The role of adipose tissue in the distribution and storage of drugs

Bickel, Marcel H.

doi:10.1007/978-3-0348-7118-1_8

Cited by 25 publications

(45 citation statements)

References 98 publications

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“…This suggests xenobiotic metabolism in adipose tissue and its importance in determining the elimination of lipophilic compounds from the tissue (and also from the body). This hypothesis is consistent with metabolismresistant TCDD having an extremely long half-life (Bickel, 1984;Flesch-Janys et al, 1996;Michalek et al, 1996).…”

Section: Discussionsupporting

confidence: 85%

“…Even with this sophisticated drug-excreting system, however, a number of highly lipophilic environmental contaminants or pharmaceutical drugs, such as TCDD and its related compounds (i.e., dioxins), polychlorinated biphenyls, 1,1-dichloro-2,2-bis-( p-chlorophenyl)ethylene, and amiodarone, are eventually accumulated at high levels in white adipose tissue (WAT). These compounds demonstrate long half-lives in the body (tissue) on the order of months to years (Bickel, 1984;Latini et al, 1984;Muhlebach et al, 1985;Flesch-Janys et al, 1996;Michalek et al, 1996). Because some of these compounds are considered endocrine disruptors, their effects on development and reproduction as well as cellular and metabolic toxicity have been studied intensively (Birnbaum, 1995;Longnecker et al, 1997).…”

mentioning

confidence: 99%

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Induction of Detoxifying Enzymes in Rodent White Adipose Tissue by Aryl Hydrocarbon Receptor Agonists and Antioxidants

Yoshinari¹,

Okino²,

Satô³

et al. 2006

Drug Metab Dispos

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ABSTRACT:The liver is the main organ of drug metabolism, but the expression and induction by xenobiotics of drug-metabolizing enzymes is also often observed in extrahepatic tissues. Recently, we reported that lipophilic cytochrome P450 inducers, ␤-naphthoflavone (BNF), phenobarbital, and dexamethasone, induced CYP1, CYP2B, and CYP3A enzymes, respectively, in rat epididymal white adipose tissue (WAT) at both mRNA and protein levels. To further confirm the xenobiotic-induced expression of drug-metabolizing enzymes in adipose tissue, we studied the induction of CYP1A1 and other detoxifying enzymes by aryl hydrocarbon receptor (AhR) agonists and antioxidants. BNF increased CYP1A1 mRNA levels in several visceral WATs (epididymal, perirenal, and mesenteric) to a greater degree than in subcutaneous WAT in rats. Using C57BL/6 and DBA/2 mice with different responsiveness to aryl hydrocarbons and detecting cytoplasmic levels of AhR proteins, we have demonstrated that AhR mediates this CYP1A1 induction by BNF in WAT. Moreover, the NF-E2-related factor 2 (Nrf2)/antioxidant responsive element pathway is also functional in WAT, since BNF, which is known to activate both AhR and Nrf2, and antioxidants including tert-butylhydroquinone, 1-chloro-2,4-dinitrobenzene, and menadione induced the expression of Nrf2-target genes (NAD-(P)H:quinone oxidoreductase, glutathione S-transferase A subunits, and heme oxygenase-1) in rats and mice. These results suggest that both AhR and Nrf2 pathways are active in WAT and that lipophilic compounds accumulated in WAT can activate these transcription factors to increase detoxification capability in the tissue.

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Section: Discussionsupporting

confidence: 85%

mentioning

confidence: 99%

Induction of Detoxifying Enzymes in Rodent White Adipose Tissue by Aryl Hydrocarbon Receptor Agonists and Antioxidants

Yoshinari¹,

Okino²,

Satô³

et al. 2006

Drug Metab Dispos

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“…This view is supported by work of Bickel et al, who have found that in vitro drug accumulation in adipose tissue slices does indeed show a good correlation with log P. 15,16 It was surprising therefore that drug tissue distribution studies in vivo show no correlation between adipose tissue build-up and lipophilicity. 17,18 In vivo it appears the key factor determining the occurrence and extent of adipose tissue storage is the binding competition between adipose tissue, lean tissues, and blood plasma proteins. It was suggested that whereas adipose tissue binding is related mainly to log P, blood and lean tissue binding is determined by log P and the drugs molecular structure.…”

