C-labeled thiocyanate was observed in circulation. This thiocyanate originated from metabolic decyanation of GDC-0425 and rapid conversion of cyanide to thiocyanate. Excretion studies indicated decyanation was a minor metabolic pathway, but placing14C at nitrile magnified its observation. Cytochrome P450s catalyzed the oxidative decyanation reaction in vitro when tested with liver microsomes, and in the presence of18O2, one atom of18O was incorporated into the decyanated product. To translate this finding to a clinical risk assessment, the total circulating levels of thiocyanate (endogenous plus drug-derived) were measured following repeated administration of GDC-0425 to rats and cynomolgus monkeys. No overt increases were observed with thiocyanate concentrations of 121-154µM in rats and 71-110µM in monkeys receiving vehicle and all tested doses of GDC-0425. These findings were consistent with results from the radiolabel rat study where decyanation accounted for conversion of <1% of the administered GDC-0425 and contributed less than 1µM thiocyanate to systemic levels. Further, in vitro studies showed only trace oxidative decyanation for humans. These data indicated that, although cyanide was metabolically released from GDC-0425 and formed low levels of thiocyanate, this pathway was a minor route of metabolism, and GDC-0425-related increases in systemic thiocyanate were unlikely to pose safety concerns for subjects of clinical studies.
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (R.H.T., J.S.H., Y.C., C.E.C.A.H., S.C.K., S.M.), and Discovery Chemistry (M.S.), Genentech, Inc., 1 DNA Way, South San Francisco, California takahashi.ryan@gene.com.
authors.forename: Ryan H
authors.initials: RH
authors.lastname: Takahashi
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (R.H.T., J.S.H., Y.C., C.E.C.A.H., S.C.K., S.M.), and Discovery Chemistry (M.S.), Genentech, Inc., 1 DNA Way, South San Francisco, California.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Halladay
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (R.H.T., J.S.H., Y.C., C.E.C.A.H., S.C.K., S.M.), and Discovery Chemistry (M.S.), Genentech, Inc., 1 DNA Way, South San Francisco, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Siu
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (R.H.T., J.S.H., Y.C., C.E.C.A.H., S.C.K., S.M.), and Discovery Chemistry (M.S.), Genentech, Inc., 1 DNA Way, South San Francisco, California.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (R.H.T., J.S.H., Y.C., C.E.C.A.H., S.C.K., S.M.), and Discovery Chemistry (M.S.), Genentech, Inc., 1 DNA Way, South San Francisco, California.
authors.forename: Cornelis E C A
authors.initials: CE
authors.lastname: Hop
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (R.H.T., J.S.H., Y.C., C.E.C.A.H., S.C.K., S.M.), and Discovery Chemistry (M.S.), Genentech, Inc., 1 DNA Way, South San Francisco, California.
authors.forename: S Cyrus
authors.initials: SC
authors.lastname: Khojasteh
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (R.H.T., J.S.H., Y.C., C.E.C.A.H., S.C.K., S.M.), and Discovery Chemistry (M.S.), Genentech, Inc., 1 DNA Way, South San Francisco, California.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Ma
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001711:Biotransformation; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D017207:Rats, Sprague-Dawley; D013861:Thiocyanates / Q000097:blood / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; D010880:Piperidines; D013861:Thiocyanates; C000614032:GDC-0425; D003577:Cytochrome P-450 Enzyme System; D000071877:Checkpoint Kinase 1