The hepato-renal syndrome: Renal amino acid transport in bile duct ligated rats (DL) — influence of treatment with triiodothyronine or dexamethasone on renal amino acid handling in amino acid loaded rats

Fleck, Christian; Engelbert, Kristina

doi:10.1016/s0940-2993(98)80016-x

Cited by 4 publications

(2 citation statements)

References 37 publications

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“…Clinical chemistry data 80 , 81 often come from earlier time-points and can provide information on the time course of a target organ lesion. Pathology findings to be correlated include organ weights 82 , lesions of other organs with potentially systemic consequences such as in case of the hepato-renal syndrome 83 , organs of the endocrine system (see second part of review), or early lesions including preneoplastic lesions 28 , 84 – 86 . It is clear that also findings from other studies, such as results from pharmacological or mechanistic studies, need to be taken into account.…”

Section: Hazard Identificationmentioning

confidence: 99%

“…In subchronic studies the end stage of target organ toxicity may be replacement of specific cells by non-specific scar tissue, which may also impinge upon other organs, such as e.g. in the hepato-renal syndrome 83 . Tumors are often preceded by signs of increased cell proliferation (see below) or by preneoplastic lesions, particularly in livers 84 – 86 , 166 .…”

Section: Hazard Characterizationmentioning

confidence: 99%

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Successful Drug Development Despite Adverse Preclinical Findings Part 1: Processes to Address Issues and Most Important Findings

Ettlin¹,

Kuroda

Plassmann³

et al. 2010

J Toxicol Pathol

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Unexpected adverse preclinical findings (APFs) are not infrequently encountered during drug development. Such APFs can be functional disturbances such as QT prolongation, morphological toxicity or carcinogenicity. The latter is of particular concern in conjunction with equivocal genotoxicity results. The toxicologic pathologist plays an important role in recognizing these effects, in helping to characterize them, to evaluate their risk for man, and in proposing measures to mitigate the risk particularly in early clinical trials. A careful scientific evaluation is crucial while termination of the development of a potentially useful drug must be avoided. This first part of the review discusses processes to address unexpected APFs and provides an overview over typical APFs in particular classes of drugs. If the mode of action (MoA) by which a drug candidate produces an APF is known, this supports evaluation of its relevance for humans. Tailor-made mechanistic studies, when needed, must be planned carefully to test one or several hypotheses regarding the potential MoA and to provide further data for risk evaluation. Safety considerations are based on exposure at no-observed-adverse-effect levels (NOAEL) of the most sensitive and relevant animal species and guide dose escalation in clinical trials. The availability of early markers of toxicity for monitoring of humans adds further safety to clinical studies. Risk evaluation is concluded by a weight of evidence analysis (WoE) with an array of parameters including drug use, medical need and alternatives on the market. In the second part of this review relevant examples of APFs will be discussed in more detail.

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Section: Hazard Identificationmentioning

confidence: 99%

Section: Hazard Characterizationmentioning

confidence: 99%

Successful Drug Development Despite Adverse Preclinical Findings Part 1: Processes to Address Issues and Most Important Findings

Ettlin¹,

Kuroda

Plassmann³

et al. 2010

J Toxicol Pathol

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Hepatorenal Effects of Ibuprofen Compared with other NSAIDs and Paracetamol

Rainsford

2015

Ibuprofen

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Regulation of renal amino acid (AA) transport by hormones, drugs and xenobiotics - a review

2003

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Major advances have recently been made in our understanding of the mechanisms and functions of amino acid transport in mammalian cells: - from the whole organism to transporter molecular structure. In this article, we present a brief overview of current knowledge concerning amino acid transporters, followed by a detailed discussion of the relevance of this new information to our broader understanding of the physiological regulation of amino acid handling in the kidney. We focus especially on the influence of hormones and xenobiotics on renal amino acid transport systems. In a growing number of cases, it now seems possible to correlate the effects of hormones, drugs, and xenobiotics with the capacity of renal amino acid transporters. This topic is of clinical relevance for the treatment of many amino acid reabsorption disorders. For example, under suitable conditions glucocorticoids and thyroid hormones stimulate renal reabsorption of amino acids and might therefore be of benefit in the treatment of different kinds of aminoaciduria. Hormonal regulation also underlies the postnatal development of renal amino acid reabsorption capacity, which can be stimulated to mature earlier after exogenous administration of e.g. glucocorticoids. In contrast, many compounds (e.g. heavy metal complexes) selectively damage renal amino acid transporters resulting in urinary amino acid loss. These types of phenomena (stimulation or inhibition of amino acid transporters in the kidney) are reviewed from the perspectives of our new molecular understanding of transport processes and of clinical relevance.

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The hepato-renal syndrome: Renal amino acid transport in bile duct ligated rats (DL) — influence of treatment with triiodothyronine or dexamethasone on renal amino acid handling in amino acid loaded rats

Cited by 4 publications

References 37 publications

Successful Drug Development Despite Adverse Preclinical Findings Part 1: Processes to Address Issues and Most Important Findings

Successful Drug Development Despite Adverse Preclinical Findings Part 1: Processes to Address Issues and Most Important Findings

Hepatorenal Effects of Ibuprofen Compared with other NSAIDs and Paracetamol

Regulation of renal amino acid (AA) transport by hormones, drugs and xenobiotics - a review

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