Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: Comparison with ritonavir

Culm-Merdek, Kerry; Moltke, Lisa L. von; Gan, Lu; Horan, Kelly A.; Reynolds, Robyn; Harmatz, Jerold S.; Court, Michael H.; Greenblatt, David J.

doi:10.1016/j.clpt.2005.11.009

Cited by 74 publications

(64 citation statements)

References 44 publications

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“…It is likely that only a small amount of the ingested dose of PCBs will be subject to intestinal first-pass metabolism, and thus inhibition of this already small amount of monooxygenation should result in little effect of co-ingested phytochemicals on the bioavailability of the PCBs. Studies have shown that the effects of grapefruit juice on drug bioavailability are due to effects only in the intestine (Culm-Merdek et al, 2006), since the systemic bioavailability of bergamottin, 6′,7′-dihydroxybergamottin and other inhibitory natural products is quite low, and the concentrations achieved in liver are too low for inhibition of hepatic biotransformation. Most phytochemicals, including flavonoids, furanocoumarins and anthocyanins are poorly bioavailable, in part because of extensive glucuronidation and sulfonation of the phytochemicals (Walle, 2004).…”

Section: Direct Effects On P450 Activitymentioning

confidence: 99%

Effects of food natural products on the biotransformation of PCBs

James

Sacco

Faux

2008

Environmental Toxicology and Pharmacology

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Many food products, particularly fruits and vegetables, contain natural products that affect biotransformation enzymes. These may be expected to affect the rate of biotransformation of PCBs that are metabolized by the affected enzymes. The first step in PCB metabolism is cytochrome P450-dependent monooxygenation. Natural products present in cruciferous vegetables have been shown to selectively up-regulate CYP1A1 and CYP1A2 isozymes on chronic ingestion, and may lead to increased metabolism of those PCB congeners that are substrates for the induced P450s. On the other hand, several natural products selectively inhibit monooxygenation, especially in the intestine, and may lead to increased bioavailability and reduced metabolism of dietary PCBs. Food natural products are known to affect phase II pathways important in the detoxication of hydroxylated PCBs, namely UDP-glucuronosyltransferase and PAPS-sulfotransferase. Continual dietary exposure to chrysin and quercetin, found in fruits and vegetables, induces UGT1A1 and may reduce exposure to hydroxylated PCBs through increased glucuronidation. These and other natural products are also inhibitors of glucuronidation and sulfonation, potentially leading to transient decreases in the elimination of hydroxylated PCBs. In summary, the expected effects of food natural products on PCB biotransformation are complex and may be biphasic, with initial inhibition followed by enhanced biotransformation through monooxygenation and conjugation pathways.

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Section: Direct Effects On P450 Activitymentioning

confidence: 99%

Effects of food natural products on the biotransformation of PCBs

James

Sacco

Faux

2008

Environmental Toxicology and Pharmacology

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“…Consequently, interaction of protease inhibitors with drugs that are cleared predominantly by CYP3A enzymes are profound and clinically significant [14]. It is still equivocal whether long-term administration of ritonavir may also lead to a certain induction of CYP3A enzymes [15].…”

Section: Introductionmentioning

confidence: 99%

Effect of ritonavir on the pharmacokinetics of the benzimidazoles albendazole and mebendazole: an interaction study in healthy volunteers

Corti

Heck

Rentsch

et al. 2009

Eur J Clin Pharmacol

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Effect of ritonavir on the pharmacokinetics of the benzimidazoles albendazole and mebendazole: an interaction study in healthy volunteers Abstract BACKGROUND: Benzimidazoles are often used concomitantly with protease inhibitors in patients with helminthic disease and HIV infection. Low bioavailability and extensive first-pass metabolism make benzimidazoles prone to pharmacokinetic drug interactions. The aim of the present study was to investigate potential drug interactions between the benzimidazoles albendazole and mebendazole and the potent CYP3A4 inhibitor ritonavir. METHODS: Sixteen healthy volunteers were administered a single oral dose of 1,000 mg mebendazole or 400 mg albendazole (2 x n = 8). AUC, C(max), and t(1/2) of mebendazole, albendazole, and albendazole sulfoxide were studied in absence and after short-term (2 doses) and long-term (8 days) treatment with ritonavir 200 mg bid. RESULTS: Pharmacokinetic parameters of albendazole and mebendazole were not changed by short-term administration of ritonavir. However, long-term administration of ritonavir resulted in significant changes in albendazole and mebendazole disposition, with a significant decrease in AUC(0-24) (27 and 43% of baseline for albendazole and mebendazole, respectively) and C(max) (26 and 41% of baseline, respectively). CONCLUSION: The AUC(0-24) of benzimidazoles decreased after long-term use of ritonavir, while no changes in pharmacokinetic profiles were observed under short-term administration. These findings might help to optimize benzimidazole efficacy when used in combination with protease inhibitors.

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“…Therefore, if some fruits can inhibit CYP2C9 activity in the human small intestine, then fooddrug interactions may occur, similar to those observed in the case of CYP3A. However, few reports are available regarding the inhibition of CYP2C9 activity by fruit juice or fruit extracts (Greenblatt et al, 2006). Hence, it is important to evaluate the effect of fruit juice on CYP2C9 activity.…”

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confidence: 99%

“…Grapefruit, star fruit, and pomelo juices increase the oral bioavailability of cytochrome P450 (P450) 3A substrates, and the mechanism of these interactions is mainly thought to be caused by the inhibition of CYP3A in the small intestine (Bailey et al, 1991(Bailey et al, , 1998Culm-Merdek et al, 2006;Grenier et al, 2006;Hidaka et al, 2006). CYP2C9 is one of three human microsomal P450s in subfamily 2C that contributes extensively to the hepatic metabolism of therapeutic drugs (Miners and Birkett, 1998).…”

mentioning

confidence: 99%

Effects of Pomegranate Juice on Human Cytochrome P450 2C9 and Tolbutamide Pharmacokinetics in Rats

Nagata¹,

Hidaka²,

Sekiya³

et al. 2007

Drug Metabolism and Disposition

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ABSTRACT:In this study, we investigated whether pomegranate juice could inhibit CYP2C9 activity. The ability of pomegranate juice to inhibit the diclofenac 4-hydroxylase activity of human CYP2C9 was examined using human liver microsomes. Pomegranate juice was shown to be a potent inhibitor of human CYP2C9. The addition of 25 l (5% v/v) of pomegranate juice resulted in almost complete inhibition of human CYP2C9 activity. In addition, we investigated the effect of pomegranate juice on the pharmacokinetics of tolbutamide (substrate for CYP2C9) in rats. Relative to the control group, the area under the concentration-time curve was approximately 1.2-fold greater when pomegranate juice (3 ml) was injected p.o. 1 h before the p.o. administration of the tolbutamide (20 mg/ kg). The elimination half-life of tolbutamide was not altered by pomegranate juice administration. These results suggest pomegranate juice ingestion inhibits the intestinal metabolism of tolbutamide without inhibiting the hepatic metabolism in rats. Thus, we discovered that pomegranate juice inhibited human CYP2C9 activity and furthermore increased tolbutamide bioavailability in rats.

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Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: Comparison with ritonavir

Cited by 74 publications

References 44 publications

Effects of food natural products on the biotransformation of PCBs

Effects of food natural products on the biotransformation of PCBs

Effect of ritonavir on the pharmacokinetics of the benzimidazoles albendazole and mebendazole: an interaction study in healthy volunteers

Effects of Pomegranate Juice on Human Cytochrome P450 2C9 and Tolbutamide Pharmacokinetics in Rats

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