Metabolism and kinetics (Part 4)

1. Introduction

Metabolism studies are used to assess the fate of the chemical in target animals and to assess the character of chemical residues in food-producing animals. The composition of a residue (parent and metabolites) and the target organs or food commodities in which it is present (ie muscle, fat, liver, kidney, milk, eggs and honey) should be known, so that residue-depletion trials and analytical methods deal with the relevant residue components. These studies are also used to facilitate the development of analytical methods for determining residue levels.

Metabolism and kinetics studies in both target animals and laboratory animals help assess:

2. Types of data

Metabolism and toxicokinetic or pharmacokinetic studies are submitted to facilitate the human-food-safety evaluation of veterinary drug residues that help to ensure that food derived from animals that have been treated with a veterinary product is safe for human consumption.

  • Metabolism studies are used to assess the fate of the chemical once it has been administered to an animal and, for food producing animals, to identify the nature of the residue and its target tissues.
  • Toxicokinetic or pharmacokinetic studies allow quantitation and determination of the time course of absorption, distribution, biotransformation and excretion of the parent compound and its metabolites.

Studies should be performed in both target animals and laboratory animals, and are generally conducted using radiolabelled substances. The recommended considerations when performing metabolism and pharmacokinetic studies are described in the guideline: Veterinary drug residues—comparative metabolism studies, selection of marker residue(s), and ratios of marker residues to total residues.

Metabolism and toxicokinetic studies in laboratory animals should characterise the metabolites to which laboratory animals are auto-exposed during the toxicological testing of the veterinary drug. This helps to determine whether the metabolites that people will consume from tissues of target food-producing animals are also present in the laboratory animals used for the safety testing.

If the laboratory animals produce similar metabolites to those produced by the food-producing animal, the laboratory animals will have been auto-exposed to the same metabolites that humans will consume from tissues of treated food-producing animals. Auto-exposure of metabolites is taken as evidence that the safety of metabolites has been adequately assessed in the toxicology studies.

Metabolism and pharmacokinetic studies in the target animal(s) should permit an assessment of the quantity and nature of residues in food derived from animals treated with a veterinary drug, and should provide data on:

  • the depletion of residues of concern from edible tissues of treated animals at varying times after drug administration
  • the individual components, or residues, that comprise the residues of concern in edible tissues
  • the residue(s) that can serve as a marker for analytical methods intended for compliance purposes (that is the monitoring of appropriate drug use)
  • the ratio of marker residue to total radioactive residues
  • the identification of a target tissue or tissues.

Kinetics data that are obtained during toxicity studies should be submitted in the toxicology section of the application.

3. Metabolism data submission and application layout

Table 1 shows a checklist of data to be submitted for Part 4 (Metabolism and kinetics) of an application to register veterinary chemical products, and the way in which you should set them out.

Table 1: Data submission for Part 4 (Metabolism and kinetics)
Submission Comments
Table of contents List the sections included in the trade submission and their page numbers

Laboratory animals

  • Metabolic and toxicokinetic studies in laboratory animals (to characterise the metabolites)
  • Summary of studies
  • Characterisation and structural identification of major metabolites
  • Distribution and storage in the tissues including bioaccumulation, if applicable
  • Biotransformation and a description of any metabolites produced
  • The mode and extent of excretion or elimination of the parent compound, and/or its degradation products
  • You should provide a single summary of all the metabolism and pharmacokinetic studies in laboratory animals, reviewing the absorption, distribution, metabolism and excretion of the drug
  • The metabolic pathway should be proposed
  • Full copies of each of the studies should be provided in the appendixes

Target animals

  • Metabolism and pharmacokinetic studies in target animals (for the determination of marker residue, marker residue to total residue, proposed target tissue and the appropriate analytical method)
  • Summary of studies
  • Characterisation and structural identification of major metabolites
  • Proposed marker residue
  • Proposed marker to total residues ratio
  • Proposed target tissue
  • The total residue concentration for each tissue for each collection time point
  • The marker residue for each collection time point for comparison to the total residue concentrations
  • The amounts of total residue radioactivity extracted (percentage extractable) using various treatments (enzyme, acid)
  • A complete description of the procedures used for chromatographic and chemical characterization of the drug residues components
  • You should provide a single summary of all the metabolism and pharmacokinetic studies in target animals, along with a review of the absorption, distribution, metabolism and excretion of the drug
  • The metabolic pathway should be proposed
  • A clear outline of the reasons for the proposed marker residue, the marker residue to total residue ratio, and the target tissue should be submitted
  • The components of the total residues should be examined to support the proposed marker residue
  • If original detailed studies are performed using laboratory animals, similar metabolic pathways should be shown to occur in target animals exposed to the product
  • Similarities and differences in the degradation of the chemical should be discussed in light of the residues that may be present in food commodities for human consumption
  • Full copies of each of the studies should be provided in the appendixes
Metabolism database You should include a metabolism database similar in format to the toxicological database described in the toxicology section

Appendixes

Copies of the full reports for metabolic and toxicokinetic studies in laboratory animals, and metabolism and pharmacokinetic studies in target animals along with complete details of the analytical method(s) and validation reports

 

 

To protect your privacy, please do not include contact information in your feedback. If you would like a response, please contact us.