Grapefruit Juice Inhibits the Metabolic Activation of Clopidogrel

Holmberg, Mikko T.; Tornio, Aleksi; Neuvonen, Mikko; Neuvonen, Pertti J.; Backman, Janne T.; Niemi, Mikko

doi:10.1038/clpt.2013.192

Cited by 53 publications

(65 citation statements)

References 44 publications

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“…Recently, grapefruit juice was shown to inhibit the first-pass metabolism of ticagrelor, another new P2Y 12 receptor antagonist, and to increase ticagrelor exposure in humans, enhancing the platelet inhibitory activity [16]. In contrast to ticagrelor, the bioactivation of clopidogrel was strongly inhibited by grapefruit juice, which resulted in greatly impaired inhibition of platelet aggregation by clopidogrel [17].…”

Section: What This Study Addsmentioning

confidence: 99%

Effect of grapefruit juice on the bioactivation of prasugrel

Holmberg

Tornio

Hyvärinen

et al. 2015

Brit J Clinical Pharma

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AIMSThe P2Y12 inhibitor prasugrel is a prodrug, which is activated after its initial hydrolysis partly by cytochrome P450 (CYP) 3A4. Grapefruit juice, a strong inactivator of intestinal CYP3A4, greatly reduces the activation and antiplatelet effects of clopidogrel. The aim of this study was to investigate the effects of grapefruit juice on prasugrel. METHODSIn a randomized crossover study, seven healthy volunteers ingested 200 ml of grapefruit juice or water three times daily for 4 days. On day 3, they ingested a single 10 mg dose of prasugrel with an additional 200 ml of grapefruit juice or water. Plasma concentrations of prasugrel metabolites and the antiplatelet effect were measured. RESULTSGrapefruit juice increased the geometric mean area under the plasma concentration-time curve (AUC 0-∞ ) of the primary, inactive metabolite of prasugrel to 164% of the control value (95% confidence interval 122-220%, P = 0.008), without a significant effect on its peak plasma concentration (C max ). The C max and AUC 0-∞ of the secondary, active metabolite were decreased to 51% (95% confidence interval 32-84%, P = 0.017) and 74% of the control value (95% confidence interval 60-91%, P = 0.014) by grapefruit juice (P < 0.05). The average platelet inhibition, assessed with the VerifyNow® method at 0-24 h after prasugrel intake, was 5 percentage points (95% confidence interval 1-10 percentage points) lower in the grapefruit juice phase than in the water phase (P = 0.034). CONCLUSIONSGrapefruit juice reduces the bioactivation of prasugrel, but this has only a limited effect on the antiplatelet effect of prasugrel.

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Section: What This Study Addsmentioning

confidence: 99%

Effect of grapefruit juice on the bioactivation of prasugrel

Holmberg

Tornio

Hyvärinen

et al. 2015

Brit J Clinical Pharma

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“…The day-to-day coefficient of variation (CV) was below 15% for all analytes at relevant concentrations. Clopidogrel, the clopidogrel active cis-5-thiol metabolite, clopidogrel carboxylic acid, and clopidogrel acyl-b-D-glucuronide were analyzed with a Nexera UPLC instrument (Shimadzu, Kyoto, Japan) connected to an AB Sciex QTrap 5500 mass spectrometer, as previously described (Holmberg et al, 2014;Tornio et al, 2014;Itkonen et al, 2015).…”

Section: Methodsmentioning

confidence: 99%

Clopidogrel Markedly Increases Plasma Concentrations of CYP2C8 Substrate Pioglitazone

