Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy

More than a decade has passed since it was unintentionally discovered that grapefruit juice interacts with certain drugs. The coadministration of these drugs with grapefruit juice can markedly elevate drug bioavailability, and can alter pharmacokinetic and pharmacodynamic parameters of the drug. The predominant mechanism for this interaction is the inhibition of cytochrome P-450 3A4 in the small intestine, resulting in a significant reduction of drug presystemic metabolism. An additional mechanism is, presumably, the inhibition of P-glycoprotein, a transporter that carries drug from the enterocyte back to the gut lumen, resulting in a further increase in the fraction of drug absorbed. Some calcium channel antagonists, benzodiazepines, HMG-CoA reductase inhibitors and cyclosporine are the most affected drugs. A single exposure to one glass of the juice can usually produce the maximal magnitude of the interaction. The data available so far, concerning this interaction and its clinical implications, are reviewed in this article. It is likely that more information regarding this interaction will accumulate in the future, and awareness of such is necessary for achieving optimal drug therapy.

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“…A 40% increase in carbamazepine AUC was observed after ingestion of a single glass of the juice (Garg et al, 1998).…”

Section: Food-drug Interaction a Dahan And H Altmanmentioning

confidence: 92%

Food–drug interaction: grapefruit juice augments drug bioavailability—mechanism, extent and relevance

2003

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“…It has been reported that grapefruit juice increased carbamazepine bioavailability by inhibiting CYP3A enzymes in the gut wall and liver in humans (Garg et al, 1998). If pomegranate inhibits CYP3A expressed in the gut wall and/or liver, as in the case of grapefruit juice, coadministration of pomegranate juice may alter carbamazepine pharmacokinetics.…”

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confidence: 99%

Effects of Pomegranate Juice on Human Cytochrome P450 3a (Cyp3a) and Carbamazepine Pharmacokinetics in Rats

Hidaka

Okumura²,

Fujita³

et al. 2005

Drug Metab Dispos

122

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ABSTRACT:In this study, we investigated whether components of pomegranate could inhibit CYP3A-mediated drug metabolism. The ability of pomegranate to inhibit the carbamazepine 10,11-epoxidase activity of CYP3A was examined using human liver microsomes, and pomegranate juice was shown to be a potent inhibitor of human CYP3A. Addition of 25 l (5.0% v/v) of pomegranate juice resulted in almost complete inhibition of the carbamazepine 10,11-epoxidase activity of human CYP3A (1.8%). The inhibition potency of pomegranate juice was similar to that of grapefruit juice. In addition, we investigated the in vivo interaction between pomegranate juice and carbamazepine pharmacokinetics using rats. In comparison with water, the area under the concentration-time curve (AUC) of carbamazepine was approximately 1.5-fold higher when pomegranate juice (2 ml) was orally injected 1 h before the oral administration of the carbamazepine (50 mg/kg). On the other hand, the elimination half-life of carbamazepine and the AUC ratio of carbamazepine 10,11-epoxide to carbamazepine were not altered by the injection of pomegranate juice. These data suggest that pomegranate juice component(s) impairs the function of enteric but not hepatic CYP3A. Thus, we discovered that a component(s) of pomegranate inhibits the human CYP3A-mediated metabolism of carbamazepine. Furthermore, pomegranate juice alters the carbamazepine pharmacokinetics in rats.

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“…No statistically significant differences were found in the time to maximum concentration of drug in plasma or elimination half-life.Grapefruit juice increases the bioavailability of a variety of drugs (3,4,10,11,13,14,18), but it scarcely affects the elimination half-life (t 1/2 ). These findings suggest that grapefruit juice alters the first-pass metabolism mainly by suppression of the cytochrome P450 enzyme CYP3A4 in the small intestine (1,2,15).…”

mentioning

confidence: 99%

Interaction between Grapefruit Juice and Praziquantel in Humans

Castro

Jung

Medina

et al. 2002

Antimicrob Agents Chemother

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After a single oral dose of praziquantel with 250 ml of grapefruit juice, the area under the concentration-time curve and the maximum concentration in plasma of praziquantel (C max ) were significantly increased (C max for water treatment, 637.71 ؎ 128.5 ng/ml; and C max for grapefruit juice treatment, 1,037.65 ؎ 305.7 ng/ml, P < 0.05). No statistically significant differences were found in the time to maximum concentration of drug in plasma or elimination half-life.Grapefruit juice increases the bioavailability of a variety of drugs (3,4,10,11,13,14,18), but it scarcely affects the elimination half-life (t 1/2 ). These findings suggest that grapefruit juice alters the first-pass metabolism mainly by suppression of the cytochrome P450 enzyme CYP3A4 in the small intestine (1,2,15).Praziquantel is an effective antihelmintic drug, widely used in the treatment of various parasitic diseases, including brain cysticercosis (7,20). It has been shown that the drug undergoes extensive metabolism by cytochrome P450; therefore, the systemic bioavailability of praziquantel is low and variable despite its almost complete gastrointestinal absorption (17). The specific cytochrome P450 enzymes involved in the metabolism of praziquantel in humans have not been characterized (5), but a significant inhibition of praziquantel hydroxylation by compounds that are inhibitors for 3A isoforms of cytochrome P450 has been observed in microsomes isolated from rat liver (16). In previous studies in humans, it was shown that cimetidine (an inhibitor of the microsomal cytochrome P450 mixed-function oxidase system) or simultaneous food administration increased the levels in plasma of praziquantel (6, 12); therefore, the aim of this study was to investigate the effect of the ingestion of grapefruit juice on the pharmacokinetics of praziquantel.Eighteen healthy male volunteers (age range, 23 to 37 years; mean, 28.8 Ϯ 5.4 years) participated in the study. Medical examination before the study showed that they were healthy and had normal results in laboratory tests that included complete blood count, serum chemistry measurement, hepatic test, and urinalysis. The volunteers signed an informed consent after detailed explanation about the purpose and design of the study, as well as the possible risks. The study was approved by the local ethics committee.The study was performed using a balanced randomized crossover design. Volunteers were separated in two groups of nine subjects each and received three tablets of 600 mg of praziquantel (Cisticid; Merck) with 250 ml of water or 250 ml of commercially squeezed grapefruit juice (Florida 7; lot L-2 05:51; Zano Alimentos S.A. de C.V., Mexico City, Mexico).The same lot number was used throughout the study. The interval between tests was 1 week. Blood samples were obtained through an indwelling catheter placed in the antecubital vein at 0.0, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, and 8.0 h after the drug administration. Samples were centrifuged; the plasma was separated and stored at Ϫ4°C until an...

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Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy

Abstract: Grapefruit juice increases the bioavailability of carbamazepine by inhibiting CYP3A4 enzymes in gut wall and in the liver.

Cited by 116 publications

References 10 publications

Food–drug interaction: grapefruit juice augments drug bioavailability—mechanism, extent and relevance

Food–drug interaction: grapefruit juice augments drug bioavailability—mechanism, extent and relevance

Effects of Pomegranate Juice on Human Cytochrome P450 3a (Cyp3a) and Carbamazepine Pharmacokinetics in Rats

Interaction between Grapefruit Juice and Praziquantel in Humans

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