Part 4 - Metabolism and Kinetics
1. INTRODUCTION
Metabolism studies are used to assess the fate of the chemical in target animals and to assess the nature and disposition 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 (e.g. meat, offal, milk, eggs etc) must be known so that supervised residue trials and analytical methods deal with the relevant residue.
These studies are also used to facilitate the development of analytical methods for determining residue levels.
1.1. Reference materials
The details of documents referred to in these instructions (including codes and standards) are given in the References section. Bibliographic details and, where appropriate, ISBN and purchase information are provided. Applicants should be aware that many of these documents are updated regularly (hence dates are not supplied in the text). It is therefore important to ensure that the latest editions of reference materials are obtained.
2. GENERAL INSTRUCTIONS
Metabolism and kinetics studies are required in order to help assess:
- user safety (as in Part 3, Toxicology and Part 6, Occupational Health and Safety) and;
- consumer safety (as in Part 5A, Residues).
Studies are required in both target animals and laboratory animals.
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 organ.
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.
Kinetics data that are obtained during toxicity studies should be submitted in Part 3 (Toxicology) of the application.
These studies are often conducted using radiolabelled substances and should be carried out according to internationally recognised protocols. Advice should be sought from the APVMA as to the suitability of nonstandard protocols for registration purposes.
These instructions describe the aims and scope of the studies required. They do not describe details of individual study protocols.
3. OUTLINE OF DATA REQUIREMENTS AND APPLICATION LAYOUT
A checklist of data requirements for Part 4 (Metabolism and Kinetics) of an application for veterinary chemical products, and the way in which they should be set out, appears in Table 1. Note the format used supersedes that described in the Appendix D of Vet Manual: The Requirements Manual for Veterinary Chemicals.Table 1: Data requirements for Part 4 (Metabolism and Kinetics)
METABOLISM AND KINETICS
Table of contents
Metabolic and toxicokinetic studies in laboratory animals
Metabolism and pharmacokinetic studies in target animals
Metabolism database
4. METABOLISM AND TOXICOKINETIC STUDIES IN LABORATORY ANIMALS
Studies are required on the fate of the substance in laboratory animals. These studies may assist in the interpretation of hazards identified in the toxicity studies and may provide information on the relevance to humans of the observed toxicological findings.
The following information would normally be expected:
- The degree of absorption after oral administration in at least one mammalian species. An investigation of the extent of absorption after dermal application is desirable.
- Distribution and storage in the tissue of animals, including bioaccumulation, if applicable.
- Biotransformation in animals, together with a description of any metabolites produced.
- The mode and extent of excretion or elimination of the parent compound, and/or its degradation products, in animals.
5. METABOLISM AND PHARMACOKINETIC STUDIES IN TARGET ANIMALS
Metabolism and kinetic studies should be performed on species representative of those to which the veterinary product will be administered using the proposed routes of administration and proposed dosages.
If original detailed studies are performed using laboratory animals, it will be necessary to show that similar metabolic pathways are followed 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.
The aims of target (food and non-food producing) animal metabolism are:
- to identify the rates of absorption, distribution, biotransformation and excretion of the parent compound and its metabolites (if active); and
- to quantify the metabolites.
The aims of food producing animal metabolism studies are:
- to provide an estimate of the total terminal residues in the edible commodity of animals;
- to identify the major components of the total terminal residues;
- to indicate the distribution and nature of residues in muscle, fat, milk, eggs, liver and kidney; to identify target tissues; and to determine if the residues are fatsoluble;
- to show efficiency of extraction procedures for various components of the residues;
- to identify bound residues;
- to assist in determining residue definitions for enforcement and risk assessment; and
- to identify the mode and extent of excretion or elimination of the parent compound, and/or its degradation products to detect any potential for bioaccumulation.
6. METABOLISM DATABASE
A metabolism database should also be included, similar in format to the toxicological database described in Part 3 (Toxicology), Section 38.
Glossary
Bioaccumulation
The accumulation of a xenobiotic chemical in a tissue or organ to levels higher than in surrounding tissues or in the environment.
Biotransformation
Term usually used to denote the activity of xenobiotic metabolising enzymes.
Laboratory/experimental animals
Animals (usually rats, mice, rabbits, dogs) bred specifically for animal testing of xenobiotic agents.
Metabolism
Fate of the chemical once it has been administered/ingested (absorption, distribution, biotransformation and excretion).
Pharmacokinetics
The study of the movement of drugs within the body (i.e. the absorption, distribution via the blood, metabolism and excretion). The term is usually applied to medicines or therapeutic agents tested at doses related to their therapeutic action but can be applied to any xenobiotic chemicals. See also Toxicokinetics.
Product
A formulation containing one or more active constituent(s), and possibly non‑active constituents (s), which is intended for application and administration, with or without dilution before use, and which is labelled with directions for use.
Registration
The process whereby the APVMA approves the sale and use of a formulated product, after the evaluation and assessment of appropriate scientific data demonstrating that the product is effective and not unduly hazardous to human health, the environment, or target plants and animals, and that it will not adversely affect trade.
Residue
The remains of the active constituent(s) in a chemical product persisting in or on food, agricultural commodities or plants, soil, water or other environmental components, together with all derivatives, metabolites, and degradation products of the active constituent(s) arising from their use.
Target animals
Animals that will be exposed to an agricultural or veterinary product, either by direct administration (as for veterinary products) or in contaminated feedstuff.
Target organ
The organ (s) in an animal/plant in which, owing to the chemical and kinetic properties of a xenobiotic agent, the pharmacological or toxic effects are seen.
Toxicokinetics
The study of the movement of xenobiotic chemical agents within the body (i.e. the absorption, distribution via the blood, metabolism and excretion), to provide key information for the assessment of possible toxicity at elevated doses. The term is sometimes used interchangeably with `pharmacokinetics' (see above) but the latter term applies more specifically to medicines or therapeutic agents.
Veterinary chemical product
A substance or mixture of substances that fits the legal definition in the Agricultural and Veterinary Chemicals Code Act 1994 (see Vet Manual, Module A).
Xenobiotic chemicals
Compounds `foreign' to an organism, including both manufactured and natural chemicals (e.g. plant toxins, environmental contaminants, agricultural and veterinary chemicals, drugs).
REVISION HISTORY
| Revision Date | Description of Revision |
|---|---|
| 1 July 2005 | First edition
|
| 1 October 2005 | Second edition
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| 1 April 2006 | Third edition
|
| 1 July 2007 | Fourth edition
|