The Biochemistry of Drug Metabolism – An Introduction

Krämer, Stefanie-Dorothea; Testa, Bernard

doi:10.1002/cbdv.200890214

Cited by 49 publications

(5 citation statements)

References 271 publications

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“…Another simple natural xanthine, theobromine ( 3 ) was shown to have only weak activity as AR antagonist (Müller et al 1993a). The major caffeine metabolites in humans, paraxanthine ( 4 ) and 1-methylxanthine ( 5 ) (Krämer and Testa 2008), the latter being also the major metabolite of theophylline, are similarly potent as caffeine and theophylline and may contribute their activity (Daly et al 1986a; Müller et al 1993b). These simple alkylxanthines are of micromolar affinity, at best, at the ARs, and variation of affinity between species has been documented (see table 1).…”

Section: Caffeine and Theophylline - Historical Aspects And Early mentioning

confidence: 99%

Xanthines as Adenosine Receptor Antagonists

Müller

Jacobson

2010

Handbook of Experimental Pharmacology

115

109

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The natural plant alkaloids caffeine and theophylline were the first adenosine receptor (AR) antagonists described in the literature. They exhibit micromolar affinities and are non-selective. A large number of derivatives and analogs have subsequently been synthesized and evaluated as AR antagonists. Very potent antagonists have thus been developed with selectivity for each of the four AR subtypes.

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Section: Caffeine and Theophylline - Historical Aspects And Early mentioning

confidence: 99%

Xanthines as Adenosine Receptor Antagonists

Müller

Jacobson

2010

Handbook of Experimental Pharmacology

115

109

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“…Induction of drug metabolism may arise as a consequence of increased synthesis, decreased degradation, activation of enzymes or a combination of these three processes, although it should be emphasized that the majority of enzymes are induced at the transcriptional activation level. Thus, enzyme induction takes place only after its prolonged exposure to the xenobiotic [20]. Cytochromes P450 (CYP), a superfamily of the most important drug-metabolizing enzymes, are involved in the metabolism of about 75% of all drugs.…”

Section: Resultsmentioning

confidence: 99%

Effect of Standardized Cranberry Extract on the Activity and Expression of Selected Biotransformation Enzymes in Rat Liver and Intestine

et al. 2014

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Abstract:The use of dietary supplements containing cranberry extract is a common way to prevent urinary tract infections. As consumption of these supplements containing a mixture of concentrated anthocyanins and proanthocyanidins has increased, interest in their possible interactions with drug-metabolizing enzymes has grown. In this in vivo study, rats were treated with a standardized cranberry extract (CystiCran ® ) obtained from Vaccinium macrocarpon in two dosage schemes (14 days, 0.5 mg of proanthocyanidins/kg/day; 1 day, 1.5 mg of proanthocyanidins/kg/day). The aim of this study was to evaluate the effect of anthocyanins and proanthocyanidins contained in this extract on the activity and expression of intestinal and hepatic biotransformation enzymes: cytochrome P450 (CYP1A1, CYP1A2, CYP2B and CYP3A), carbonyl reductase 1 (CBR1), glutathione-S-transferase (GST) and UDP-glucuronosyl transferase (UGT). Administration of cranberry extract led to moderate increases in the activities of hepatic CYP3A (by 34%), CYP1A1 (by 38%), UGT (by 40%), CBR1 (by 17%) and GST (by 13%), while activities of these enzymes in the small intestine were unchanged. No changes in the relative amounts of these proteins were found. Taken together, the interactions of cranberry extract with simultaneously administered drugs seem not to be serious.

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“…Numerous drugs have been shown to be metabolized differently by mice and rats. 27 In addition, TDF is an ester prodrug of the potent antiviral tenofovir. Higher esterase activity in the intestine may lead to a decrease in oral absorption of the prodrug TDF.…”

Section: Discussionmentioning

confidence: 99%

Tenofovir Disoproxil Fumarate

Stock

Rausch

et al. 2015

Int J Toxicol

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Tenofovir disoproxil fumarate (TDF) is a prodrug of tenofovir that exhibits activity against human immunodeficiency virus (HIV) and hepatitis B. The goals of this study were to evaluate the molecular mechanism of TDF-induced toxicity in mice after 13 weeks of daily oral administration (50–1000 mg/kg) by correlating transcriptional changes with plasma drug levels and traditional toxicology endpoints. Plasma levels and systemic exposure of tenofovir increased less than dose-proportionally, and were similar on Days 1 and 91. No overt toxicity was observed following the completion of TDF administration. The kidneys of TDF-treated mice were histopathologically normal. This result is consistent with the genomic microarray results, which showed no significant differences in kidney transcriptional levels between TDF-treated animals and controls. In liver, cytomegaly was observed in mice treated with 1000 mg/kg of TDF after 4 and 13 weeks of TDF-treatment, but mice recovered from this effect following cessation of administration. Analysis of liver transcripts on Day 91 reported elevated levels of Cdkn1a in TDF-treated animals compared with controls, which may have contributed to the inhibition of liver cell cycle progression.

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The Biochemistry of Drug Metabolism – An Introduction

Cited by 49 publications

References 271 publications

Xanthines as Adenosine Receptor Antagonists

Xanthines as Adenosine Receptor Antagonists

Effect of Standardized Cranberry Extract on the Activity and Expression of Selected Biotransformation Enzymes in Rat Liver and Intestine

Tenofovir Disoproxil Fumarate

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