Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir.

Article Details

Citation

von Moltke LL, Greenblatt DJ, Grassi JM, Granda BW, Duan SX, Fogelman SM, Daily JP, Harmatz JS, Shader RI

Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir.

J Clin Pharmacol. 1998 Feb;38(2):106-11.

PubMed ID
9549640 [ View in PubMed
]
Abstract

Four protease inhibitor antiviral agents (ritonavir, indinavir, nelfinavir, saquinavir) were evaluated as in vitro inhibitors of the activity of six human cytochromes using an in vitro model based on human liver microsomes. Ritonavir was a highly potent inhibitor of P450-3A activity (triazolam hydroxylation), having inhibitory potency slightly less than ketoconazole. Indinavir was also a potent 3A inhibitor, while nelfinavir and saquinavir were less potent. Ritonavir had high inhibition potency against cytochrome P450-2C9 (tolbutamide hydroxylation), -2C19 (S-mephenytoin hydroxylation), and -2D6 (dextromethorphan O-demethylation and desipramine hydroxylation), while the other protease inhibitors had one or more orders of magnitude lower inhibitory activity against these reactions. None of the protease inhibitors had important inhibitory potency against P450-1A2 (phenacetin O-deethylation) or -2E1 (chlorzoxazone hydroxylation). Thus, among available protease inhibitors, ritonavir carries the highest risk of incurring drug interactions due to inhibition of cytochrome P450 activity.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
RitonavirCytochrome P450 2C19ProteinHumans
No
Inducer
Details
RitonavirCytochrome P450 2D6ProteinHumans
Unknown
Substrate
Inhibitor
Details
Drug Interactions
DrugsInteraction
Interactions
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