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Radiolabel Uncovers Nonintuitive Metabolites of BIIB104: Novel Release of [14C]Cyanide from 2-Cyanothiophene and Subsequent Formation of [14C]Thiocyanate.
Gu, Chungang; Huang, Jiansheng; Muste, Cathy; Zhong, Jeremy; Walker, Gregory S; Obach, R Scott; Shaffer, Christopher L.
Affiliation
  • Gu C; Drug Metabolism and Pharmacokinetics (C.G., J.H., C.M.), External Innovation Unit (C.L.S.), and Physical Biochemistry (J.Z.), Biogen, Inc., Cambridge, Massachusetts and Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Groton, Connecticut (G.S.W., R.S.O.) chuck.gu@biogen.com.
  • Huang J; Drug Metabolism and Pharmacokinetics (C.G., J.H., C.M.), External Innovation Unit (C.L.S.), and Physical Biochemistry (J.Z.), Biogen, Inc., Cambridge, Massachusetts and Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Groton, Connecticut (G.S.W., R.S.O.).
  • Muste C; Drug Metabolism and Pharmacokinetics (C.G., J.H., C.M.), External Innovation Unit (C.L.S.), and Physical Biochemistry (J.Z.), Biogen, Inc., Cambridge, Massachusetts and Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Groton, Connecticut (G.S.W., R.S.O.).
  • Zhong J; Drug Metabolism and Pharmacokinetics (C.G., J.H., C.M.), External Innovation Unit (C.L.S.), and Physical Biochemistry (J.Z.), Biogen, Inc., Cambridge, Massachusetts and Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Groton, Connecticut (G.S.W., R.S.O.).
  • Walker GS; Drug Metabolism and Pharmacokinetics (C.G., J.H., C.M.), External Innovation Unit (C.L.S.), and Physical Biochemistry (J.Z.), Biogen, Inc., Cambridge, Massachusetts and Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Groton, Connecticut (G.S.W., R.S.O.).
  • Obach RS; Drug Metabolism and Pharmacokinetics (C.G., J.H., C.M.), External Innovation Unit (C.L.S.), and Physical Biochemistry (J.Z.), Biogen, Inc., Cambridge, Massachusetts and Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Groton, Connecticut (G.S.W., R.S.O.).
  • Shaffer CL; Drug Metabolism and Pharmacokinetics (C.G., J.H., C.M.), External Innovation Unit (C.L.S.), and Physical Biochemistry (J.Z.), Biogen, Inc., Cambridge, Massachusetts and Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Groton, Connecticut (G.S.W., R.S.O.).
Drug Metab Dispos ; 52(5): 323-336, 2024 Apr 16.
Article in En | MEDLINE | ID: mdl-38360917
ABSTRACT
BIIB104 (formerly PF-04958242), N-((3S,4S)-4-(4-(5-cyanothiophen-2-yl)phenoxy)tetrahydrofuran-3-yl)propane-2-sulfonamide, is an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiator investigated for the treatment of cognitive impairment associated with schizophrenia. Preliminary in vitro metabolism studies with non-radiolabeled BIIB104 in rat, dog, and human liver microsomes (RLM, DLM, and HLM) showed O-dealkylation in all three species, tetrahydrofuran hydroxylation dominating in DLM and HLM, and thiophene hydroxylation prevalent in RLM. However, a subsequent rat mass balance study with [nitrile-14C]BIIB104 showed incomplete recovery of administered radioactivity (∼80%) from urine and feces over 7 days following an oral dose, and an exceptionally long plasma total radioactivity half-life. Radiochromatographic metabolite profiling and identification, including chemical derivation, revealed that [14C]cyanide was a major metabolite of [nitrile-14C]BIIB104 in RLM, but a minor and trace metabolite in DLM and HLM, respectively. Correspondingly in bile duct-cannulated rats, [14C]thiocyanate accounted for ∼53% of total radioactivity excreted over 48 hours postdose and it, as an endogenous substance, explained the exceptionally long plasma radioactivity half-life. The release of [14C]cyanide from the 2-cyanothiophene moiety is postulated to follow an epoxidation-initiated thiophene-opening based on the detection of non-radiolabeled counterpart metabolites in RLM. This unusual biotransformation serves as a lesson regarding placement of the radioactive label on an aryl nitrile when material will be used for evaluating the metabolism of a new drug candidate. Additionally, the potential cyanide metabolite of nitrile-containing drug molecules may be detected in liver microsomes with liquid chromatography-mass spectrometry following a chemical derivatization. SIGNIFICANCE STATEMENT Using [nitrile-14C]BIIB104, non-intuitive metabolites of BIIB104 were discovered involving a novel cyanide release from the 2-cyanothiophene motif via a postulated epoxidation-initiated thiophene-opening. This unusual biotransformation serves as a lesson regarding placement of the radioactive label on an aryl nitrile when material will be used for evaluating the metabolism of a new drug candidate.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Thiocyanates / Cyanides Limits: Animals / Humans Language: En Journal: Drug Metab Dispos Journal subject: FARMACOLOGIA Year: 2024 Type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Thiocyanates / Cyanides Limits: Animals / Humans Language: En Journal: Drug Metab Dispos Journal subject: FARMACOLOGIA Year: 2024 Type: Article