PROTEASE INHIBITORS AS INHIBITORS OF HUMAN CYTOCHROMES P450 - HIGH-RISK ASSOCIATED WITH RITONAVIR

Four protease inhibitor antiviral agents (ritonavir, indinavir, nelfin avir, saquinavir) were evaluated as in vitro inhibitors of the activit y of six human cytochromes using an in vitro model based on human live r microsomes. Ritonavir was a highly potent inhibitor of P450-3A activ ity (triazolam hydroxylation), having inhibitory potency slightly less than ketoconazole. Indinavir was also a potent 3A inhibitor, while ne lfinavir and saquinavir were less potent. Ritonavir had high inhibitio n potency against cytochrome P450-2C9 (tolbutamide hydroxylation), -2C 19 (S-mephenytoin hydroxylation), and -2D6 (dextromethorphan O-demethy lation adn desipramine hydroxylation), while the other protease inhibi tors had one or more orders of magnitude lower inhibitory activity aga inst these reactions. None of the protease inhibitors had important in hibitory potency against P450-1A2 (phenacetin O-deethylation) or 2E1 ( chlorzoxazone hydroxylation). Thus, among available protease inhibitor s, ritonavir carries the highest risk of incurring drug interactions d ue to inhibition of cytochrome P450 activity.