Key result
Atorvastatin co-administration boosts systemic cilostazol exposure ~3-fold and prolongs arterial occlusion time.
Why the study?
Cilostazol and atorvastatin are often co-prescribed, but the drug-drug interaction potential on pharmacokinetics and anti-thrombotic properties of cilostazol is not well understood.
Does atorvastatin co-administration alter the pharmacokinetics and anti-thrombotic properties of cilostazol in male Wistar rats?
Does atorvastatin co-administration alter the pharmacokinetics and anti-thrombotic properties of cilostazol in male Wistar rats?
Effect estimate: Css(max) increased by ~1.75 fold; AUC by ~3.0 fold
Atorvastatin co-administration significantly increases systemic exposure to cilostazol and enhances its anti-thrombotic effect on artery occlusion time in rats, indicating a potential clinically relevant drug-drug interaction.
ATV co-administration alters CLZ pharmacokinetics and anti-thrombotic effects in rats; hypothesis-generating for human DDI and leaves clinical relevance open.
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.
No takes yet. Share an insight, caveat, or question.
Vats et al. (2012) studied this question. Atorvastatin co-administration with cilostazol vs. Cilostazol alone was evaluated on Systemic exposure to cilostazol (Css(max) and AUC) (Css(max) increased by ~1.75 fold; AUC by ~3.0 fold). Atorvastatin co-administration significantly increased systemic exposure to cilostazol (Css(max) by ~1.75 fold; AUC by ~3.0 fold) and delayed artery occlusion time in male Wistar rats.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: