Differential inhibition of cytochrome P450 3A4, 3A5 and 3A7 by five human immunodeficiency virus (HIV) protease inhibitors in vitro.

Article Details

Citation

Granfors MT, Wang JS, Kajosaari LI, Laitila J, Neuvonen PJ, Backman JT

Differential inhibition of cytochrome P450 3A4, 3A5 and 3A7 by five human immunodeficiency virus (HIV) protease inhibitors in vitro.

Basic Clin Pharmacol Toxicol. 2006 Jan;98(1):79-85. doi: 10.1111/j.1742-7843.2006.pto_249.x.

PubMed ID
16433896 [ View in PubMed
]
Abstract

The effects of five HIV protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir and saquinavir) on cytochrome P450 (CYP) 3A4, 3A5 and 3A7 activities were studied in vitro using testosterone 6beta-hydroxylation in recombinant CYP3A4, CYP3A5 and CYP3A7 enzymes. The protease inhibitors showed differential inhibitory effects on the three CYP3A forms. Ritonavir and saquinavir were non-selective and preferential inhibitors of CYP3A4 and CYP3A5 (K(i) 0.03 microM and 0.6-0.8 microM for ritonavir and saquinavir, respectively), and weaker inhibitors of CYP3A7 (K(i) 0.6 microM and 1.8 microM, respectively). Nelfinavir was a potent and non-selective inhibitor of all three CYP3A forms (K(i) 0.3-0.4 microM). Amprenavir and indinavir preferentially inhibited CYP3A4 (K(i) 0.1 microM and 0.2 microM, respectively), with weaker inhibitory effects on CYP3A5 (K(i) 0.5 microM and 2.2 microM, respectively) and CYP3A7 (K(i) 2.1 microM and 10.6 microM, respectively). In conclusion, significant differences exist in the inhibitory potency of protease inhibitors for different CYP3A forms. Ritonavir, nelfinavir, saquinavir and amprenavir seem to be prone to drug-drug interactions by inhibiting both CYP3A4 and CYP3A5. Especially nelfinavir and ritonavir also have a potential to inhibit foetal CYP3A7-mediated drug metabolism and some endogenous pathways that may be crucial to normal foetal development, while indinavir has the lowest potential to inhibit CYP3A5 and CYP3A7.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
AmprenavirCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inhibitor
Inducer
Details
IndinavirCytochrome P450 3A5ProteinHumans
Unknown
Substrate
Inhibitor
Details
IndinavirCytochrome P450 3A7ProteinHumans
Unknown
Inhibitor
Details
NelfinavirCytochrome P450 3A4ProteinHumans
No
Substrate
Inhibitor
Details
NelfinavirCytochrome P450 3A5ProteinHumans
No
Substrate
Inhibitor
Details
NelfinavirCytochrome P450 3A7ProteinHumans
No
Inhibitor
Details
SaquinavirCytochrome P450 3A5ProteinHumans
Unknown
Substrate
Inhibitor
Details
SaquinavirCytochrome P450 3A7ProteinHumans
Unknown
Substrate
Inhibitor
Details
Drug Interactions
DrugsInteraction
Voriconazole
Delavirdine
The serum concentration of Voriconazole can be increased when it is combined with Delavirdine.