Drug research encompasses several diverse disciplines united by a common goal, namely the development of novel therapeutic agents. The search for new drugs can be divided functionally into two stages: discovery and development. The former consists of setting up a working hypothesis of the target

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Role of Pharmacokinetics and Metabolism in Drug Discovery and Development

Potassium bromate (KBrO3) is an oxidizing agent that has been used as a food additive, mainly in the bread-making process. Although adverse effects are not evident in animals fed bread-based diets made from flour treated with KBrO3, the agent is carcinogenic in rats and nephrotoxic in both man and experimental animals when given orally. It has been demonstrated that KBrO3 induces renal cell tumors, mesotheliomas of the peritoneum, and follicular cell tumors of the thyroid. In addition, experiments aimed at elucidating the mode of carcinogenic action have revealed that KBrO3 is a complete carcinogen, possessing both initiating and promoting activities for rat renal tumorigenesis. However, the potential seems to be weak in mice and hamsters. In contrast to its weak mutagenic activity in microbial assays, KBrO3 showed relatively strong potential inducing chromosome aberrations both in vitro and in vivo. Glutathione and cysteine degrade KBrO3 in vitro; in turn, the KBrO3 has inhibitory effects on inducing lipid peroxidation in the rat kidney. Active oxygen radicals generated from KBrO3 were implicated in its toxic and carcinogenic effects, especially because KBrO3 produced 8-hydroxydeoxyguanosine in the rat kidney. A wide range of data from applications of various analytical methods are now available for risk assessment purposes.

/pdf/toxicity-and-carcinogenicity-of-potassium-bromate-a-new-1u3zhwz8dr.pdf

Toxicity and Carcinogenicity of Potassium Bromate-A New Renal Carcinogen

Summary Because of its high density of negatively charged phosphate groups, phytic acid (PA) forms very stable complexes with mineral ions rendering them unavailable for intestinal uptake. Indeed, the first step in mineral absorption requires that the mineral remains in the ionic state. As the PA content of the diet increases, the intestinal absorption of zinc, iron and calcium decreases. The inhibitory effects of PA on magnesium or copper are more controversial. Nevertheless, PA does not occur alone in foods and is often consumed with various compounds. Phytates are always present in vegetal matrix composed of fibres, minerals, trace elements and other phytomicronutrients. Thus, in order to evaluate mineral absorption from phytate-rich products, all components of diet and food interactions should be considered and it is hard to predict mineral bioavailability in such products by using only the phytate content.

Minerals and phytic acid interactions: is it a real problem for human nutrition?

Analysis of organ weight in toxicology studies is an important endpoint for identification of potentially harmful effects of chemicals. Differences in organ weight between treatment groups are often accompanied by differences in body weight between these groups, making interpretation of organ weight differences more difficult. Using data from control rats that were part of 26 toxicity studies conducted under similar conditions, we have evaluated the relationship between organ weight and body/brain weight to determine which endpoint (organ weight, organ-to-body weight ratio, or organ-to-brain weight ratio) is likely to accurately detect target organ toxicity. This evaluation has shown that analysis of organ-to-body weight ratios is predictive for evaluating liver and thyroid gland weights, and organ-to-brain weight ratios is predictive for evaluating ovary and adrenal gland weights. Brain, heart, kidney, pituitary gland, and testes weights are not modeled well by any of the choices, and alternative analysis methods such as analysis of covariance should be utilized.

https://journals.sagepub.com/doi/pdf/10.1080/01926230490465874

Relationships Between Organ Weight and Body/Brain Weight in the Rat: What Is the Best Analytical Endpoint?:

The evaluation of organ weights in toxicology studies is an integral component in the assessment of pharmaceuticals, chemicals, and medical devices. The Society of Toxicologic Pathology (STP) has created recommendations for weighing organs in GLP general toxicology studies lasting from 7 days to 1 year. The STP recommends that liver, heart, kidneys, brain, testes, and adrenal glands be weighed in all multidose general toxicology studies. Thyroid gland and pituitary gland weights are recommended for all species except mice. Spleen and thymus should be weighed in rodent studies and may be weighed in non-rodent studies. Weighing of reproductive organs is most valuable in sexually mature animals. Variability in age, sexual maturity, and stage of cycle in non-rodents and reproductive senescence in female rodents may complicate or limit interpretation of reproductive organ weights. The STP recommends that testes of all species be weighed in multidose general toxicology studies. Epididymides and prostate should be weighed in rat studies and may be weighed on a case-by-case basis in non-rodent and mouse studies. Weighing of other organs including female reproductive organs should be considered on a case-by-case basis. Organ weights are not recommended for any carcinogenicity studies including the alternative mouse bioassays. Regardless of the study type or organs evaluated, organ weight changes must be evaluated within the context of the compound class, mechanism of action, and the entire data set for that study.

https://journals.sagepub.com/doi/pdf/10.1080/01926230701595300

Society of Toxicologic Pathology position paper: organ weight recommendations for toxicology studies.

Comparison of short-term renal effects due to oral administration of decalin or d-limonene in young adult male Fischer-344 rats

Characterization of spontaneous and decalin-induced hyaline droplets in kidneys of adult male rats

Morphogenesis of decalin-induced renal alterations in the male rat.

Decalin-induced nephrotoxicity: light and electron microscopic examination of the effects of oral dosing on the development of kidney lesions in the rat.

R.L. Kanerva

Papers

Comparison of short-term renal effects due to oral administration of decalin or d-limonene in young adult male Fischer-344 rats

Characterization of spontaneous and decalin-induced hyaline droplets in kidneys of adult male rats

Morphogenesis of decalin-induced renal alterations in the male rat.

Decalin-induced nephrotoxicity: light and electron microscopic examination of the effects of oral dosing on the development of kidney lesions in the rat.

Assessment of the subchronic oral toxicity of d-limonene in dogs.