Safety evaluation, metabolism

In summary, in studies of chemical toxicity, pathways and rates of metabolism as well as effects resulting from toxicokinetic factors and receptor affinities are critical in the choice of the animal species and experimental design. Therefore it is important that the animal species chosen as a model for humans in safety evaluations metabolize the test chemical by the same routes as humans and, furthermore, that quantitative differences are considered in the interpretation of animal toxicity data. Risk assessment methods involving the extrapolation of toxic or carcinogenic potential of a chemical from one species to another must consider the metabolic and toxicokinetic characteristics of both species. 

Regardless, it is important to carry out the safety evaluation for all flavoring substances. In many cases, it is possible to use pharmacokinetic or metabolic data on the substance in addition to toxicity data or other information on structurally-related compounds. 

The JECFA safety evaluation procedure for flavoring substances leads the evaluator through a decision tree with two branches, one for substances that are metabolized to innocuous end products and the second for substances that are not metabolized to innocuous end products (Fig. 9.1). The decision tree is applied using a series of questions ... 

Since the introduction of the JECFA safety evaluation procedure, over 900 flavoring substances have been evaluated by JECFA using this procedure. This procedure provides a practical and efficient scientific means to evaluate flavoring substances by integrating knowledge of toxicity, stmcture-activity relationships, structural class, metabolic fate and exposure. 

Khera KS. 1976. Distribution, metabolism and perinatal toxicity of pesticides with reference to food safety evaluation Review of selected literature. Adv Mod Toxicol (Part 1) 369-420. 

The pharmacokinetics and metabolism of ondansetron will first be considered in rat and dog, the major species used in safety evaluation of the compound Table 7.7). Comparison will then be made with the available information on the pharmacokinetics of ondansetron in man. 

Dome, J.L. (2004) Impact of inter-individual differences in dmg metabolism and pharmacokinetics on safety evaluation. Fundam. Clin. Pharmacol. 18, 609-620. 

In general, safety evaluation is primarily based on the toxicological testing of the parent drug. However, consumers of edible animal products are also exposed to many other products of drug metabolism, including free metabolites of... 

There are many different examples of species differences in the toxicity of foreign compounds, some of which are commercially useful to man, as in the case of pesticides and antibiotic drugs where there is exploitation of selective toxicity. Species differences in toxicity are often related to differences in the metabolism and disposition of a compound, and an understanding of such differences is extremely important in the safety evaluation of compounds in relation to the extrapolation of toxicity from animals to man and hence risk assessment. 

To date, no studies on the metabolism of cetuximab have been performed in humans or in animals. Indeed, metabolism studies are not generally performed for mAbs. Several pathways have been described that may contribute to antibody metabolism, all of which involve biodegradation of the antibody to smaller molecules (i. e., small peptides or amino acids). This fact has been recognized in the International Conference on Harmonization (ICH) guidance document Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals [22], where it is stated in Section 4.2.3 that "... the expected consequence of metabolism of biotechnology-derived pharmaceuticals is the degradation to small peptides and individual amino acids. .. and that therefore classical biotransformation studies as performed for traditional small molecule pharmaceuticals are not needed. 

The use of SRM methods for quantitative bioanalysis represents increased dimensions of mass spectrometry analysis. SRM methods that use APCI-LC/MS/MS for the quantitative analysis of an antipsychotic agent, clozapine, in human plasma were described by Dear and co-workers (Dear et al., 1998). Preclinical development studies of clozapine in rats and dogs used HPLC with fluorescence detection (FLD). With this method, a better limit of quantitation (LOQ) of 1 ng/mL was obtained. As the compound moved into the clinical stages of development, a more sensitive method of analysis was required to obtain rapid metabolic information in support of drug safety evaluation studies. A standard LC/MS/MS method is used for the quantitative analysis of clozapine (I) and four metabolites (II-V) in human plasma (Figure 6.34). 

EU EUDRALEX 3BSlla Pharmacokinetics and Metabolic Studies in the Safety Evaluation of new Medicinal Products in Animals. April 1994... 

D. V. Parke, Acta Pharm. Nord., 2, 231 (1989). Drug Metabolism in the Design and Safety Evaluation of New Drugs. The Scheele Memorial Lecture 1989. 

Pharmacokinetics and metabolic studies in the safety evaluation of new drugs in animals (10/1983) III... 

Much of the present day safety evaluation follows precepts (Table VI) which were promulgated by FDA for new drugs. This requires that therapeutic and toxic doses be studied for all toxic effects, site of action, mechanism of action, rates of absorption, distribution in the body, metabolism, excretion, time of onset and duration of effects. 

While in vitro experiments offer a partial solution to the safety evaluation of chemicals, they cannot completely replace animal experiments for this purpose. Many chemicals are poisonous because they affect organs or systems as well as, or rather than, individual cells. The human body, like that of any mammal, is a highly complex, integrated system and reacts to chemicals in many different ways, far more than can be predicted from one or two different types of isolated cells. Most of the cells in our bodies have some similarities (for example, they all have a nucleus), but brain cells are very different from muscle cells, otherwise we would not be able to think Different types of cells have specialized functions which can make them a target for chemicals in specific ways. In particular, their metabolic capabihties are different and they may be unable to detoxify chemicals in the same way as hver cells, for example. This is illustrated by the story on p. 296. There is no doubt that the world would be a more hazardous place if the safety of chemicals were evaluated only in vitro. 

Saccharin is not metabolized and does not react with DNA. Although it was mutagenic in vitro, this was only at high concentrations. It was concluded that saccharin was not a genotoxic carcinogen. Assuming that there was no threshold was, therefore, not appropriate. A threshold model could be applied to the dose-response data from these safety evaluation studies. 

The fully automated computational procedure is a valuable ne v tool in virtual screening and in early ADME-Tox, vhere drug safety and metabolic profile patterns must be evaluated in order to enhance and streamline the process of developing neiv drug candidates. 

USE OF METABOLISM AND PHARMACOKINETIC DATA IN DRUG SAFETY EVALUATION... 

The reasons for this are not difficult to understand. Like novel pharmacological agents, a novel excipient must go through numerous safety and metabolic evaluation processes before it can be used in humans. In essence, it would be necessary to apply for a Type 4... 

Biotransformation and generation of reactive intermediate metabolites are associated with a variety of toxicities and idiosyncratic reactions.37 Toxicologists should always consider how drug disposition and fate contribute to toxicity, as target organ dosimetry, biotransformation, and detoxification reactions can be important determinants of toxicity. In all cases, understanding how biotransformation may differ across species, with emphasis on human metabolism, is an important component in determining whether preclinical effects are predictive of and relevant for human safety evaluation. 

Drug Metabolism Studies Supporting Drug Safety Evaluations 550... 

In vitro Drug Metabolism Studies Guiding Early Drug Safety Evaluations 551... 

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