Differential inhibition of cytochrome P450 3A4, 3A5 and 3A7 by five human immunodeficiency virus (HIV) protease inhibitors in vitro.
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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
Drug Enzyme Kind Organism Pharmacological Action Actions Amprenavir Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorInducerDetails Indinavir Cytochrome P450 3A5 Protein Humans UnknownSubstrateInhibitorDetails Indinavir Cytochrome P450 3A7 Protein Humans UnknownInhibitorDetails Nelfinavir Cytochrome P450 3A4 Protein Humans NoSubstrateInhibitorDetails Nelfinavir Cytochrome P450 3A5 Protein Humans NoSubstrateInhibitorDetails Nelfinavir Cytochrome P450 3A7 Protein Humans NoInhibitorDetails Saquinavir Cytochrome P450 3A5 Protein Humans UnknownSubstrateInhibitorDetails Saquinavir Cytochrome P450 3A7 Protein Humans UnknownSubstrateInhibitorDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareVoriconazoleDelavirdine The serum concentration of Voriconazole can be increased when it is combined with Delavirdine.