Drug Metabolism

We provide a full range of drug metabolism services for determining metabolic stability, metabolic profiling and potential drug-drug interactions. Our experienced team can provide support from early-stage screening assays to late-stage regulatory packages.

A drug that is rapidly metabolized may require multiple daily dosing or continuous infusion to maintain a concentration in the bloodstream or target organ that is sufficient to elicit a therapeutic effect. However, a slowly metabolized drug may remain in the body for long periods, causing toxic build-up. For more background information on the significance of stability studies in early ADME and DMPK see our ADME Guide.

Understanding the metabolite profiles of a drug candidate during preclinical and clinical phases is crucial to ensure that the animal models used for toxicological evaluations accurately represent humans. Consequently, there is a growing emphasis on investigating human drug metabolites, given their potential impact on pharmacological activity, safety, and drug-drug interactions. Regulatory agencies stress the importance of early safety evaluations of human metabolites and recommend comparing drug metabolism between non-clinical animal models and humans to identify any unique or disproportional metabolite exposures that could lead to drug toxicity. Identifying such differences late in drug development can result in significant delays.

Before administering a drug candidate to humans, researchers conduct in vitro metabolite identification studies to assess potential differences in metabolic profiles across species and identify the formation of potentially harmful derivatives. Furthermore, analyzing plasma samples from preclinical species can help evaluate the consistency between in vitro and in vivo metabolism or support targeted investigations.

Metabolites in Safety Testing (MIST) has become a prominent focus in the drug development process. The demand for early evaluation of relevant human circulating metabolites has led to the implementation of appropriate approaches for identifying and semi-quantifying human metabolites. Techniques such as 1H- or 19F-NMR and LC-UV/MS are used for semi-quantification without the need for radiolabeled compounds, metabolite synthetic standards, or validated assays. Additionally, a "radio-metabolites" approach can serve as a valuable tool when other methods are not feasible.

For definitive quantitative metabolism data, radiolabeled studies (involving absorption, metabolism, and excretion) are conducted, where a radiolabeled drug is administered to animals and human volunteers (Human Radiolabeled Studies - HRS). Metabolic profiles in laboratory animals and humans are typically determined through mass balance and excretion studies, which evaluate total radioactivity and provide quantitative information about the metabolites.

• In vitro metabolic profiling in human and preclinical species using non-radiolabelled and radiolabelled material
• Ex vivo metabolic profiling in non-radiolabeled and radiolabeled matrices from preclinical species
• Safety Testing of Metabolites (MIST)
• Human Radiolabeled Study (HRS)

The most common types of metabolic drug–drug interactions are the inhibition and induction of the drug metabolizing enzymes. These interactions can cause increased or decreased drug exposures when two or more drugs are co-administered. For example, cytochrome P450 (CYP) inhibition may increase the plasma levels of co-administered drugs leading to toxicity. Conversely, if a CYP enzyme is induced it may increase the metabolism of the co-administered compound; this can reduce plasma levels resulting in decreased efficacy or an increased formation of a toxic metabolite. For more background information on DDI studies, see our online ADME Guide and our DDI regulatory guidance booklet.

We offer full regulatory DDI packages according to the European Medicines Agency guideline, US FDA guidance and the Japanese Ministry of Health, Labor and Welfare guideline. These packages are used to support both IND (Investigational New Drug) and NDA (New Drug Application) submissions.

• Nuclear Receptor Activation
• Cytochrome P450 Induction
  
• Cytochrome P450 Induction: Relative Induction Score
  
• Cytochrome P450 Inhibition (IC₅₀ Determination)
  
• Cytochrome P450 Inhibition (K_i Determination)
  
• Time Dependent Inhibition (IC₅₀ Shift)
  
• Time Dependent Inhibition (k_inact/K_I)
• Non-CYP Inhibition

Radiolabeled studies also known as ADME studies are required by regulatory authorities for the registration of a new drug and, therefore, are an integral part of the majority of drug development programs. Excretion studies are usually conducted in at least two preclinical species which are used for long-term safety assessment of the drug and in most cases in humans as well. These studies not only determine the rates and routes of excretion, but also provide very critical information on the metabolic pathways of drugs in preclinical species and humans.
Quantitative whole-body autoradiography (QWBA) studies in preclinical species must be performed to ensure drug safety and to calculate the maximum radioactive dose that can be administered to humans. QWBA studies also provide information on the distribution, accumulation, and retention of drug material.

• Radiolabelled Pharmacokinetics
• Excretion Balance in Rodents
• Excretion Balance in Non-rodents
• Whole Body Autoradiography (QWBA)