Drug–drug interaction study to assess the effects of atorvastatin co‐administration on pharmacokinetics and anti‐thrombotic properties of cilostazol in male Wistar rats

Abstract

Cilostazol (CLZ) and atorvastatin (ATV) are often co-prescribed to treat conditions such as peripheral arterial disease. In the present study, the drug-drug interaction potential of multi-dose ATV co-administration with CLZ on both pharmacokinetics and the anti-thrombotic property of CLZ is demonstrated. The pharmacokinetic parameters of CLZ (6 mg/kg, twice daily) were determined in male Wistar rats after 7 days co-administration with ATV (5 mg/kg, once daily) in order to assess the interaction potential between CLZ and ATV on chronic treatment. In vitro metabolic inhibition and everted gut sac studies were conducted to elucidate the mechanism of this interaction. Pharmacodynamic drug-drug interaction was evaluated on anti-thrombotic models including time to occlusion, platelet aggregation and rat tail bleeding time. A validated LC-MS/MS method was employed simultaneously to quantify both ATV and CLZ in rat plasma matrix. A statistically significant increase in systemic exposure (Css(max) by ~1.75 fold; AUC by ~3.0 fold) to CLZ was observed in ATV pre-treated rats. In vitro metabolism studies using liver microsomes (RLM and HLM) demonstrated statistically significant inhibition of CLZ metabolism when co-incubated with ATV. No change in apparent permeability of CLZ was observed in the presence of ATV. Atorvastatin showed a significant delay in artery occlusion time without altering CLZ's bleeding time and platelet aggregation profile. Collectively the results of these studies provide metabolic insight into the nature of drug-drug interaction between the selected drugs. Co-administration with ATV influences the pharmacokinetics and anti-thrombotic property of CLZ. A thorough clinical investigation is required before extrapolation of data to humans.

Simultaneous and comprehensive in vivo analysis of cytochrome P450 activity by using a cocktail approach in rats

“…There are multiple approaches for studying drug–drug interactions that focus on CYP activity, including in vitro studies using liver microsomes, in vivo pharmacokinetic studies using animals such as rats, and clinical studies in healthy subjects or patients that investigate the pharmacokinetics of CYP isoform substrates . In addition, recent studies have used a modeling and simulation technique that predicts the results of drug–drug interactions in humans on the basis of findings of in vitro studies .…”

Organic Anion–Transporting Polypeptide and Efflux Transporter–Mediated Hepatic Uptake and Biliary Excretion of Cilostazol and Its Metabolites in Rats and Humans

“…Indeed, rifampicin could affect the hepatic uptake of many drugs, such as pitavastatin (K i ¼ 0.5 mM for OATP1B1) 31 and bosentan (IC 50 ¼ 3.2 and 1.6 mM for OATP1B1 and OATP1B3, respectively). 32 The free telmisartan serum concentration might be too low to influence cilostazol. Moreover, we investigated the biliary excretion of cilostazol and its metabolites using an in situ rat liver perfusion study.…”

Aspirin and Probenecid Inhibit Organic Anion Transporter 3–Mediated Renal Uptake of Cilostazol and Probenecid Induces Metabolism of Cilostazol in the Rat

“…In rats, nearly 43% of cilostazol and metabolites are excreted in urine (Vats et al, 2012). The majority of the metabolite is OPC-13213 (Mallikaarjun et al, 1999a).…”

“…Seventy-two hours after an oral dose, 43% of cilostazol and its metabolites are excreted in the urine (Vats et al, 2012). OPC-13213 [3,4-dihydro-6-[4-[1-(trans-4-hydroxycyclohexyl)-1H-tetrazol-5-yl] butoxy]-2-(1H)-quinolinone] is the main metabolite of cilostazol in urine, and unchanged cilostazol is nearly 1% (Bramer and Forbes, 1999).…”