Effects of Daily Ingestion of Cranberry Juice on the Pharmacokinetics of Warfarin, Tizanidine, and Midazolam—Probes of CYP2C9, CYP1A2, and CYP3A4

Lilja, Jari J.; Backman, Janne T.; Neuvonen, Pertti J.

doi:10.1038/sj.clpt.6100149

Cited by 81 publications

(68 citation statements)

References 46 publications

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“…First experiment using a baculovirus expression system showed that CrJ extract inhibited the metabolite production concentration-dependently. A previous report showed that CrJ had moderate inhibitory potential on flurbiprofen hydroxylation by human liver microsomes 5) , which is similar to the present data. The IC50 report than in this study.…”

Section: Discussionsupporting

confidence: 82%

“…On the other hand, there are reports indicating that CrJ has a minimal effect on the pharmacokinetics and pharmacodynamics of warfarin 5,6) . However, we think that it is too early to reach a conclusion about the effect of CrJ on CYP2C9 activity, because, although CrJ is reported to inhibit metabolism of CYP2C9 substrates 7) , such effect of CrJ has not been sufficiently evaluated in vitro, and thus there are controversial results between in vivo and in vitro findings.…”

Section: Introductionmentioning

confidence: 99%

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The Inhibitory Effect of Cranberry Juice on Phenytoin Metabolism by Human Liver Microsomes

Ushijima

Koshimizu

Fujimura

2009

Jpn. J. Clin. Pharmacol. Ther.

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CYP2C9 is involved in the metabolism of many drugs such as warfarin and phenytoin（PHT). It is well known that some foods cause pharmacokinetic alterations of drugs and lead to toxicity. Regarding the interaction caused by cranberry juice（CrJ), its influence on the metabolism of warfarin, a CYP2C9 substrate, is controversial. In addition, information concerning the influence of CrJ on the pharmacokinetics of other substrate drugs of CYP2C9 is not available. To examine the inhibitory effect of CrJ on the metabolism of PHT, we performed experiments using a baculovirus expression microsome system and human liver microsome assay. CrJ concentration-dependently inhibited the substrate metabolism both in a baculovirus-expressed microsome system and in human liver microsome assay. These data support the idea that CrJ inhibits CYP2C9 activity, and the subsequent metabolism of drugs metabolized by CYP2C9. In this study, we did not identify the specific substance(s）which inhibits CYP2C9 activity. However, as CrJ did not enhance the PHT accumulation in 3D-HepG2 cells, it is thought that the penetration into hepatic cells of inhibitory substances in CrJ seems to be small.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

The Inhibitory Effect of Cranberry Juice on Phenytoin Metabolism by Human Liver Microsomes

Ushijima

Koshimizu

Fujimura

2009

Jpn. J. Clin. Pharmacol. Ther.

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“…Recent studies have shown that cranberry juice potently inhibits CYP3A and CYP2C9 in vitro (9, 34); however, in vivo studies with probe substrates for CYP2C9 (S-warfarin), (20). Despite the lack of an effect of cranberry juice on the pharmacokinetics of warfarin (20), several case reports have indicated that cranberry juice results in an enhanced antithrombotic effect of warfarin (8,12,23,27,32,33), suggesting a possible pharmacodynamic effect. A number of studies have reported incidences of apple-, orange-, and grapefruit-drug interactions (6,7,21,29).…”

Section: Discussionmentioning

confidence: 99%

Effects of Cranberry Juice on Pharmacokinetics of β-Lactam Antibiotics following Oral Administration

Li¹,

Andrew

Wang³

et al. 2009

Antimicrob Agents Chemother

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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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“…25 mg) in the absence or presence of steady-state treatment of the drug that has potential to interact with warfarin; the use of a higher single dose of warfarin allows greater potential to detect an interaction as well as reduces the exposure of healthy volunteers to a prolonged period of anticoagulation. In some published studies, the interaction of a drug with warfarin has been assessed by administration of a single lower (10-15 mg) oral dose of warfarin [13,14]. A 7% decrease in S-warfarin AUC could be demonstrated after a single 10-mg dose of warfarin.…”

Section: Introductionmentioning

confidence: 99%

Effects of fesoterodine on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers

Malhotra

Alvey

Gong

et al. 2011

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Drug-drug interactions with warfarin are common with potentially harmful consequences. Preclinical in vitro studies suggest that fesoterodine or 5-hydroxymethyl tolterodine are not likely to affect warfarin metabolism, but a lack of interaction has not been demonstrated in a clinical study. WHAT THIS STUDY ADDS• This study shows that the pharmacokinetics and pharmacodynamics of warfarin 25 mg in healthy adults are unaffected by fesoterodine 8 mg, and that co-administration of warfarin 25 mg and fesoterodine 8 mg is safe and well tolerated. AIMSTo confirm the lack of an interaction of fesoterodine 8 mg with warfarin pharmacokinetics and pharmacodynamics in healthy adults. METHODSIn this open-label, two-treatment, crossover study, subjects (n = 14) aged 20-41 years with normal prothrombin time (PT) and International Normalized Ratio (INR) were randomized to receive a single dose of warfarin 25 mg alone in one period and fesoterodine 8 mg once daily on days 1-9 with a single dose of warfarin 25 mg co-administered on day 3 in the other period. There was a 10-day washout between treatments. Pharmacokinetic endpoints were area under the plasma concentration-time curve from time 0 to infinity (AUC(0,•)), maximum plasma concentration (C max), AUC from time 0 to the time of the last quantifiable concentration (AUC(0,last)), time to Cmax (tmax), and half-life (t1/2) for S-and R-warfarin. Pharmacodynamic endpoints were area under the INR-time curve (AUCINR), maximum INR (INRmax), area under the PT-time curve (AUCPT) and maximum PT (PTmax). RESULTSAcross all pharmacokinetic and pharmacodynamic comparisons, the point estimates of treatment ratio (warfarin co-administered with fesoterodine vs. warfarin alone) were 92-100%. The 90% confidence intervals for the ratios of the adjusted geometric means were contained within (80%, 125%). There were no clinically relevant changes in laboratory tests, vital signs or ECG recordings. CONCLUSIONSThe pharmacokinetics and pharmacodynamics of warfarin 25 mg in healthy adults are unaffected by fesoterodine 8 mg. Concomitant administration of fesoterodine and warfarin was well tolerated.

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Effects of Daily Ingestion of Cranberry Juice on the Pharmacokinetics of Warfarin, Tizanidine, and Midazolam—Probes of CYP2C9, CYP1A2, and CYP3A4

Cited by 81 publications

References 46 publications

The Inhibitory Effect of Cranberry Juice on Phenytoin Metabolism by Human Liver Microsomes

The Inhibitory Effect of Cranberry Juice on Phenytoin Metabolism by Human Liver Microsomes

Effects of Cranberry Juice on Pharmacokinetics of β-Lactam Antibiotics following Oral Administration

Effects of fesoterodine on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers

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