Induction of both P‐glycoprotein and specific cytochrome P450 by aspirin eventually does not alter the antithrombotic effect of clopidogrel

Abstract

Exposure to Clopidogrel Through Modulation of P-Glycoprotein but Does Not Alter Its Antithrombotic Activity" by Oh et al., which elucidated the effect of aspirin coadministration on the pharmacokinetics/ pharmacodynamics of clopidogrel in healthy subjects. 1 The results of their study demonstrated that the clopidogrel area under the concentration-time curve (AUC) significantly decreased, but the AUC of H4 remained unchanged and RPI increased after aspirin administration. In addition, the plasma level of miR-27a, a microRNA involved in regulation of P-glycoprotein (P-gp) expression, was significantly increased after aspirin administration. However, no change in plasma MDR1 mRNA or miR-451 was observed. The authors proposed that coadministration of low-dose aspirin decreased the systemic exposure to clopidogrel, but the antithrombotic effect of clopidogrel was not affected.Previous study has indicated that prolonged use of aspirin may reduce the intestinal absorption of clopidogrel by inducing P-gp expression in human and rat intestinal cells. 2 And a similar trend in the PK profile of clopidogrel was also observed in the study of Oh et al., but the decrements were not statistically significant due to an insufficient dose of aspirin. Although the exposure to clopidogrel was lowered, the level of H4 was not changed after aspirin administration. For these seemingly contradictory results, the authors give two explanations. One is that the decrement in exposure to clopidogrel might not be sufficient to alter the exposure to H4. The other is bioactivation of effluxed clopidogrel to H4 in the intestine by CYP3A4. But we consider that there is another more reasonable explanation for this phenomenon. In a study presented previously, we demonstrated that low-dose aspirin significantly increased the activity of CYP2C19 and CYP3A4 in healthy volunteers. 3 As 15% of the clopidogrel converted to the biologically active thiol metabolite via a two-step CYP-dependent oxidative pathway, even small changes in activities of CYP isoenzymes seem to influence formation of its active metabolite. 4 Given the fact that oxidation of clopidogrel is catalyzed by CYP2C19, CYP3A4, and CYP3A5, 5 increased CYP2C19 and CYP3A4 activity by low-dose aspirin likely increases the activation of clopidogrel, thus enhancing the efficacy of this antiplatelet prodrug. So aspirin coadministration eventually does not alter the exposure of H4 by the combined two effects of aspirin. Further studies are needed to confirm the clinical significance regarding aspirin-increased CYP2C19 and CYP3A4 activity on clopidogrel activation. ACKNOWLEDGMENTS

Interpretation of Drug Interaction Using Systemic and Local Tissue Exposure Changes

“…Nevertheless, the clinically relevant DDIs, leading to the loss of efficacy or advent of toxicity, have been increasing because polypharmacotherapy is becoming progressively more common. In addition, the underlying mechanisms of DDIs have been variously interpreted, which makes it difficult to explain a correlation of PK and PD changes in DDIs, as well as to predict their clinical relevance [25][26][27][28][29]. In other words, if the alteration of a PD effect is negligible even through a PK change of a victim drug was observed later, the DDI would be ignored at the time.…”