Ritonavir CYP3A4/5/7 substrate

Of aU the HIV protease inhibitors, saquinavir is the least potent inhibitor of CYP3A4. Nonetheless, it is recommended that the drug not be coadministered with ergot derivatives, triazolam, midazolam, or other CYP3A4 substrates with a low therapeutic index. Saquinavir clearance is increased with CYP3A4 induction thus coadministration of rifampin, nevirapine, or efavirenz lowers saquinavir concentrations and should be avoided. The effect of nevirapine or efavirenz on saquinavir may be partially or completely reversed with ritonavir. 

Ritonavir decreases pethidine (meperidine) and increases norpethidine levels, which may possibly increase toxicity on long-term use. Similarly, ritonavir and other protease inhibitors increase buprenorphine levels. Ritonavir may increase the metabolism of morphine, and decrease the metabolism of dextropropoxyphene (CYP3A4 substrate) and tramadol or other CYP2D6 substrates (such as codeine). 

Fosamprenavir (fAPV) Lexiva 700-mg tabs ARV-na ive pts fAPV 1,400 mg bid or fAPV 700 mg + RTV 1 00 mg bid PS-experienced pts fAPV 700 mg + RTV 1 00 mg bid Co-admin is tra tion w/EFV fAPV 700 mg + RTV 1 00 mg bid or fAPV 1400 mg + RTV 300 mg qday Child-Pugh Dose Class 5-8 700 mg bid 9-12 Not recommended Ritonavir should not be used in patients with hepatic impairment None Skin rash diarrhea, nausea and vomiting headache hyperlipidemia LFT elevation hyperglycemia fat maldistribution increased bleeding episodes in patients with hemophilia CYP3A4 inhibitor, inducer, and substrate... 

Trazodone is a substrate but not a potent inhibitor of CYP3A4. As a result, combining trazodone with potent inhibitors of CYP3A4, such as ritonavir or ketoconazole, may lead to substantial increases in trazodone levels. 

Saquinavir is subject to extensive first-pass metabolism by CYP3A4, and functions as a CYP3A4 inhibitor as well as a substrate thus, it should be used with the same precautions regarding drug-drug interactions as the other protease inhibitors. Coadministration with the CYP3A4 inhibitor ritonavir has been adopted by clinicians because inhibition of first-pass metabolism of saquinavir by ritonavir can result in higher—and thus more efficacious—levels of saquinavir (see Table 49-3 and Table 49-4). Liver function tests should be monitored if saquinavir is coadministered with delavirdine. 

The advent of highly active antiretroviral therapy (HAART) to minimize the rapid development of viral resistance in the treatment of HIV infection may result in multiple drug interactions (110-113). Both the nonnucleoside reverse transcriptase inhibitors and the protease inhibitors are substrates and inhibitors of some CYP enzymes, and some act as inducers as well (110,111). The major effects are on the CYP3A isoforms, and this has been used to advantage to increase concentrations of some HIV drugs. For example, delavirdine is a mechanism-based irreversible inhibitor of CYP3A4, and thereby is used to increase exposure to protease inhibitors (114). Ritonavir is a protease inhibitor, but it is used primarily for its ability as a potent inhibitor of CYP3A4 to increase concentrations of other protease inhibitors (115). 

Sildenafil is contraindicated in patients who are taking organic nitrates, for their metabolism is blocked and severe and acute hypotension result. Patients with recent stroke or myocardial infarction or whose blood pressure is known to be < 90/50 mmHg should not use it. Sildenafil is a substrate for the P450 isoenzyme CYP3A4 (and to a lesser extent CYP2C9) which gives scope for interaction with inhibitors or inducers of this system. The metabolic inhibitors erythromycin, saquinavir and ritonavir (protease inhibitors used for AIDS), and cimetidine, for example, produce substantial rises in the plasma concentration of sildenafil. 

Tipranavir is administered with a booster dose of ritonavir. The tipranavir/ritonavir must be taken with other anti-HIV drugs. Normal dosing consists of 500 mg of tipranavir and 200 mg of ritonavir twioe daily. Whereas tipranavir is a substrate for CYP3A4, in the presence of ritonavir very little metabolism of tipranavir occurs, although the combination leads to induction of P-glyooprotein, which may increase the bioavailability of tipranavir. By itself, tipranavir exhibits increased absorption in the presence of food. Initially, tipranavir was available as the disodium salt, but it was demonstrated that the free acid, in the form of a self-emulsifying drug delivery system (soft-gel capsules), showed improved bioavailability. 

The human immunodeficiency virus (HIV) protease inhibitor ritonavir is an inhibitor of both CYP3A4 and P-glycoprotein. Substrates of these two elimination pathways are particularly susceptible to interactions with ritonavir. 

Protease inhibitors are inhibitors and substrates of the eytochrome P450 isoenzyme CYP3A4, with ritonavir being the most potent inhibitor and saquinavir the least (see Antivirals , (p.772)). They probably interact by inhibiting each other s gut (pre-absorption) and hepatie (post-absorption) metabolism, so resulting in increased absorption and deereased elimination. A meehanism involving inhibition of P-glyeoprotein may also be involved. ... 

Trazodone is a substrate for CYP3A4 and inhibitors of this enzyme such as ritonavir and indinavir may inhibit its metabolism, leading to substantial increases in trazodone plasma concentrations with the potential for adverse effects. ... 

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