The toxicological significance of xenobiotic metabolism

Caldwell, John; Howes, Angela; Hotchkiss, Sharon A.M.

doi:10.1080/02652039009373862

Cited by 4 publications

(3 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…At low doses, the metabolism of allylbenzenes largely follows the safe metabolic pathway via 0-diemethylation, but this pathway is saturated at higher doses, leading to a disproportionate increase in the metabolism via I'-hydroxylation to the proximate carcinogen (14). The I'-hydroxy allylbenzene is then conjugated with sulfate by sulfotransferase enzymes to form the sulfate ester (6).…”

Section: Variations In Metabolism and Toxicitymentioning

confidence: 99%

An Introduction to Drug Disposition: The Basic Principles of Absorption, Distribution, Metabolism, and Excretion

1995

Self Cite

View full text Add to dashboard Cite

A knowledge of the fate of a drug, its disposition (absorption, distribution, metabolism, and excretion, known by the acronym ADME) and pharmacokinetics (the mathematical description of the rates of these processes and of concentration-time relationships), plays a central role throughout pharmaceutical research and development. These studies aid in the discovery and selection of new chemical entities, support safety assessment, and are critical in defining conditions for safe and effective use in patients. ADME studies provide the only basis for critical judgments from situations where the behavior of the drug is understood to those where it is unknown: this is most important in bridging from animal studies to the human situation. This presentation is intended to provide an introductory overview of the life cycle of a drug in the animal body and indicates the significance of such information for a full understanding of mechanisms of action and toxicity.

show abstract

Section: Variations In Metabolism and Toxicitymentioning

confidence: 99%

An Introduction to Drug Disposition: The Basic Principles of Absorption, Distribution, Metabolism, and Excretion

1995

Self Cite

View full text Add to dashboard Cite

show abstract

“…In this study, we have concentrated on the skin since it expresses high levels of speci®c CYP isozymes and low thiol levels (i.e. the balance is in favour of bioactivation), in relation to the liver (Caldwell et al, 1990;Roos & Merk, 2000), and may therefore represent an environment susceptible to haptenation by chemically reactive drug metabolites. In accordance with this, nitroso sulphamethoxazole, but not sulphamethoxazole hydroxylamine or sulphamethoxazole, was found to bind to the surface of keratinocytes, and to a lesser extent, to PBMC and splenocytes in vivo (Figures 3 and 4).…”

Section: British Journal Of Pharmacology Vol 133 (2)mentioning

confidence: 99%

Antigenicity and immunogenicity of sulphamethoxazole: demonstration of metabolism‐dependent haptenation and T‐cell proliferation in vivo

Naisbitt

Gordon

Pirmohamed

et al. 2001

British J Pharmacology

124

116

View full text Add to dashboard Cite

1 Sulphamethoxazole has been associated with the occurrence of hypersensitivity reactions. There is controversy as to whether the immune response is metabolism-dependent or -independent. We have therefore investigated the site of antigen formation and the nature of the drug signal presented to the immune system in vivo. 2 Male Wistar rats were dosed with sulphamethoxazole, sulphamethoxazole hydroxylamine or nitroso sulphamethoxazole. Antigen formation on cell surfaces was determined by¯ow cytometry using a speci®c anti-sulphamethoxazole antibody. Immunogenicity was determined by assessment of ex vivo T-cell proliferation. 3 Administration of nitroso sulphamethoxazole, but not sulphamethoxazole or sulphamethoxazole hydroxylamine, resulted in antigen formation on the surface of lymphocytes, splenocytes and epidermal keratinocytes, and a strong proliferative response of splenocytes on re-stimulation with nitroso sulphamethoxazole. Rats dosed with sulphamethoxazole or sulphamethoxazole hydroxylamine did not respond to any of the test compounds. 4 CD4 + or CD8 + depleted cells responded equally to nitroso sulphamethoxazole. The proliferative response to nitroso sulphamethoxazole was seen even after pulsing for only 5 min, and was not inhibited by glutathione. Responding cells produced IFN-g, but not IL-4. 5 Haptenation of cells by sulphamethoxazole hydroxylamine was seen after depletion of glutathione by pre-treating the rats with diethyl maleate. Splenocytes from the glutathione-depleted sulphamethoxazole hydroxylamine-treated rats responded weakly to nitroso sulphamethoxazole, but not to sulphamethoxazole or sulphamethoxazole hydroxylamine. 6 Dosing of rats with sulphamethoxazole produced a cellular response to nitroso sulphamethoxazole (but not to sulphamethoxazole or its hydroxylamine) when the animals were primed with complete Freund's adjuvant. 7 These studies demonstrate the antigenicity of nitroso sulphamethoxazole in vivo and provide evidence for the role of drug metabolism and cell surface haptenation in the induction of a cellular immune response in the rat.

show abstract

“…drugs, food additives, environmental contaminants or pesticides, each of which often requires the development of specific analytical strategies. Following their absorption, the biotransformation of xenobiotics is achieved via two principal classes of enzymatic systems (mainly localised in the liver for mammals), leading to the so-called phase I and phase II metabolites [1,2]. Phase I metabolites result from reactions of oxydation, …”

Section: Introductionmentioning

confidence: 99%

Use of LC-MS/MS for xenobiotic metabolism studies in animals

Debrauwer¹

2000

Analusis

View full text Add to dashboard Cite

The toxicological significance of xenobiotic metabolism

Cited by 4 publications

References 15 publications

An Introduction to Drug Disposition: The Basic Principles of Absorption, Distribution, Metabolism, and Excretion

An Introduction to Drug Disposition: The Basic Principles of Absorption, Distribution, Metabolism, and Excretion

Antigenicity and immunogenicity of sulphamethoxazole: demonstration of metabolism‐dependent haptenation and T‐cell proliferation in vivo

Use of LC-MS/MS for xenobiotic metabolism studies in animals

Contact Info

Product

Resources

About