Section: Resultsmentioning

confidence: 99%

“…It was suggested that whereas adipose tissue binding is related mainly to log P, blood and lean tissue binding is determined by log P and the drugs molecular structure. 18 Bickel introduced the concept of Adipose Tissue Storage Index, ASI, to quantify tissue distribution of drugs. The ASI was defined as where C ad max is the maximum concentration in adipose tissue after a single dose and D ad max is the hypothetical (average) concentration of evenly distributed drug at t ) t ad max .…”

Section: Resultsmentioning

confidence: 99%

Drug-Phospholipid Interactions. 2. Predicting the Sites of Drug Distribution Using n-Octanol/Water and Membrane/Water Distribution Coefficients

Barton

Davis

McCarthy

et al. 1997

Journal of Pharmaceutical Sciences

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The in vivo tissue distribution of seventeen drugs has been modeled by using estimated n-octanol/water and membrane/water distribution coefficients. In this study, the membrane affinities are estimated using the new technique of immobilized artificial membrane (IAM) column chromatography. delta (log D(n-octanol/water-membrane/water)), which measures a hypothetical equilibrium of the drug between of n-octanol and membrane phase, is a better model of in vivo tissue distribution, as measured by Adipose Tissue Storage Index (ASI), than either n-octanol/ water or membrane/water distribution coefficients alone. This demonstrates the importance of membrane distribution coefficients as a complementary descriptor of lipophilicity to n-octanol/water distribution coefficients, in modeling in vivo distribution of drugs. This rapid method for predicting in vivo distribution of drugs, based on n-octanol and membrane/water distribution coefficients, may be a useful tool to aid the selection of drugs with beneficial pharmacokinetic profiles.

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“…However, Bickel (1984) summarized a tremendous amount of data related to the distribution and storage of drugs and found that basic drugs such as chlorpromazine and imipramine do not accumulate in adipose tissue despite their high lipophilicity. Moreover, it was reported that there were large differences in the pharmacokinetics of lipophilic model compounds.…”

Section: Discussionmentioning

confidence: 99%

Expression and Induction of Cytochromes P450 in Rat White Adipose Tissue

Yoshinari¹,

Satô²,

Okino³

et al. 2004

J Pharmacol Exp Ther

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Lipophilic environmental pollutants are often stored in adipose tissues after exposure. These compounds have been well studied in terms of their cell toxicity in organs such as liver and kidney, and their xenoestrogenic action on reproductive tissues as endocrine disruptors. However, the effects of these chemicals on the depot, adipose tissue, have not been studied, although adipose tissue is an important endocrine tissue secreting obesity/diabetes-related hormones and cytokines. In this study, we identified the expression of cytochromes P450 in rat white adipose tissues and investigated the effects of typical lipophilic cytochrome P450 inducers, namely phenobarbital, dexamethasone, and ␤-naphthoflavone. The results showed that ␤-naphthoflavone was a strong CYP1A inducer in adipose tissue as well as in liver. It increased CYP1A1 mRNA, protein, and its related activity, ethoxyresorufin O-deethylase. Phenobarbital and dexamethasone also induced both the mRNA and protein of CYP2Bs and CYP3As, respectively, in adipose tissue, although significant interindividual differences were observed. Furthermore, we demonstrated that 48 h of fasting was as effective in adipose tissue as in the liver in the induction of CYP2E1 mRNA and protein. These results suggest that the mechanisms by which cytochrome P450 genes are regulated in the liver are also functional in rat adipose tissues. This has raised the possibility that lipophilic environmental contaminants accumulated in adipose tissue may dysregulate the gene expression profile.

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The role of adipose tissue in the distribution and storage of drugs

Cited by 25 publications

References 98 publications

Induction of Detoxifying Enzymes in Rodent White Adipose Tissue by Aryl Hydrocarbon Receptor Agonists and Antioxidants

Induction of Detoxifying Enzymes in Rodent White Adipose Tissue by Aryl Hydrocarbon Receptor Agonists and Antioxidants

Drug-Phospholipid Interactions. 2. Predicting the Sites of Drug Distribution Using n-Octanol/Water and Membrane/Water Distribution Coefficients

Expression and Induction of Cytochromes P450 in Rat White Adipose Tissue

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