Metabolism and disposition of JNJ-10450232 (NTM-006) in rats, dogs, nonhuman primates and humans.

JNJ-10450232 (NTM-006), a novel non-opioid, non-nonsteroidal anti-inflammatory drug with structural similarities to acetaminophen, demonstrated anti-pyretic and/or analgesic activities in preclinical models and humans and reduced potential to cause hepatotoxicity in preclinical species. Metabolism and disposition of JNJ-10450232 (NTM-006) following oral administration to rats, dogs, monkeys and humans are reported. Urinary excretion was the major route of elimination based on recovery of 88.6% (rats) and 73.7% (dogs) of oral dose. The compound was extensively metabolized based on low recovery of unchanged drug in excreta from rats (11.3%) and dogs (18.4%). Clearance is driven by O-glucuronidation, amide hydrolysis, O-sulfation and methyl oxidation pathways. The combination of metabolic pathways driving clearance in human is covered in at least one preclinical species despite a few species-dependent pathways. O-Glucuronidation was the major primary metabolic pathway of JNJ-10450232 (NTM-006) in dogs, monkeys and humans, although amide hydrolysis was another major primary metabolic pathway in rats and dogs. A minor bioactivation pathway to quinone-imine is observed only in monkeys and humans. Unchanged drug was the major circulatory component in all species investigated. Except for metabolic pathways unique to the 5-methyl-1H-pyrazole-3-carboxamide moiety, metabolism and disposition of JNJ-10450232 (NTM-006) are similar to acetaminophen across species.

• Publication year

  2023

• Venue

  Regulatory toxicology and pharmacology : RTP

• Publication date

  2023-03-01

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1016/j.yrtph.2023.105379PMID 36931586
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• First-in-human study to evaluate the safety, tolerability and pharmacokinetics of a novel analgesic and antipyretic drug with structural similarity to acetaminophen.

  2022cited by this paper
• Drug metabolism in drug discovery and development

  2018cited by this paper
• Exposure to acetaminophen and all its metabolites upon 10, 15, and 20 mg/kg intravenous acetaminophen in very-preterm infants

  2017cited by this paper
• Standard-Free Bioanalytical Approach for Absolute Quantitation of Drug Metabolites Utilizing Biosynthesis of Reciprocal Radio and Stable Isotopologues and Its Application.

  2017cited by this paper
• Metabolism by conjugation appears to confer resistance to paracetamol (acetaminophen) hepatotoxicity in the cynomolgus monkey

  2015cited by this paper
• PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses

  2015cited by this paper
• In vitro approach to assess the potential for risk of idiosyncratic adverse reactions caused by candidate drugs.

  2012cited by this paper
• Radiolabeled absorption, distribution, metabolism, and excretion studies in drug development: why, when, and how?

  2012cited by this paper
• Comprehensive quantitative and qualitative liquid chromatography-radioisotope-mass spectrometry analysis for safety testing of tolbutamide metabolites without standard samples.

  2011cited by this paper
• Metabolism of [14C]GSK977779 in Rats and Its Implication with the Observed Covalent Binding

  2011cited by this paper
• Overcoming the genotoxicity of a pyrrolidine substituted arylindenopyrimidine as a potent dual adenosine A(2A)/A(1) antagonist by minimizing bioactivation to an iminium ion reactive intermediate.

  2011cited by this paper
• Structures of Human Cytochrome P-450 2E1

  2008cited by this paper
• Development and evaluation of an electrochemical method for studying reactive phase-I metabolites: correlation to in vitro drug metabolism.

  2007cited by this paper
• A rapid method for quantitatively estimating metabolites in human plasma in the absence of synthetic standards using a combination of liquid chromatography/mass spectrometry and radiometric detection.

  2007cited by this paper
• The ion suppression phenomenon in liquid chromatography–mass spectrometry and its consequences in the field of residue analysis

  2005cited by this paper
• Simultaneous HPLC Determination of Acetaminophen and Four of Its Major Metabolites in Small-Volume Biologic Fluids

  2002cited by this paper
• Paracetamol (Acetaminophen)-Induced Toxicity: Molecular and Biochemical Mechanisms, Analogues and Protective Approaches

  2001cited by this paper
• Disposition of glutathione conjugates in rats by a novel glutamic acid pathway: characterization of unique peptide conjugates by liquid chromatography/mass spectrometry and liquid chromatography/NMR.

  2000cited by this paper
• Plasma-pooling methods to increase throughput for in vivo pharmacokinetic screening.

  1998cited by this paper
• Species variation in toxication and detoxication of acetaminophen in vivo: a comparative study of biliary and urinary excretion of acetaminophen metabolites.

  1988cited by this paper
• The toxicity and biotransformation of single doses of acetaminophen in dogs and cats.

  1984cited by this paper
• Determination of mean valproic acid serum level by assay of a single pooled sample

  1981cited by this paper
• Kinetics and metabolism of paracetamol and phenacetin.

  1980cited by this paper
• Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo.

  1973cited by this paper

• In-depth understanding of the structure-based reactive metabolite formation of organic functional groups

  2025cites this paper
• The Discovery and Preclinical Pharmacology of JNJ-10450232 (NTM-006), a Centrally Penetrant, Non-Opioid Structural Analog of Acetaminophen with Comparable Analgesic and Anti-Pyretic Properties but No Evidence of Hepatotoxicity.

  2025cites this paper
• Old and New Analgesic Acetaminophen: Pharmacological Mechanisms Compared with Non-Steroidal Anti-Inflammatory Drugs

  2025cites this paper
• Exploring acetaminophen prodrugs and hybrids: a review

  2024cites this paper
• Bioactivation and reactivity research advances – 2023 year in review

  2024cites this paper