Pharmacokinetic interactions between clopidogrel and rosuvastatin: Effects on vascular protection in subjects with coronary heart disease

Pinheiro, Luiz; França, Carolina Nunes; Izar, Maria Cristina de Oliveira; Barbosa, Simone P.; Bianco, Henrique Tria; Kasmas, Soraia H.; Mendes, Gustavo Duarte; Póvoa, Rui Manuel dos Santos; Fonseca, Francisco A.H.

doi:10.1016/j.ijcard.2012.04.051

Cited by 37 publications

(36 citation statements)

References 35 publications

(21 reference statements)

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“…Our result is consistent with the lack of clinically relevant OATP1B1-mediated DDI of clopidogrel with simvastatin and fluvastatin, although it causes an increase in the AUC of repaglinide (5.0-fold) mainly via the inhibition of CYP2C8 by clopidogrel acyl-b-glucuronide (Ayalasomayajula et al, 2007;Tornio et al, 2014;Itkonen et al, 2015). A clinical study found that a single oral dose of 300 mg clopidogrel increased the AUC of rosuvastatin (1.7-fold) in patients with coronary heart disease (Pinheiro et al, 2012). Rosuvastatin is relatively hydrophilic, with lower passive permeability and lower oral absorption (50%) than fluvastatin, simvastatin, pitavastatin, and cerivastatin, which are lipophilic and have high oral absorption (98%, 65-85%, 80%, and 98%, respectively) (Mukhtar et al, 2005;Shitara and Sugiyama, 2006).…”

Section: Discussionsupporting

confidence: 89%

“…However, the clopidogrel-mediated DDIs with OATP1B1 or OATP1B1/CYPs substrates are not consistent. Although rosuvastatin, simvastatin, and fluvastatin are substrates of OATP1B1, clopidogrel increased the plasma concentration of rosuvastatin (1.7-fold for AUC) but did not change those of simvastatin and fluvastatin (Ayalasomayajula et al, 2007;Pinheiro et al, 2012;Itkonen et al, 2015).…”

Section: Introductionmentioning

confidence: 88%

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Clarification of the Mechanism of Clopidogrel-Mediated Drug-Drug Interaction in a Clinical Cassette Small-dose Study and Its Prediction Based on In Vitro Information

Kim

Yoshikado

Ieiri

et al. 2016

Drug Metabolism and Disposition

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Clopidogrel is reported to be associated with cerivastatin-induced rhabdomyolysis, and clopidogrel and its metabolites are capable of inhibiting CYP2C8 and OATP 1B1 in vitro. The objective of the present study was to identify the mechanism of clopidogrelmediated drug-drug interactions (DDIs) on the pharmacokinetics of OATP1B1 and/or CYP2C8 substrates in vivo. A clinical cassette small-dose study using OATPs, CYP2C8, and OATP1B1/CYP2C8 probe drugs (pitavastatin, pioglitazone, and repaglinide, respectively) with or without the coadministration of either 600 mg rifampicin (an inhibitor for OATPs), 200 mg trimethoprim (an inhibitor for CYP2C8), or 300 mg clopidogrel was performed, and the area under the concentration-time curve (AUC) ratios (AUCRs) for probe substrates were predicted using a static model. Clopidogrel increased the AUC of pioglitazone (2.0-fold) and repaglinide (3.1-fold) but did not significantly change the AUC of pitavastatin (1.1-fold). In addition, the AUC of pioglitazone M4, a CYP2C8-mediated metabolite of pioglitazone, was reduced to 70% of the control by coadministration of clopidogrel. The predicted AUCRs using the mechanism-based inhibition of CYP2C8 by clopidogrel acyl-b-glucuronide were similar to the observed AUCRs, and the predicted AUCR (1.1) of repaglinide using only the inhibition of OATP1B1 did not reach the observed AUCR (3.1). In conclusion, a single 300 mg of clopidogrel mainly inhibits CYP2C8-mediated metabolism by clopidogrel acylb-glucuronide, but its effect on the pharmacokinetics of OATP1B1 substrates is negligible. Clopidogrel is expected to have an effect not only on CYP2C8 substrates, but also dual CYP2C8/OATP1B1 substrates as seen in the case of repaglinide.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 88%

Clarification of the Mechanism of Clopidogrel-Mediated Drug-Drug Interaction in a Clinical Cassette Small-dose Study and Its Prediction Based on In Vitro Information

