Comparison of inhibitory potential of Paxlovid and ritonavir against cytochrome P450 in human liver microsomes

抄録

Paxlovid, a combination of nirmatrelvir (NTV) and ritonavir (RTV), has been granted emergency use authorization by the US FDA for the treatment of COVID-19. The objective of this study was to compare the effects of Paxlovid and RTV on the activities of cytochrome P450 (CYP) isoforms and to predict drug-drug interaction potential using pooled human liver microsomes and LC-MS/MS system. In the direct inhibition assay, the activities of nine CYP isoforms including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 were determined. NTV inhibited CYP2E1, 2C19, and 3A4 with an IC₅₀ value of 18.0, 61.5, and 77.8 µM, respectively. RTV exhibited inhibitory potential against CYP2B6, 2C8, 2C9, 2C19, 2D6, and 2E1, with IC₅₀ values ranging from 4.60 to 11.6 µM, and exhibited very strong inhibition against 3A4 with IC₅₀ values of 0.302 µM. In NTV/RTV, the IC₅₀ values for CYP2B6, 2C8, 2C9, 2C19, 2D6, and 2E1 ranged from 4.77 to 11.7 µM, and 3A4 was 0.230 µM, showing a similar tendency to that of RTV alone. In the time-dependent inhibition (TDI) assay, as ritonavir was rapidly depleted during the microsomal incubation, the IC₅₀ values were calculated based on the remaining amount of ritonavir after the 30 min preincubation. The IC₅₀ values of RTV and NTV/RTV in CYP3A4 using midazolam as a substrate were 0.014 and 0.034 µM, respectively, and IC₅₀ shifts were 3.52- and 1.58-fold, respectively, after preincubation. In conclusion, these results suggest that NTV interferes with the metabolism of RTV by acting as a substrate of CYP3A4, showing attenuation of TDI potential of RTV.