Evaluation of cytochrome P450 3A4‑mediated drug‑drug interaction potential between P2Y12 inhibitors and statins

Abstract

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 ic 50 and inhibitor constant (K i) values of 68.74 and 26.47 µM, respectively; prasugrel also inhibited cYP3a4, activity with ic 50 and K i 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 , auc 0-∞ and t 1/2 ] 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.

Clinical Translation of Targeted Protein Degraders

“…Preclinically, ARV-110 was shown to exhibit low MDCK II permeability and was a potent inhibitor of P-gp, BCRP, and BSEP efflux transporters in membrane vesicle assays. 52 As a result, drug-drug interaction studies with transporter substrates are ongoing clinically. The physicochemistry of PROTACs may make them liable to transporter inhibition, or to act as substrates, and these results suggest that related bifunctional degraders should be profiled for these effects early in their development.…”

“…ARV‐110 appears to degrade AR in patients, as shown through histological staining. Preclinically, ARV‐110 was shown to exhibit low MDCK II permeability and was a potent inhibitor of P‐gp, BCRP, and BSEP efflux transporters in membrane vesicle assays 52 . As a result, drug–drug interaction studies with transporter substrates are ongoing clinically.…”