Key result
Co-administration of ticagrelor or prasugrel with statins markedly inhibited CYP3A4 activity by promoting its proteasomal degradation, significantly altering the pharmacokinetics of the probe drug dapsone compared to either drug alone.
Why the study?
Co-administration of ticagrelor or prasugrel with statins in acute coronary syndrome has drawn attention, prompting evaluation of potential CYP3A4-mediated drug interactions to guide safe and effective clinical use.
Does co-administration of P2Y12 inhibitors (ticagrelor or prasugrel) with statins inhibit CYP3A4 activity in vitro and in vivo?
Does co-administration of P2Y12 inhibitors (ticagrelor or prasugrel) with statins inhibit CYP3A4 activity in vitro and in vivo?
Co-administration of ticagrelor or prasugrel with simvastatin synergistically inhibits CYP3A4 activity, potentially increasing the risk of statin-induced toxicity such as rhabdomyolysis and long QT syndrome.
Ticagrelor and prasugrel inhibit CYP3A4 in vitro; leaves open clinical relevance for statin co-administration.
Ticagrelor and prasugrel are widely used in the treatment of acute coronary syndrome. The co‑administration of ticagrelor or prasugrel with statins in the clinic has already drawn a great deal of attention. The aims of the present study were to evaluate the safety and effectiveness, and guide the rational clinical use of, co‑administration of ticagrelor or prasugrel with statins by exploring potential drug interactions. The activity of cytochrome P450 family 3 subfamily A member 4 (CYP3A4) was detected, and its protein and mRNA expression levels were measured in a rat model and liver microsomes to evaluate the effect of the drug combinations on CYP3A4. High performance liquid chromatography, western blotting and reverse transcription‑quantitative PCR were used to perform these investigations. The in vitro experiments suggested that ticagrelor inhibited CYP3A4 activity, with IC50 and inhibitor constant (Ki) values of 68.74 and 26.47 µM, respectively; prasugrel also inhibited CYP3A4, activity with IC50 and Ki values of 16.24 and 10.84 µM, respectively. When different dosages of the antagonists were combined with simvastatin or atorvastatin, the metabolic rate was reduced more effectively at higher dosages when compared with lower dosages. An in vivo pharmacokinetic study demonstrated that the co‑administration of ticagrelor or prasugrel with simvastatin caused an increase in the principal pharmacokinetic parameters of the probe drug dapsone [area under the concentration/time curve (AUC)0‑t, AUC0‑∞ and t1/2] and a decrease in clearance compared with ticagrelor, prasugrel or simvastatin alone. Additional studies confirmed that the two investigated P2Y12 inhibitors were able to decrease the protein level of CYP3A4 by promoting protein degradation through the proteasomal pathway, and combination with statins such as simvastatin had a synergistic inhibitory effect on CYP3A4 activity. These results demonstrated that the co‑administration of P2Y12 inhibitors with simvastatin could markedly inhibit the activity of CYP3A4, and these findings will further influence the assessment of the clinical effectiveness (reduced or enhanced efficacy) and safety (bleeding and rhabdomyolysis) in the clinic.
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Zhang et al. (2019) studied Drug-drug interaction (n=76). Ticagrelor or prasugrel co-administered with statins (simvastatin or atorvastatin) vs. Ticagrelor alone, prasugrel alone, simvastatin alone, or control was evaluated on CYP3A4 activity and pharmacokinetic parameters of probe drug dapsone (p=<0.05). Co-administration of ticagrelor or prasugrel with statins markedly inhibited CYP3A4 activity by promoting its proteasomal degradation, significantly altering the pharmacokinetics of the probe drug dapsone compared to either drug alone.
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