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

Abstract

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.

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

“…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).…”

“…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).…”

Clopidogrel Markedly Increases Plasma Concentrations of CYP2C8 Substrate Pioglitazone

“…Both cerivastatin and repaglinide are substrates for CYP2C8, as well as for CYP3A4 and OATP1B1 (Mück, 1998;Kantola et al, 1999;Backman et al, 2002;Wang et al, 2002;Niemi et al, 2003;Kajosaari et al, 2005;Niemi et al, 2005). According to a recent study, clopidogrel does not cause a significant change in the disposition of simvastatin or its active acid form in humans (Itkonen et al, 2015). As simvastatin is among the most sensitive drugs to changes in CYP3A4 and OATP1B1 activity (Neuvonen et al, 1998;Backman et al, 2000;Ichimaru et al, 2001;Prueksaritanont et al, 2003;Pasanen et al, 2006;Niemi et al, 2011), clopidogrel is unlikely to have a clinically relevant effect on CYP3A4 or OATP1B1 activity (Itkonen et al, 2015).…”

“…As simvastatin is among the most sensitive drugs to changes in CYP3A4 and OATP1B1 activity (Neuvonen et al, 1998;Backman et al, 2000;Ichimaru et al, 2001;Prueksaritanont et al, 2003;Pasanen et al, 2006;Niemi et al, 2011), clopidogrel is unlikely to have a clinically relevant effect on CYP3A4 or OATP1B1 activity (Itkonen et al, 2015). These findings indicate that inhibition of CYP2C8 by clopidogrel acyl-b-D-glucuronide is the main mechanism of the clopidogrel-cerivastatin and clopidogrel-repaglinide interactions (Floyd et al, 2012;Tornio et al, 2014;Itkonen et al, 2015). This conclusion is also supported by a recent case report, which suggests that clopidogrel significantly reduces the metabolic clearance of the CYP2C8 substrate anticancer agent paclitaxel (Bergmann et al, 2016).…”

“…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).…”