The Effect of Bergamottin on Diazepam Plasma Levels and P450 Enzymes in Beagle Dogs

Sahi, Jasminder; Reyner, Eric L.; Bauman, Jonathan N.; Gueneva-Boucheva, Kristina; Burleigh, James E.; Thomas, V. Hayden

doi:10.1124/dmd.30.2.135

Cited by 22 publications

(15 citation statements)

References 25 publications

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“…In comparison, the intravenous pharmacokinetics of drugs were not significantly altered by oral grapefruit juice (Ducharme et al, 1995;Kupferschmidt et al, 1995;Rashid et al, 1995). However, purified bergamottin given to dogs, either orally or i.v., produced a similar increase in AUC and C max of orally administered diazepam indicating that bergamottin can also inhibit the liver-metabolizing enzymes (Sahi et al, 2002). In agreement with this data, we found potent inhibition of CYP3A-and CYP1A1/2-mediated activities by bergamottin in both human and monkey hepatocytes.…”

Section: Wen Et Alsupporting

confidence: 79%

“…The minimal effect of grapefruit juice on the liver-metabolizing capacity in human could in part be explained by intestinal metabolism of bergamottin. However, if delivered to the liver it would inhibit phase I enzymes, as was recently demonstrated in dogs (Sahi at al., 2002).…”

Section: Wen Et Almentioning

confidence: 97%

“…In rats, administration of bergamottin in duodenum at doses equivalent to that in grapefruit juice resulted in increased AUC of nifedipine, an effect similar to grapefruit juice (Mohri and Uesawa, 2001). Bergamottin administered to dogs either orally or intravenously prior to oral diazepam resulted in a similar increase in plasma levels of diazepam, suggesting the inhibition of hepatic-metabolizing enzymes (Sahi et al, 2002). This study was designed to directly evaluate the effect of bergamottin on phase I and phase II drug-metabolizing enzymes in human and monkey cultured hepatocytes after acute or prolonged treatments.…”

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confidence: 99%

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Effects of Bergamottin on Human and Monkey Drug-Metabolizing Enzymes in Primary Cultured Hepatocytes

Wen¹,

Sahi²,

Urda³

et al. 2002

Drug Metab Dispos

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ABSTRACT:We investigated the effect of bergamottin, a major furanocoumarin in grapefruit juice, on phase I and phase II drug-metabolizing enzymes using cultured human and monkey hepatocytes. Both cultured systems were compared and evaluated for the direct effects of bergamottin as well as control treatments on liver enzymes. Treatment of hepatocytes with 0.1, 1, 5, and 10 M bergamottin resulted in a concentration-dependent reduction in CYP3A4 activity (40-100%) in both human and monkey cells, as measured by testosterone 6␤-hydroxylase activity. Bergamottin was potent at eliciting these inhibitory effects at both basal and induced states of CYP3A. Bergamottin (5 M) completely inhibited ␣-naphthoflavone-induced ethoxyresorufin O-dealkylase (EROD) and methoxyresorufin O-dealkylase (MROD) activities in human hepatocytes and caused a 100% decrease in EROD activity in monkey hepatocytes. A 48-h exposure of cultured human hepatocytes to bergamottin resulted in increased levels of immunoreactive CYP3A4, CYP1A1, and CYP1A2 proteins, and CYP3A4, CYP1A1, CYP1A2, CYP2B6, and UDP-glucuronosyl transferase mRNAs. There was only a 20 to 30% reduction in glucuronidation and sulfation of 4-methylumbelliferone in human hepatocytes by 10 M bergamottin and no effect on conjugation in the monkey hepatocytes. These results suggest that bergamottin causes both inhibition of CYP3A and CYP1A1/2 enzymatic activities and induction of correspondent proteins and mRNAs.

