In addition to the idiopathic (primary or genetic) dystonias, the mechanisms of some secondary forms, such as tardive, metabolic, and posttraumatic dystonias, are being studied.

Studies of the distribution, uptake and transformation of mercury in the environment, plant life, animals and man in the area of Idrija and the site of an abandoned mine at Podljubelj are described by Kosta et al. (1974).

Metabolism studies in mammals.

These studies measured the markers of bone metabolism.

No interaction studies and no in vitro metabolism studies have been performed.

In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other substances.

According to results of in vitro studies the metabolic pathway of atorvastatin via glucuronidation is inhibited by Gemfibrozil.

Specific interaction or metabolism studies have not been performed, however, clinical studies have not indicated an interaction of Neupopeg with any other medicinal products. od

In clinical studies, caspofungin did not induce or inhibit the CYP3A4 metabolism of other medicinal products.

Based on evidence from in vitro and animal studies the major cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism.

In humans, studies demonstrated that valdecoxib metabolism is predominantly mediated via CYP3A4 and 2C9 isozymes.

Studies in many different species show that praziquantel is rapidly metabolised in the liver.

The metabolism studies have also to take into account the different properties of the active substance and the intended method of application.

Mutagenicity Indinavir did not have any mutagenic or genotoxic activity in studies with or without metabolic activation.

If residues of the biocidal product remain on feedingstuffs for a significant period of time, then feeding and metabolism studies in livestock shall be required to permit evaluation of residues in food of animal origin

In-vitro studies in human liver microsomes indicate that ertapenem does not inhibit metabolism mediated by any of the six major CYP isoforms:

In vitro and in vivo studies indicate that venlafaxine is biotransformed to its major active metabolite, ODV, by CYP2D6.

The major metabolite (para-hydroxy-sulphate) with high affinity to the soluble human PPARγ, exhibited relatively high potency in a glucose tolerance assay in obese mouse.

The in vitro studies suggest that CYP3A4 and CYP2B6 are the major isoenzymes responsible for efavirenz metabolism and that it inhibits P450 isoenzymes 2C9, 2C19, and 3A4.

If studies are available for crops from three of these categories and the results indicate that the route of degradation is similar in all three categories then it is unlikely that any more studies will be needed unless it could be expected that a different metabolism will occur.

If residues of the active substance remain on feedingstuffs for a significant period of time then feeding and metabolism studies in livestock shall be required to permit evaluation of residues in food of animal origin

In vitro and in vivo studies indicate that venlafaxine is metabolised to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4.

Carcinogenicity studies have not been conducted with temsirolimus; however, sirolimus, the major metabolite of temsirolimus in humans, was carcinogenic in mice and rats.

In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a poor substrate for cytochrome P450- based metabolism.

Study of the metabolic fate of the additive in food producing target animals and in laboratory species used for toxicity testing, is required in order to:

Preclinical studies have shown that venlafaxine and its major metabolite, O-desmethylvenlafaxine (ODV), are inhibitors of serotonin and noradrenaline reuptake.

Test conditions Metabolism studies have to involve crops or categories of crops in which plant protection products containing the active substance in question would be used.

Biotransformation and elimination: In vivo studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites.

Specific interaction or metabolism studies have not been performed, however, clinical studies have not indicated an interaction of Neulasta with any other medicinal products.

Pharmacodynamic investigations of copper metabolism in patients with Wilson’ s disease included determinations of net copper balance and radiolabelled copper uptake.

The metabolism of Pegasys is not fully characterised; however studies in rats indicate that the kidney is a major organ for excretion of radiolabelled material.

Where it appears from the metabolism studies submitted in accordance with the provisions of point 6.2 that metabolic pathways differ significantly in the pig as compared to ruminants, a pig feeding study must be conducted unless the expected intake by pigs is not significant.

In vitro studies in human liver microsomes indicate that tigecycline does not inhibit metabolism mediated by any of the following 6 cytochrome P450 (CYP) isoforms:

In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 also can catalyse the main metabolic pathway, but their quantitative roles in vivo have not been studied.

In vitro metabolism studies with human liver microsomes indicated that CYP3A4 is the predominant CYP isoform involved in tipranavir metabolism.

During in vitro temsirolimus metabolism studies, sirolimus, seco-temsirolimus and seco-sirolimus were observed; additional metabolic pathways were hydroxylation, reduction and demethylation.

Supplementary metabolism studies only need to be performed where it is not possible to extrapolate from data obtained on the active substance in accordance to the requirements of Annex II, Section 6, points 6.1 and 6.2.

Where it becomes apparent that metabolic pathways differ significantly in the rat as compared to ruminants a pig study must be conducted unless the expected intake by pigs is not significant.

If a wide range of uses in different crop categories or in the category fruits is envisaged, studies have to be carried out on at least three crops unless it can be justified that a different metabolism is unlikely to occur.

In a study in subjects with varying degrees of renal impairment, mild to moderate renal disease had no influence on plasma concentration of rosuvastatin or the N-desmethyl metabolite.

Information about the substances on purity, chemical specification, natural occurrence in food, total amount added to foods and results of toxicological and metabolic studies are considered to be essential for the evaluation.

The relative non-toxicity of monomethoxy-polyethylene glycol (mPEG), which is liberated from ViraferonPeg by metabolism in vivo has been demonstrated in preclinical acute and subchronic toxicity studies in rodents and monkeys, standard embryo-foetal development studies and in in vitro mutagenicity assays.

If the data provided on chemical identity of a substance and the amount added to foods or the toxicological and metabolic studies on a substance or on closely related substances appear to be insufficient, further data may be requested.

No evidence of carcinogenicity was found in studies in mice and rats at the maximum tolerated dose, although the exposure to rivastigmine and its metabolites was lower than the human exposure.

Nevirapine metabolites: Studies using human liver microsomes indicated that the formation of nevirapine hydroxylated metabolites was not affected by the presence of dapsone, rifabutin, rifampicin, and trimethoprim/ sulfamethoxazole.

A single-dose study in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C) did not reveal a significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and dehydro-aripiprazole, but the study included only 3 patients with Class C liver cirrhosis, which is insufficient to draw conclusions on their metabolic capacity.

when metabolism studies indicate that significant residues (0,01 mg/kg or above the limit of determination if this would be higher than 0,01 mg/kg) may occur in any edible animal tissue taking into account the residue levels in potential feedingstuffs obtained at the 1× dose rate.

As a general rule, studies to establish the identity, conditions of use, physico-chemical properties, methods of determination and efficacy of the additive, and also its metabolic fate and residues, physiological and toxicological effects on target species must be provided.

8 In a radiotracer study in three healthy volunteers, the parent compound (rufinamide) was the main radioactive component in plasma, representing about 80 % of the total radioactivity, and the metabolite CGP 47292 constituting only about 15 %.

Cytochromes P450- CYP 1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites, both exhibited significantly less in vivo pharmacological activity than olanzapine in animal studies.