Association Between Nonalcoholic Hepatic Steatosis and Hepatic Cytochrome P-450 3A Activity

Kolwankar, Dhanashri; Vuppalanchi, Raj; Ethell, Brian T.; Jones, David R.; Wrighton, Steven; Hall, Stephen D.; Chalasani, Naga

doi:10.1016/j.cgh.2006.12.021

Cited by 77 publications

(80 citation statements)

References 32 publications

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“…In accordance, in vitro studies have also demonstrated reduced CYP3A4 activity in human steatotic livers. [19] CYP1A2, CYP2D6, and CYP2C9 activity were not altered in the current study. It has been suggested previously that individual P450 enzymes could be selectively modulated by degree of liver disease.…”

Section: Discussionmentioning

confidence: 62%

A short-term high fat diet increases exposure to midazolam and omeprazole in healthy subjects

Achterbergh

Lammers

Nierop

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Objectives: Knowledge of factors contributing to variation in drug metabolism is of vital importance to optimize drug treatment. This study assesses the effects of a short-term hypercaloric high fat diet on metabolism of five oral drugs, which are each specific for a single P450 isoform: midazolam (CYP3A4), omeprazole (CYP2C19), metoprolol (CYP2D6), S-warfarin (CYP2C9) and caffeine (CYP1A2). Methods: In 9 healthy volunteers, pharmacokinetics of the five drugs were assessed after an overnight fast at two separate occasions: after a regular diet and after 3 days of a hypercaloric high fat diet (i.e. regular diet supplemented with 500 mL cream [1715 kcal, 35% fat]). Pharmacokinetic parameters (mean [SEM]) were estimated by non-compartmental analysis. Results: The high fat diet increased exposure to midazolam by 19% from 24.7 (2.6) to 29.5 (3.6) ng ml1h-1 (p=0.04) and exposure to omeprazole by 31% from 726 (104) to 951 (168) ng ml-1h-1 (p=0.05). Exposure to metoprolol, caffeine and S-warfarin was not affected by the high fat diet. Conclusion: A short-term hypercaloric high fat diet increases exposure to midazolam and omeprazole, possibly reflecting modulation of CYP3A4 and CYP2C19.ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 62%

A short-term high fat diet increases exposure to midazolam and omeprazole in healthy subjects

Achterbergh

Lammers

Nierop

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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“…These changes in activity are not associated with altered protein levels [63] whereas a trend towards reduced protein with NAFLD progression has also been identified [64] Fig. (1C).…”

Section: Phase I Enzymes Cytochrome P450 Familymentioning

confidence: 87%

Does Hepatic Steatosis Affect Drug Metabolizing Enzymes in the Liver?

Buechler¹,

Weiss

2011

CDM

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Bioavailability and effects of xenobiotics are dependent on absorption, metabolism and elimination of the respective compounds. Hepatocytes are critically important in drug modification and excretion. Molecules like organic anion transporters mediate hepatocyte uptake of xenobiotics, which are subsequently modified by phase I enzymes with cytochrome (CYP) P450 isoenzymes like CYP3A4 being the most important. Phase II enzymes including glucuronosyltransferases further increase aqueous solubility of the respective compounds. The canalicular transport of these substances into the bile is mainly arranged by ATP-binding cassette transporters. Variations in the activity of these enzymes and transporters explain altered drug activity, elimination and eventually increased half-life and toxicity of xenobiotics. Body composition affects distribution of several drugs and fat mass may have to be taken into account in determining appropriate doses of lipophilic compounds. Adiposity is increasingly prevalent in western countries and about half of the adult population is overweight or even obese. Obesity is often associated with an enhanced storage of fat in hepatocytes and hepatic steatosis is diagnosed in nearly 30% of adults. Although this is a benign condition fatty liver is more susceptible to insults leading to non-alcoholic steatohepatitis (NASH) associated with inflammation and liver fibrosis. There is increasing evidence that drug metabolizing enzymes/transporters are differentially expressed in hepatic steatosis and NASH. Studies in animals, humans and in-vitro models suggesting altered expression of transcription factors, transporters and enzymes involved in drug metabolism in non-alcoholic fatty liver disease are summarized in the current review.

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“…We speculate that the unexpected finding of higher hepatic CYP3A activity in the RYGB group is possibly due to decreased hepatic steatosis after the RYGB. We have previously shown that hepatic steatosis is associated with significantly lower hepatic CYP3A activity 48 and it is well known that hepatic steatosis rapidly improves after bariatric surgery. 49 If this observation is confirmed in other studies, it may have important therapeutic implications, such as an RYGB patient requiring higher doses of intravenously administered CYP3A substrates (eg, diltiazem, midazolam) to avoid suboptimal response.…”

Section: Discussionmentioning

confidence: 98%

Pharmacokinetic and Pharmacodynamic Alterations in the Roux-en-Y Gastric Bypass Recipients

Tandra¹,

Chalasani²,

Jones³

et al. 2013

Annals of Surgery

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Association Between Nonalcoholic Hepatic Steatosis and Hepatic Cytochrome P-450 3A Activity

Cited by 77 publications

References 32 publications

A short-term high fat diet increases exposure to midazolam and omeprazole in healthy subjects

A short-term high fat diet increases exposure to midazolam and omeprazole in healthy subjects

Does Hepatic Steatosis Affect Drug Metabolizing Enzymes in the Liver?

Pharmacokinetic and Pharmacodynamic Alterations in the Roux-en-Y Gastric Bypass Recipients

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