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Section: Wen Et Alsupporting

confidence: 79%

Section: Wen Et Almentioning

confidence: 97%

mentioning

confidence: 99%

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Effects of Bergamottin on Human and Monkey Drug-Metabolizing Enzymes in Primary Cultured Hepatocytes

Wen¹,

Sahi²,

Urda³

et al. 2002

Drug Metab Dispos

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“…A typical example is the inhibition of CYP3A4 by grapefruit juice, which can result in an increase of bioavailability of CYP3A4 substrates (Bailey et al, 1998). Some furanocoumarins are the causative components in grapefruit juice for CYP3A4 inhibition (Edwards et al, 1996;Sahi et al, 2002). Schisandra extract has also a potent inhibitory effect on human liver microsomal erythromycin N-demethylation activity mediated by CYP3A4, and known components of schisandra fruit, gomisins B, C, G, and N and ␥-shizandrin, have inhibitory effects on N-demethylation activity (Iwata et al, 2004).…”

mentioning

confidence: 99%

Inhibitory Effects of Seven Components of Danshen Extract on Catalytic Activity of Cytochrome P450 Enzyme in Human Liver Microsomes

Qiu¹,

Zhang²,

Sun³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The potential for herb-drug interactions has recently received greater attention worldwide, considering the fact that the use of herbal products becomes more and more widespread. The goal of this work was to examine the potential for the metabolism-based drug interaction arising from seven active components (danshensu, protocatechuic aldehyde, protocatechuic acid, salvianolic acid B, tanshinone I, tanshinone IIA, and cryptotanshinone) of danshen extract. Probe substrates of cytochrome P450 enzymes were incubated in human liver microsomes (HLMs) with or without each component of danshen extract. IC 50 and K i values were estimated, and the types of inhibition were determined. Among the seven components of danshen extract, tanshinone I, tanshinone IIA, and cryptotanshinone were potent competitive inhibitors of CYP1A2 (K i ‫؍‬ 0.48, 1.0, and 0.45 M, respectively); danshensu was a competitive inhibitor of CYP2C9 (K i ‫؍‬ 35 M), and cryptotanshinone was a moderate mixed-type inhibitor of CYP2C9 (K i ‫؍‬ 8 M); cryptotanshinone inhibited weakly and in mixed mode against CYP2D6 activity (K i ‫؍‬ 68 M), and tanshinone I was a weak inhibitor of CYP2D6 (IC 50 ‫؍‬ 120 M); and protocatechuic aldehyde was a weak inhibitor of CYP3A4 (IC 50 ‫؍‬ 130 and 160 M for midazolam and testosterone, respectively). These findings provided some useful information for safe and effective use of danshen preparations in clinical practice. Our data indicated that it was necessary to study the in vivo interactions between drugs and pharmaceuticals with danshen extract.

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“…Oral pretreatment or coadministration of bergamottin (a furanocoumarin derived from grapefruit juice) resulted in a >20-fold increase in oral diazepam exposure in dogs (53). Intravenous administration of bergamottin also resulted in an increase in oral diazepam exposure.…”

Section: Hepatic Metabolismmentioning

confidence: 99%

Issues Related to the Use of Canines in Toxicologic Pathology—Issues With Pharmacokinetics and Metabolism

Tibbitts

2003

Toxicol Pathol

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The dog is a commonly used animal model by virtue of its size, well-characterized physiology, and ease of handling. For these reasons and others, dogs are also useful in pharmacokinetic and metabolism studies during the development of both human and veterinary pharmaceutical products. In comparison with humans, or with other animals, dogs have some unique physiologic attributes that can affect the disposition of drugs. Species differences in gastrointestinal physiology, metabolism, renal function, and protein binding can affect the correlation of the pharmacokinetics and toxicology of dogs with those of other species. With the use of relevant examples, this article will provide an introduction to characteristics of dog physiology and their impact on pharmacokinetics, metabolism, drug disposition, toxicity, and dose selection.

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The Effect of Bergamottin on Diazepam Plasma Levels and P450 Enzymes in Beagle Dogs

Cited by 22 publications

References 25 publications

Effects of Bergamottin on Human and Monkey Drug-Metabolizing Enzymes in Primary Cultured Hepatocytes

Effects of Bergamottin on Human and Monkey Drug-Metabolizing Enzymes in Primary Cultured Hepatocytes

Inhibitory Effects of Seven Components of Danshen Extract on Catalytic Activity of Cytochrome P450 Enzyme in Human Liver Microsomes

Issues Related to the Use of Canines in Toxicologic Pathology—Issues With Pharmacokinetics and Metabolism

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