Accelerator mass spectrometry for 14C drug metabolism analysis

Accelerator mass spectrometry (AMS) is an extremely sensitive analytical technique that detects and quantifies ¹⁴C atoms at trace concentrations, offering 500 to 10,000 times greater sensitivity than traditional liquid scintillation counting (LSC) or liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods.

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The original application for AMS was radiocarbon dating. However, in the early 2000s, it was taken up for biomedical applications and is now a staple in pharmaceutical research and development. With no matrix interference or ionization issues, AMS can be used for the analysis of drugs with low doses and systemic exposure and long half-lives.

Image Credit: Pharmaron

AMS (Accelerator Mass Spectrometry) capabilities

• Clinical and non-clinical support: Absorption, distribution, metabolism, and excretion (ADME), absolute bioavailability, pharmacokinetics (PK), toxicokinetics (TK), and metabolites in safety testing (MIST)
• Sample types: Plasma, blood, urine, feces, bile, cerebrospinal fluid (CSF), expired air, tissues, and peripheral blood mononuclear cells (PBMCs)
• Instrumentation:
  • Ionplus 50 kV LEA: Low-energy, gaseous (¹⁴CO₂) AMS for rapid sample analysis
  • NEC 250 kV SS-AMS: Ultra-sensitive, graphite (¹⁴C) AMS with dual ion sources for high-volume sample analysis (over 2000 samples per week)
• Software: 21 CFR Part 11-compliant, with audit trails and automated workflows (Ionplus AMS only)
• Microtracer hADME studies: Provides complete metabolism data with a minimal ¹⁴C dose in humans
• Absolute bioavailability IVPK studies: Concomitant oral/¹⁴C intravenous (IV) dosing for determining absolute bioavailability in humans
• Metabolite profiling: Liquid chromatography (LC) coupled with AMS for high-resolution profiling, including quantitation of ultra-low-level metabolites
• Mass balance metabolite profiling studies: Conducted in toxicology species

AMS (Accelerator Mass Spectrometry) workflow

The fundamental workflow below demonstrates how strategies using ¹⁴C AMS can combine the full characterization of drug metabolism in humans with the assessment of absolute bioavailability, systemic clearance, and volume of distribution (IV pharmacokinetics) for a particular compound.

These complementary approaches can be run in parallel in the clinic, providing a detailed, data-driven understanding of drug metabolism, systemic PK, and biotransformation.

Image Credit: Pharmaron

Advantages of AMS services at Pharmaron

• Recognized global leader: Over 25 years of experience with world-class AMS facilities in the United States, United Kingdom, and China
• Accelerated timelines: End-to-end integrated ¹⁴C metabolism programs, including radiosynthesis, non-clinical, and clinical
• Cost efficiency: Minimal Good Manufacturing Practice (GMP) and human dosimetry requirements
• Regulatory acceptance: Good Clinical Practice (GCP)-compliant for submissions to the United States Food and Drug Administration (FDA); European Medicines Agency (EMA); Medicines and Healthcare products Regulatory Agency (MHRA); and Japan’s Ministry of Health, Labor, and Welfare (MHLW)
• High-quality data: Rich, quantitative datasets for confident decision-making and de-risking

About Pharmaron

Pharmaron is a premier service provider for the life sciences industry. Founded in 2004, Pharmaron has invested in its people and facilities and established a broad spectrum of research, development, and manufacturing service capabilities throughout the entire drug discovery, preclinical, and clinical development process across multiple therapeutic modalities, including small molecules, biologics, and CGT products. With over 29,000 employees and operations in China, United States, United Kingdom, and Singapore, Pharmaron has an excellent track record in delivering R&D solutions to its partners in North America, Europe, Japan, and China.

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