Itkonen

Tornio

Neuvonen

et al. 2016

Drug Metabolism and Disposition

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The glucose-lowering drug pioglitazone undergoes hepatic CYP2C8-mediated biotransformation to its main metabolites. The antiplatelet drug clopidogrel is metabolized to clopidogrel acyl-b-D-glucuronide, which was recently found to be a strong time-dependent inhibitor of CYP2C8 in humans. Therefore, we studied the effect of clopidogrel on the pharmacokinetics of pioglitazone. In a randomized crossover study, 10 healthy volunteers ingested either 300 mg of clopidogrel on day 1, and 75 mg on days 2 and 3, or placebo. Pioglitazone 15 mg was administered 1 hour after placebo and clopidogrel on day 1. Plasma concentrations of pioglitazone, clopidogrel, and their main metabolites were measured up to 72 hours. Clopidogrel increased the area under the plasma concentration-time curve (AUC 0-' ) of pioglitazone 2.1-fold [P < 0.001, 90% confidence interval (CI) 1.8-2.6] and prolonged its half-life from 6.7 to 11 hours (P = 0.002). The peak concentration of pioglitazone was unaffected but the concentration at 24 hours was increased 4.5-fold (range 1.6-9.8; P < 0.001, 90% CI 3.17-6.45) by clopidogrel. The M-IV-to-pioglitazone AUC 0-' ratio was 49% (P < 0.001, 90% CI 0.40-0.59) of that during the control phase, indicating that clopidogrel inhibited the CYP2C8-mediated biotransformation of pioglitazone. Clopidogrel increases the exposure to pioglitazone by inhibiting its CYP2C8-mediated biotransformation. In consequence, use of clopidogrel may increase the risk of fluid retention and other concentration-related adverse effects of pioglitazone.

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“…The sample preparation was carried out, and plasma concentrations of clopidogrel, the clopidogrel active cis-5-thiol metabolite, clopidogrel carboxylic acid, and clopidogrel acyl-b-D-glucuronide were measured with a Nexera X2 series liquid chromatograph (Shimadzu, Kyoto, Japan) coupled to a 5500 Qtrap tandem mass spectrometer (AB Sciex) according to a previously described method, with slight modifications (Holmberg et al, 2014;Tornio et al, 2014). In short, plasma proteins were precipitated by acetonitrile, and samples were centrifuged and loaded into the autosampler.…”

Section: Methodsmentioning

confidence: 99%

Clopidogrel Has No Clinically Meaningful Effect on the Pharmacokinetics of the Organic Anion Transporting Polypeptide 1B1 and Cytochrome P450 3A4 Substrate Simvastatin

et al. 2015

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Simvastatin and clopidogrel are commonly used together in the treatment of cardiovascular diseases. Organic anion transporting polypeptide (OATP) 1B1 activity markedly affects the hepatic uptake of simvastatin acid, whereas both simvastatin and simvastatin acid are sensitive to changes in cytochrome P450 3A4 activity. Clopidogrel and its metabolites inhibit OATP1B1 and CYP3A4 in vitro. We studied the effect of clopidogrel on the pharmacokinetics of simvastatin in a randomized crossover study. Twelve healthy volunteers ingested either a dose of placebo (control) or 300 mg of clopidogrel on day 1 and 75 mg on days 2 and 3. Simvastatin 40 mg was administered 1 hour after placebo and after clopidogrel on days 1 and 3. Plasma drug concentrations were measured for up to 12 hours. Clopidogrel 300 mg (day 1) increased the concentrations of simvastatin and simvastatin acid during the absorption phase. After clopidogrel 300 mg, the area under the concentration time curve (AUC) of simvastatin from 0 to 2 hours was 156% (P = 0.02) and its AUC 0-12 hours was 132% (P = 0.08) of that during placebo, whereas the AUC 0-2 hours and the AUC 0-12 hours of simvastatin acid were 148% (P = 0.04) and 112% (P = 0.52) of control. Clopidogrel 75 mg (day 3) had no significant effect on the pharmacokinetic variables of simvastatin or simvastatin acid compared with placebo. The effect of clopidogrel seemed independent of the SLCO1B1 c.521T>C genotype. In conclusion, as clopidogrel did not have significant effects on the total exposure to simvastatin or simvastatin acid, clopidogrel does not seem to inhibit OATP1B1 or CYP3A4 to a clinically relevant extent.

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Grapefruit Juice Inhibits the Metabolic Activation of Clopidogrel

Cited by 53 publications

References 44 publications

Effect of grapefruit juice on the bioactivation of prasugrel

Effect of grapefruit juice on the bioactivation of prasugrel

Clopidogrel Markedly Increases Plasma Concentrations of CYP2C8 Substrate Pioglitazone

Clopidogrel Has No Clinically Meaningful Effect on the Pharmacokinetics of the Organic Anion Transporting Polypeptide 1B1 and Cytochrome P450 3A4 Substrate Simvastatin

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