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Drug Interactions: Human

Displaying 11 - 17 of 17

Effect of high-dose cranberry juice on the pharmacodynamics of warfarin in patients

Posted: 
November 6, 2010
Authors: 
Mellen CK, Ford M, Rindone JP
Journal: 
Br J Clin Pharmacol 70(1):139-42
Abstract: 

SUBJECT: Case reports suggest an association between cranberry juice and potentiation of warfarin. Studies using 240 ml of cranberry juice daily demonstrated no interaction. It is unknown if higher amounts of cranberry juice will interact with warfarin.

WHAT THIS STUDY ADDS: Cranberry juice at 240 ml twice daily does not alter the pharmacodynamics of warfarin.

AIM: To determine if high-dose cranberry juice (240 ml twice daily) alters the pharmacodynamic action of warfarin.

METHODS: Ten male patients taking stable doses of warfarin were given cranberry juice at 240 ml twice daily for 7 days. Prothrombin times were drawn at baseline and days 2, 6 and 8 after administration of the juice. Prothrombin times were averaged for each day and mean times were compared from each study day to baseline using repeated measures ANOVA.

RESULTS: There was no statistical difference between mean prothrombin time at baseline and any day tested during juice administration.

CONCLUSIONS: Cranberry juice (240 ml twice daily for 1 week) did not alter the pharmacodynamics of warfarin in patients.

Cranberry juice suppressed the diclofenac metabolism by human liver microsomes, but not in healthy human subjects

Posted: 
November 2, 2010
Authors: 
Ushijima K, Tsuruoka S, Tsuda H, Hasegawa G, Obi Y, Kaneda T, Takahashi M
Journal: 
Br J Clin Pharmacol 68(2):194-200
Abstract: 

AIM: To investigate a potential interaction between cranberry juice and diclofenac, a substrate of CYP2C9.

METHODS: The inhibitory effect of cranberry juice on diclofenac metabolism was determined using human liver microsome assay. Subsequently, we performed a clinical trial in healthy human subjects to determine whether the repeated consumption of cranberry juice changed the diclofenac pharmacokinetics.

RESULTS: Cranberry juice significantly suppressed diclofenac metabolism by human liver microsomes. On the other hand, repeated consumption of cranberry juice did not influence the diclofenac pharmacokinetics in human subjects.

CONCLUSIONS: Cranberry juice inhibited diclofenac metabolism by human liver microsomes, but not in human subjects. Based on the present and previous findings, we think that although cranberry juice inhibits CYP2C9 activity in vitro, it does not change the pharmacokinetics of medications metabolized by CYP2C9 in clinical situations.

Identification of a cranberry juice product that inhibits enteric CYP3A-mediated first-pass metabolism in humans

Posted: 
November 2, 2010
Authors: 
Ngo N, Yan Z, Graf TN, Carrizosa DR, Kashuba AD, Dees EC, Oberlies NH, Paine MF.
Journal: 
Drug Metabol Dispos 37(3):514-22
Abstract: 

An in vivo study in rats showed a cranberry juice product to inhibit the intestinal first-pass metabolism of the CYP3A substrate nifedipine. However, a clinical study involving the CYP3A probe substrate midazolam and a different cranberry juice product showed no interaction. Because the composition of bioactive components in natural products can vary substantially, a systematic in vitro-in vivo approach was taken to identify a cranberry juice capable of inhibiting enteric CYP3A in humans. First, the effects of five cranberry juices, coded A through E, were evaluated on midazolam 1'-hydroxylation activity in human intestinal microsomes. Juice E was the most potent, ablating activity at 0.5% juice (v/v) relative to control. Second, juice E was fractionated to generate hexane-, chloroform-, butanol-, and aqueous-soluble fractions. The hexane- and chloroform-soluble fractions at 50 microg/ml were the most potent, inhibiting by 77 and 63%, respectively, suggesting that the CYP3A inhibitors reside largely in these more lipophilic fractions. Finally, juice E was evaluated on the oral pharmacokinetics of midazolam in 16 healthy volunteers. Relative to water, juice E significantly increased the geometric mean area under the curve (AUC)(0-infinity) of midazolam by approximately 30% (p=0.001), decreased the geometric mean 1'-hydroxymidazolam/midazolam AUC(0-infinity) ratio by approximately 40% (p

