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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 106-111 |
| Number of pages | 6 |
| Journal | Journal of Clinical Pharmacology |
| Volume | 38 |
| Issue number | 2 |
| State | Published - Feb 1998 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Pharmacology (medical)
- Pharmacology, Toxicology and Pharmaceutics(all)
Cite this
Protease inhibitors as inhibitors of human cytochromes P450 : High risk associated with ritonavir. / Von Moltke, Lisa L.; Greenblatt, David J.; Grassi, Jeffrey M.; Granda, Brian W.; Duan, Su Xiang; Fogelman, Steven M.; Daily, Johanna P.; Harmatz, Jerold S.; Shader, Richard I.
In: Journal of Clinical Pharmacology, Vol. 38, No. 2, 02.1998, p. 106-111.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Protease inhibitors as inhibitors of human cytochromes P450
T2 - High risk associated with ritonavir
AU - Von Moltke, Lisa L.
AU - Greenblatt, David J.
AU - Grassi, Jeffrey M.
AU - Granda, Brian W.
AU - Duan, Su Xiang
AU - Fogelman, Steven M.
AU - Daily, Johanna P.
AU - Harmatz, Jerold S.
AU - Shader, Richard I.
PY - 1998/2
Y1 - 1998/2
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=0031931102&partnerID=8YFLogxK
M3 - Article
VL - 38
SP - 106
EP - 111
JO - Journal of Clinical Pharmacology
JF - Journal of Clinical Pharmacology
SN - 0091-2700
IS - 2
ER -