Pharmacokinetics, metabolism and off-target effects in the rat of 8-[(1H- benzotriazol-1-yl)amino]octanoic acid, a selective inhibitor of human cytochrome P450 4Z1: <i>β</i>-oxidation as a potential augmenting pathway for inhibition
Creators: name: Kowalski, John P.
name: Pelletier, Robert D.
name: McDonald, Matthew G.
name: Kelly, Edward J.
name: Rettie, Allan E.
Publisher: name: Taylor & Francis
Year: 2021
Subjects: subject: Biochemistry
subject: Medicine
subject: Cell Biology
subject: Genetics
subject: FOS: Biological sciences
subject: Molecular Biology
subject: Pharmacology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: 69999 Biological Sciences not elsewhere classified

description: 8‐[(1H‐1,2,3‐benzotriazol‐1‐yl)amino]octanoic acid (8-BOA) was recently identified as a selective and potent mechanism-based inactivator (MBI) of breast cancer-associated CYP4Z1 and exhibited favourable inhibitory activity <i>in vitro,</i> thus meriting <i>in vivo</i> characterization.The pharmacokinetics and metabolism of 8-BOA in rats was examined after a single IV bolus dose of 10 mg/kg. A biphasic time-concentration profile resulted in relatively low clearance and a prolonged elimination half-life.The major circulating metabolites identified in plasma were products of <i>β</i>-oxidation; congeners losing two and four methylene groups accounted for &gt;50% of metabolites by peak area. The –(CH<sub>2</sub>)<sub>2</sub> product was characterized previously as a CYP4Z1 MBI and so represents an active metabolite that may contribute to the desired pharmacological effect.<i>Ex vivo</i> analysis of total CYP content in rat liver and kidney microsomes showed that off-target CYP inactivation was minimal; liver microsomal probe substrate metabolism also demonstrated low off-target inactivation. Standard clinical chemistries provided no indication of acute toxicity.<i>In silico</i> simulations using the free concentration of 8-BOA in plasma suggested that the <i>in vivo</i> dose used here may effectively inactivate CYP4Z1 in a xenografted tumour. 8‐[(1H‐1,2,3‐benzotriazol‐1‐yl)amino]octanoic acid (8-BOA) was recently identified as a selective and potent mechanism-based inactivator (MBI) of breast cancer-associated CYP4Z1 and exhibited favourable inhibitory activity <i>in vitro,</i> thus meriting <i>in vivo</i> characterization. The pharmacokinetics and metabolism of 8-BOA in rats was examined after a single IV bolus dose of 10 mg/kg. A biphasic time-concentration profile resulted in relatively low clearance and a prolonged elimination half-life. The major circulating metabolites identified in plasma were products of <i>β</i>-oxidation; congeners losing two and four methylene groups accounted for &gt;50% of metabolites by peak area. The –(CH<sub>2</sub>)<sub>2</sub> product was characterized previously as a CYP4Z1 MBI and so represents an active metabolite that may contribute to the desired pharmacological effect. <i>Ex vivo</i> analysis of total CYP content in rat liver and kidney microsomes showed that off-target CYP inactivation was minimal; liver microsomal probe substrate metabolism also demonstrated low off-target inactivation. Standard clinical chemistries provided no indication of acute toxicity. <i>In silico</i> simulations using the free concentration of 8-BOA in plasma suggested that the <i>in vivo</i> dose used here may effectively inactivate CYP4Z1 in a xenografted tumour.