The warfarin-cranberry juice interaction revisited: A systematic in vitro-in vivo evaluation

Posted: 
November 2, 2010
Authors: 
Ngo N, Brantley SJ, Carrizosa DR, Kashuba AD, Dees EC, Kroll DJ, Oberlies NH, Paine MF
Journal: 
J Exp Pharmacol 2010(2):83-91
Abstract: 

BACKGROUND: Cranberry products have been implicated in several case reports to enhance the anticoagulant effect of warfarin. The mechanism could involve inhibition of the hepatic CYP2C9-mediated metabolic clearance of warfarin by components in cranberry. Because dietary/natural substances vary substantially in bioactive ingredient composition, multiple cranberry products were evaluated in vitro before testing this hypothesis in vivo.

METHODS: The inhibitory effects of five types of cranberry juices were compared with those of water on CYP2C9 activity (S-warfarin 7-hydroxylation) in human liver microsomes (HLM). The most potent juice was compared with water on S/R-warfarin pharmacokinetics in 16 healthy participants given a single dose of warfarin 10 mg.

RESULTS: Only one juice inhibited S-warfarin 7-hydroxylation in HLM in a concentration-dependent manner (P 95% at 0.05% to 0.5% juice (v/v), respectively. However, this juice had no effect on the geometric mean AUC(0-∞) and terminal half-life of S/R-warfarin in human subjects.

CONCLUSIONS: A cranberry juice that inhibited warfarin metabolism in HLM had no effect on warfarin clearance in healthy participants. The lack of an in vitro-in vivo concordance likely reflects the fact that the site of warfarin metabolism (liver) is remote from the site of exposure to the inhibitory components in the cranberry juice (intestine).

Interaction of flurbiprofen with cranberry juice, grape juice, tea, and fluconazole: in vitro and clinical studies

Posted: 
November 1, 2010
Authors: 
Greenblatt DJ, von Moltke LL, Perloff ES, Luo Y, Harmatz JS, Zinny MA
Journal: 
Clin Pharmacol Ther 79(1):125-33
Abstract: 

OBJECTIVES: Recent anecdotal, unvalidated case reports have suggested potentiation of warfarin-induced anticoagulation by cranberry juice, possibly through inhibition of human cytochrome P450 (CYP) 2C9, the enzyme responsible for the clearance of the active S-enantiomer of warfarin. To address this question, the effect of cranberry juice and other beverages on CYP2C9 activity was evaluated in vitro and in vivo.

METHODS: The effects of 4 beverages on CYP2C9 activity were studied in human liver microsomes, by use of flurbiprofen hydroxylation as the index reaction. In a clinical study 14 healthy volunteers received 100 mg flurbiprofen on 5 occasions in a crossover fashion, with at least 1 week separating the 5 trials. Flurbiprofen was preceded in random sequence by the following: (1) cranberry juice placebo (8 oz), (2) cranberry juice (8 oz), (3) brewed tea (8 oz), (4) grape juice (8 oz), and (5) fluconazole, a CYP2C9 inhibitor serving as a positive control, with 8 oz of water.

