title: Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir.
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.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: L L
authors.initials: LL
authors.lastname: von Moltke
authors.forename: D J
authors.initials: DJ
authors.lastname: Greenblatt
authors.forename: J M
authors.initials: JM
authors.lastname: Grassi
authors.forename: B W
authors.initials: BW
authors.lastname: Granda
authors.forename: S X
authors.initials: SX
authors.lastname: Duan
authors.forename: S M
authors.initials: SM
authors.lastname: Fogelman
authors.forename: J P
authors.initials: JP
authors.lastname: Daily
authors.forename: J S
authors.initials: JS
authors.lastname: Harmatz
authors.forename: R I
authors.initials: RI
authors.lastname: Shader
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D012307:Risk Factors; D019438:Ritonavir / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D003577:Cytochrome P-450 Enzyme System; D019438:Ritonavir