The
protease inhibitors are extensively metabolised by cytochrome P450, particularly CYP3A4. All of the
protease inhibitors inhibit CYP3A4, with
ritonavir being the most potent inhibitor, followed by indinavir, nelfinavir,
amprenavir, and saquinavir. The
protease inhibitors therefore have the potential to interact with other drugs metabolised by CYP3A4, and are also affected by CYP3A4 inhibitors and inducers. Ritonavir and nelfinavir also affect some other cytochrome P450 isoenzymes. In addition,
protease inhibitors are substrates as well as inhibitors of P-glycoprotein. The
plasma level of
protease inhibitors is thought to be critical in maintaining
efficacy and minimising the potential for development of viral resistance. Therefore even modest reductions in levels are potentially clinically important.