Effect of ponatinib on the metabolism of cariprazine in vitro and in vivo and the underlying mechanism

Cariprazine is an antipsychotic medication that has been approved for the treatment of schizophrenia and manic or mixed episodes. Patients with tumors frequently develop psychiatric disorders, necessitating the combination of antitumor and antipsychotic drugs. The objective of the present study was to examine the inhibitory impacts of three antitumor drugs (olmutinib, napabucasin and ponatinib) on the metabolism of cariprazine, and the molecular docking of cariprazine and ponatinib in relation to CYP3A4 was also evaluated. As the results, the half-maximal inhibitory concentration (IC₅₀) values of ponatinib and olmutinib in vitro were < 10 μM, whereas napabucasin was >20 μM. Among these, ponatinib exhibited the smallest IC₅₀ value. The metabolic stability of cariprazine was observed in the presence or absence of ponatinib in rat liver microsomes (RLM). The IC₅₀ shift experiments demonstrated that the inhibition of cariprazine by ponatinib was non-time-dependent. In addition, ponatinib was shown to inhibit cariprazine in a mixed manner (RLM) and a competitive manner (HLM), respectively. In the in vivo study, the co-administration of ponatinib resulted in a significant 0.35-fold increase in both AUC_(0-t) and AUC_(0-∞) for cariprazine, accompanied by a significant 0.25-fold decrease in the CL_z/F. Furthermore, the metabolites desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR) exhibited disparate increases in both AUC_(0-t) and AUC_(0-∞). Molecular docking studies had demonstrated that both cariprazine and ponatinib could engage in hydrophobic interactions with residue PHE-304 on CYP3A4. Consequently, when ponatinib is employed in conjunction with cariprazine in a clinical setting, it is imperative to assess the efficacy and adverse effects, and adjust the dosage to attain the optimal efficacy.