Kim

Yoshikado

Ieiri

et al. 2016

Drug Metabolism and Disposition

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“…Second, as simvastatin acid is very sensitive to the inhibition of both CYP3A4 and OATP1B1, clopidogrel is not a clinically relevant inhibitor of CYP3A4 or OATP1B1 in vivo. Third, the previously reported clopidogrel-rosuvastatin interaction is most likely explained by some other mechanism than OATP1B1 inhibition, as rosuvastatin is less sensitive to changes in OATP1B1 activity than simvastatin acid (Pasanen et al, 2007;Pinheiro et al, 2012). Lastly, this study suggests that the contribution of CYP2C8 to the metabolism of simvastatin is of very small importance in vivo.…”

Section: Discussionmentioning

confidence: 63%

“…Recent studies showed that concurrent use of clopidogrel in standard therapeutic doses increases the AUC of rosuvastatin by 50-100% in patients (Pinheiro et al, 2012;Remsberg et al, 2013). Rosuvastatin is excreted principally unchanged, and only a small proportion of rosuvastatin is eliminated via metabolism by CYP2C9 (Neuvonen et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…The antiplatelet drug clopidogrel and its metabolites inhibit CYP2C8, CYP3A4, and OATP1B1 in vitro (Floyd et al, 2012;Tamraz et al, 2013;Tornio et al, 2014). Additionally, clopidogrel was reported to increase the plasma concentration of rosuvastatin in humans, suggesting that clopidogrel could be an inhibitor of OATP1B1 also in vivo (Pinheiro et al, 2012;Remsberg et al, 2013). Furthermore, clopidogrel was shown to markedly increase the exposure to repaglinide, which is a substrate for CYP2C8, CYP3A4, and OATP1B1 (Kajosaari et al, 2005;Tornio et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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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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Ticagrelor Increases Exposure to the Breast Cancer Resistance Protein Substrate Rosuvastatin

Lehtisalo,

Tarkiainen,

Neuvonen

et al. 2023

Clin Pharma and Therapeutics

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Ticagrelor and rosuvastatin are often used concomitantly after atherothrombotic events. Several cases of rhabdomyolysis during concomitant ticagrelor and rosuvastatin have been reported, suggesting a drug‐drug interaction. We showed recently that ticagrelor inhibits breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 1B1, 1B3, and 2B1 ‐mediated rosuvastatin transport in vitro. The aim of this study was to investigate the effects of ticagrelor on rosuvastatin pharmacokinetics in humans. In a randomized, cross‐over study, nine healthy volunteers ingested a single dose of 90 mg ticagrelor or placebo, followed by a single 10 mg dose of rosuvastatin 1 hour later. Ticagrelor 90 mg or placebo were additionally administered 12, 24, and 36 hours after their first dose. Ticagrelor increased rosuvastatin area under the plasma concentration‐time curve (AUC) and peak plasma concentration 2.6‐fold (90% confidence intervals 1.8‐3.8 and 1.7‐4.0, P=0.001 and P=0.003), and prolonged its half‐life from 3.1 to 6.6 hours (P=0.009). Ticagrelor also decreased the renal clearance of rosuvastatin by 11% (3‐19%, P=0.032). The N‐desmethylrosuvastatin:rosuvastatin AUC0‐10 h ratio remained unaffected by ticagrelor. Ticagrelor had no effect on the plasma concentrations of the endogenous OATP1B substrates glycodeoxycholate 3‐O‐glucuronide, glycochenodeoxycholate 3‐O‐glucuronide, glycodeoxycholate 3‐O‐sulfate, and glycochenodeoxycholate 3‐O‐sulfate, or the sodium‐taurocholate cotransporting polypeptide substrate taurocholic acid. These data indicate that ticagrelor increases rosuvastatin concentrations more than two‐fold in humans, probably mainly by inhibiting intestinal BCRP. Since the risk for rosuvastatin‐induced myotoxicity increases along with rosuvastatin plasma concentrations, using ticagrelor concomitantly with high doses of rosuvastatin should be avoided.

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Pharmacokinetic interactions between clopidogrel and rosuvastatin: Effects on vascular protection in subjects with coronary heart disease

Cited by 37 publications

References 35 publications

Clarification of the Mechanism of Clopidogrel-Mediated Drug-Drug Interaction in a Clinical Cassette Small-dose Study and Its Prediction Based on In Vitro Information

Clarification of the Mechanism of Clopidogrel-Mediated Drug-Drug Interaction in a Clinical Cassette Small-dose Study and Its Prediction Based on In Vitro Information

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

Ticagrelor Increases Exposure to the Breast Cancer Resistance Protein Substrate Rosuvastatin

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