RESULTS: Flubiprofen hydroxylation in vitro was reduced to 11% +/- 8% of control by 2.5% (vol/vol) brewed tea, to 10% +/- 7% of control by grape juice, to 56% +/- 16% of control by cranberry juice, to 85% +/- 5% of control by cranberry juice placebo, and to 21% +/- 6% of control by the index inhibitor sulfaphenazole (2.5 micromol/L) (P <.01 for="" all="" comparisons="" versus="" control="" flurbiprofen="" clearance="" ml="" and="" elimination="" half-life="" hours="" did="" not="" differ="" significantly="" among="" trials="" however="" in="" the="" fluconazole="" treatment="" condition="" was="" reduced="" compared="" with="" placebo="" p="" prolonged="" formation="" of="" correspondingly="" by="">

CONCLUSIONS: Although grape juice and tea impaired CYP2C9 activity in vitro, none of the 3 beverages altered CYP2C9-mediated clearance of flurbiprofen in humans, making a pharmacokinetic interaction with warfarin highly unlikely.

The absence of an interaction between warfarin and cranberry juice: a randomized, double-blind trial.

Posted: 
October 19, 2010
Authors: 
Ansell J, McDonough M, Zhao Y, Harmatz JS, Greenblatt DJ.
Journal: 
J Clin Pharmacol 49(7):824-30
Abstract: 

The question of potentiation of warfarin anticoagulation by cranberry juice (CJ) is a topic of biomedical importance. Anecdotal reports of CJ-warfarin interaction are largely unconfirmed in controlled studies. Thirty patients on stable warfarin anticoagulation (international normalized ratio [INR], 1.7-3.3) were randomized to receive 240 mL of CJ or 240 mL of placebo beverage, matched for color and taste, once daily for 2 weeks. The INR values and plasma levels of R- and S-warfarin were measured during the 2-week period and a 1-week follow-up period. The CJ and placebo groups (n=14 and 16, respectively) did not differ significantly in mean plasma R- and S-warfarin concentrations. Eight patients (4 on CJ, 4 on placebo) developed minimally elevated INR (range, 3.38-4.52) during the treatment period. Mean INR differed significantly (P<.02 only="" on="" treatment="" day="" at="" all="" other="" time="" points="" the="" groups="" did="" not="" differ.="" cranberry="" juice="" has="" no="" effect="" plasma="" s-="" or="" r-warfarin="" levels="" excluding="" a="" pharmacokinetic="" interaction.="" small="" though="" statistically="" significant="" pharmacodynamic="" enhancement="" of="" inr="" by="" cj="" single="" point="" is="" unlikely="" to="" be="" clinically="" important="" and="" may="" random="" change.="" enhanced="" warfarin="" anticoagulation="" attributed="" in="" anecdotal="" reports="" represent="" chance="" temporal="" association.="">

Effects of Cranberry Juice on Pharmacokinetics of -Lactam

Posted: 
October 13, 2010
Authors: 
Li M, Andrew MA, Wang J, Salinger DH, Vicini P,
Journal: 
Antimicrob Agents Chemother 53(7):2725-32
Abstract: 

Cranberry juice consumption is often recommended along with low-dose oral antibiotics for prophylaxis for
recurrent urinary tract infection (UTI). Because multiple membrane transporters are involved in the intestinal
absorption and renal excretion of -lactam antibiotics, we evaluated the potential risk of pharmacokinetic
interactions between cranberry juice and the -lactams amoxicillin (amoxicilline) and cefaclor. The amoxicillin-
cranberry juice interaction was investigated in 18 healthy women who received on four separate occasions
a single oral test dose of amoxicillin at 500 mg and 2 g with or without cranberry juice cocktail (8 oz) according
to a crossover design. A parallel cefaclor-cranberry juice interaction study was also conducted in which 500 mg
cefaclor was administered with or without cranberry juice cocktail (12 oz). Data were analyzed by noncompartmental
methods and nonlinear mixed-effects compartmental modeling. We conclude that the concurrent
use of cranberry juice has no significant effect on the extent of oral absorption or the renal clearance of
amoxicillin and cefaclor. However, delays in the absorption of amoxicillin and cefaclor were observed. These
results suggest that the use of cranberry juice at usual quantities as prophylaxis for UTI is not likely to alter
the pharmacokinetics of these two oral antibiotics.

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