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"We had planned a discussion forum on this subject, but we have now decided
to drop the idea. However, we will try and
update the related articles from time to time and would welcome any suggestions.
Don't hesitate to e-mail us if you have interesting references to add or
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1:
Curr
Clin Pharmacol. 2006 May;1(2):157-61.
Effect
of grapefruit juice in relation to human pharmacokinetic study.
Department
of Clinical Pharmacology, Hirosaki University School of Medicine, Hirosaki,
Japan. Grapefruit
juice (GFJ) interacts with a number of drugs, and can alter pharmacokinetics
parameters of the drugs. As for these interactions, most reports have focused on
the elevation of drug bioavailability by GFJ, but a few recent reports have
indicated that GFJ reduced the absorption of drugs not metabolized by cytochrome
P450 (CYP). The predominant mechanisms of GFJ-drug interaction are thought to be
due primarily to the inhibition of intestinal CYP3A4 activity without an
apparent inhibition of hepatic CYP3A4. GFJ is also an inhibitor of
P-glycoprotein, an efflux pump in intestinal cell wall enterocytes, although
clinical support for this mechanism remains unclear. In addition, GFJ has
recently been shown to be a potent in vitro inhibitor of the organic
anion-transporting polypeptides (OATP) 1A2, intestinal uptake transporters of
structurally anionic drugs. It is therefore noteworthy that intestinal
OATPs-mediated drug uptake are reduced by GFJ. The furanocoumarins, major
active ingredients in relation to GFJ-drug interaction, were detected in fresh
grapefruit, commercial GFJ and seville orange juice. However, the specific
furanocoumarins responsible for the inhibition of CYP3A4 activity in in vitro
study have yet to be fully determined and corresponded with GFJ effects in in
vivo study. This article summarizes our data concerning GFJ-drug interaction and
many GFJ-drug effects, and reviews the mechanism of this interaction, possible
active ingredients and clinical implications. PMID: 18666368 [PubMed - indexed for MEDLINE] Related
Articles
·
A
furanocoumarin-free grapefruit juice establishes furanocoumarins as the
mediators of the grapefruit juice-felodipine interaction.
[Am J Clin Nutr.
2006] ·
Further
characterization of a furanocoumarin-free grapefruit juice on drug disposition:
studies with cyclosporine. [Am
J Clin Nutr. 2008] ·
Pharmacokinetic
analysis of felodipine-grapefruit juice interaction based on an irreversible
enzyme inhibition model. [Br
J Clin Pharmacol. 2000]
·
Exposure-dependent
inhibition of intestinal and hepatic CYP3A4 in vivo by grapefruit juice.
[J Clin Pharmacol. 2003]
·
Interactions
between grapefruit juice and cardiovascular drugs.
[Am J Cardiovasc Drugs. 2004]
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 1:
Br
J Clin Pharmacol. 2006
Jan;61(1):49-57.
The
impact of CYP2C8 polymorphism and grapefruit juice on the pharmacokinetics
of repaglinide.
Bidstrup
TB,
Damkier
P, Olsen
AK, Ekblom
M, Karlsson
A, Brøsen
K. Clinical
Pharmacology, University of Southern Denmark, Denmark. tbidstrup@health.sdu.dk AIMS:
The primary aim of the study was to investigate the possible effect of the
CYP2C8*3 allele and of grapefruit juice on the pharmacokinetics of repaglinide.
Furthermore, the impact of a single dose of grapefruit juice on the
pharmacokinetics of repaglinide in relation to dose. METHODS: Thirty-six healthy
male subjects, genotyped for CYP2C8*3 (11 genotyped as CYP2C8*1/*3, one as
CYP2C8*3/*3 and 24 as CYP2C8*1/*1), participated in a randomized, cross-over
trial. In the two phases, the subjects drank 300 mL water or 300 mL grapefruit
juice, in randomized order, 2 h before administration of a single dose of either
0.25 mg or 2 mg repaglinide. RESULTS: Neither the mean AUC(0-infinity) (geometric
mean ratio: 1.01; 95% CI: 0.93-1.1, P = 0.88) nor the mean C(max) (geometric
mean ratio: 1.05; 95% CI: 0.94-1.2, P = 0.35) of repaglinide were statistically
significantly different in the group carrying the CYP2C8*3 mutant allele
compared with wild-types. Grapefruit juice caused a 19% decrease in the
geometric mean ratio of the 3-hydroxyquinidine to quinidine ratio (difference:
0.81; 95% CI: 0.75-0.87, P < 0.0001), which was used as an index of CYP3A4
activity, and an increase in the mean AUC(0-infinity) of repaglinide (geometric
mean ratio: 1.13; 95% CI: 1.04-1.2, P = 0.0048), but had no statistically
significant effect on the t(1/2). There was no statistically significant
difference in blood glucose concentration in subjects who had or had not
ingested grapefruit juice. The effect was more pronounced at the low dose of
repaglinide (0.25 mg) than at the therapeutic dose of 2 mg. CONCLUSIONS: The
pharmacokinetics of repaglinide in subjects carrying the CYP2C8*3 mutant allele
did not differ significantly from those in the wild-types. Grapefruit juice
increased the bioavailability of repaglinide, suggesting significant intestinal
elimination of the drug which was assumed to be primarily mediated by CYP3A4 in
the gut. PMID:
16390351 [PubMed - indexed for MEDLINE] PMCID:
PMC1884987 Related
Articles
·
Polymorphism
in CYP2C8 is associated with reduced plasma concentrations of repaglinide.
[Clin Pharmacol Ther. 2003]
·
Cyclosporine
markedly raises the plasma concentrations of repaglinide. [Clin
Pharmacol Ther. 2005] ·
Polymorphic
organic anion transporting polypeptide 1B1 is a major determinant of repaglinide
pharmacokinetics. [Clin Pharmacol Ther. 2005]
·
ReviewDrug-drug
and food-drug pharmacokinetic interactions with new insulinotropic agents
repaglinide and nateglinide. [Clin
Pharmacokinet. 2007] ·
ReviewEffect
of genetic polymorphisms in cytochrome p450 (CYP) 2C9 and CYP2C8 on the
pharmacokinetics of oral antidiabetic drugs: clinical relevance.
[Clin
Pharmacokinet. 2005]
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