An integrated metabonomic approach to describe temporal metabolic disregulation induced in the rat by the model hepatotoxin allyl formate.

The time-related metabolic events in rat liver, plasma, and urine following hepatotoxic insult with allyl formate (75 mg/kg) were studied using a combination of high-resolution liquid state and magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopic methods together with pattern recognition analysis. The metabonomics results were compared with the results of conventional plasma chemistry and histopathological assessments of liver damage. Various degrees of liver damage were observed in different animals, and this variation was reflected in all of the analyses.

Hepatotoxin-induced hypertyrosinemia and its toxicological significance.

A (1)H Nuclear Magnetic Resonance (NMR) spectroscopic investigation of the effects of single doses of four model hepatotoxins on male Sprague-Dawley rats showed that hypertyrosinemia was induced by three of the treatments (ethionine 300 mg/kg, galactosamine hydrochloride 800 mg/kg and isoniazid 400 mg/kg) but not by the fourth (thioacetamide 200 mg/kg). Concomitant histopathological and clinical chemistry analyses showed that hypertyrosinemia could occur with or without substantial hepatic damage and that substantial hepatic damage could occur without hypertyrosinemia. However, in the rats dosed with galactosamine hydrochloride, which showed highly variable amounts of liver damage at ca.

Pharmaco-metabonomic phenotyping and personalized drug treatment.

There is a clear case for drug treatments to be selected according to the characteristics of an individual patient, in order to improve efficacy and reduce the number and severity of adverse drug reactions. However, such personalization of drug treatments requires the ability to predict how different individuals will respond to a particular drug/dose combination. After initial optimism, there is increasing recognition of the limitations of the pharmacogenomic approach, which does not take account of important environmental influences on drug absorption, distribution, metabolism and excretion.

Sertoli cell junctional proteins as early targets for different classes of reproductive toxicants.

In the testis, Sertoli cells establish intercellular junctions that are essential for spermatogenesis. The SerW3 Sertoli cell line displays some features of native Sertoli cells. Western blot and immunofluorescence analyses showed that SerW3 Sertoli cells expressed typical components of tight (occludin and zonula occludens-1), anchoring (N-cadherin) and gap (connexin 43) junctions.

Preclinical safety profile of sildenafil.

Sildenafil citrate, marketed as Viagra, for the treatment of erectile dysfunction, has a proven record of safety in humans as predicted by the results of extensive pharmacological and toxicological testing in animals and in vitro, and confirmed by pharmacokinetic exposure data. The aim of this paper is to review succinctly the main findings resulting from these experiments. Daily doses of sildenafil, within and far beyond the human therapeutic range, were given to dogs and rodents for up to 1 and 2 y, respectively.

Hepatotoxin-induced hypercreatinaemia and hypercreatinuria: their relationship to one another, to liver damage and to weakened nutritional status.

Hypercreatinuria is a well-known feature of liver and testicular toxicity and we have recently proposed that hepatotoxin-induced hypercreatinuria would arise as a consequence of increased cysteine synthesis associated with the provision of protective substances (glutathione and/or taurine). Here a direct relationship between hepatotoxin-induced hypercreatinaemia and hypercreatinuria is shown and the possible relationships of hepatotoxin-induced hypercreatinaemia and hypercreatinuria to hepatic damage and to weakened nutritional status are examined. Male Sprague-Dawley rats were dosed with a variety of model hepatotoxins at two dose levels per toxin.

An hypothesis for a mechanism underlying hepatotoxin-induced hypercreatinuria.

As part of a wider metabonomic investigation into the early detection and discrimination of site-specific hepatotoxicity, male Sprague-Dawley rats were dosed with the model hepatotoxins allyl formate, ethionine and alpha-naphthylisothiocyanate (ANIT). Urine samples collected pre- and post-dose were examined by (1)H nuclear magnetic resonance (NMR) spectroscopy and the toxin-induced changes in urinary taurine and creatine excretion were quantified. Hypertaurinuria and hypercreatinuria were observed following allyl formate dosing, hypertaurinuria with no change in creatine excretion was observed after ethionine dosing, and hypotaurinuria and hypercreatinuria were observed after ANIT dosing.

In vitro toxicity of zamifenacin (UK-76,654) and metabolites in primary hepatocyte cultures.

1. We compared the sensitivities of primary hepatocytes from rat, dog and monkey to zamifenacin and two major metabolites, the methylenedioxy ring-opened catechol, UK-80,178 and its methylated product, UK-82,201. Toxicity was determined both via neutral red uptake and enzyme leakage data.

Establishment of a rat Sertoli cell line that displays the morphological and some of the functional characteristics of the native cell.

Primary rat Sertoli cells are widely used as a model for mechanistic and toxicological studies, since they are often the target of toxicants in vivo. However, their isolation from testicular homogenates is tedious and requires the regular use of numerous immature animals. It is therefore of great interest to have available established cell lines that are usable in vitro for unlimited periods and closely similar to native cells.

Diurnal exposure profile in rats from dietary administration of a chemical (doxazosin) with a short half-life: interplay of age and diurnal feeding pattern.

Doxazosin, an alpha-adrenergic blocking agent, has a plasma half-life in male rats of 1-2 h after i.v. administration.

Design of toxicokinetic studies.

1. Toxicokinetics is defined as pharmacokinetic studies in animals during actual toxicity studies or under conditions mimicking them (species, duration, dose level, etc.).

A comparative study of the effects of ketoconazole and fluconazole on 17-beta estradiol production by rat ovaries in vitro.

In this study we have compared the effects of ketoconazole and fluconazole, a novel triazole antifungal agent, on 17-beta estradiol production in rat ovaries in vitro. For both compounds there was a lag phase, immediately after addition to the test system, during which the rate of oestradiol synthesis remained at control values. This may have been due to the time required for uptake of the compound and transfer to its site of action or for depletion of endogenous pools of intermediates.

The effect of luteinizing hormone on parturition in rats; imidazole antifungals may affect parturition via luteinizing hormone.

Studies were carried out to investigate the mechanism whereby the imidazole anti-fungal, tioconazole, affects parturition in rats. Administration s.c.

Dazoxiben, a prototype inhibitor of thromboxane synthesis, has little toxicity in laboratory animals.

Dazoxiben, an orally active specific inhibitor of thromboxane synthetase, was administered by mouth daily to dogs and rats for 6 months. Dogs showed no evidence of toxicity up to 300 mg day-1 kg-1, the highest dose level used. Rats showed no evidence of toxicity after 100 mg day-1 kg-1, but at 300 mg day-1 kg-1 there were slight increases in plasma calcium and urea concentrations and a moderate incidence of focal nephrosis; males showed a slightly increased platelet count.

A second peak in uptake of gentamicin by rat kidney after cessation of treatment.

Gentamicin was administered s.c. to rats once daily for 7 days at 5 mg kg-1.