Atazanavir metabolism

Metabolism/Excretion- Atazanavir is extensively metabolized and eliminated primarily by the liver. Following a single 400 mg dose of atazanavir, 79% and 13% was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the... 

Hepatic function impairment Atazanavir is principally metabolized by the liver exercise caution when administering this drug to patients with hepatic impairment because atazanavir concentrations may be increased. 

This class of antiretrovirals may be considered the most potent therapeutic agents for HIV to date. Protease inhibitors are used in combination regimens and combinations of reverse-transcriptase inhibitors and protease inhibitors have been proven most effective to decrease viral load and prolong survival. However, the protease inhibitors generally show poor penetration into the CNS and thus have no effect on aids dementia. The present Pis available for the treatment of HIV are indinavir, ritonavir, nel-finavir, saquinavir and (fos)amprenavir, atazanavir and lopinavir (in combination with ritonavir as ritonavir improves the bioavailability of lopinavir by inhibiting its metabolism in the liver by CYP3A). 

Drugs that may inhibit cytochrome P450 metabolism of other drugs include amiodarone, androgens, atazanavir, chloramphenicol, cimetidine, ciprofloxacin, clarithromycin, cyclosporine, delavirdine, diltiazem, diphenhydramine, disulfiram, enoxacin, erythromycin, fluconazole, fluoxetine, fluvoxamine, furanocoumarins (substances in grapefruit juice), indinavir, isoniazid, itraconazole, ketoconazole, metronidazole, mexile-tine, miconazole, nefazodone, omeprazole, paroxetine, propoxyphene, quinidine, ritonavir, sulfamethizole, verapamil, voriconazole, zafirlukast, and zileuton. 

Perloff ES, Duan SX, Skolnik PR, et al. Atazanavir effects on P-glycoprotein transport and CYP3A metabolism in vitro. Drug Metab Dispos 2005 33 764-770. 

AMITRIPTYLINE PROTEASE INHIBITORS t adverse effects when amitriptyline is co-administered with ritonavir (with or without lopinavir) and possibly atazanavir Inhibition of CYP3A4-mediated metabolism. Note that SSRIs are metabolized by a number of enzymes, including CYP2C9, CYP2C19, CYP2D6 as well as CYP3A4 therefore the effect of protease inhibitors is variable Monitor closely... 

AMOXAPINE, CLOMIPRAMINE, DOXEPIN, IMIPRAMINE, NORTRIPTYLINE, TRIMIPRAMINE PROTEASE INHIBITORS Possibly t adverse effects of amoxapine with atazanavir and ritonavir Inhibition of CYP3A4-mediated metabolism of amoxapine, clomipramine and doxepin inhibition of CYP3A4-, CYP2D6-and CYP2C9-mediated metabolism of imipramine inhibition of CYP2D6-mediated metabolism of nortriptyline and trimipramine Monitor closely... 

CLARITHROMYCIN, ERYTHROMYCIN PROTEASE INHIBITORS Possibly t adverse effects of macrolide with atazanavir, ritonavir (with or without lopinavir) and saquinavir Inhibition of CYP3A4- and possibly CYP1 A2-mediated metabolism. Altered transport via P-gp may be involved. Amprenavir and indinavir are also possibly t by erythromycin Consider alternatives unless there is Mycobacterium avium intracellulare infection if combined, 1 dose by 50% (75% in the presence of renal failure with a creatinine clearance of <30mL/min)... 

RIFABUTIN PROTEASE INHIBITORS t efficacy and t adverse effects of rifabutin Inhibition of CYP3A4-mediated metabolism. Nelfinavir also competitively inhibits 2C19 1 rifabutin dose by at least 50% when given with amprenavir, indinavir or nelfinavir, and by 75% with atazanavir, ritonavir (with or without lopinavir) or tipranavir... 

EFAVIRENZ ATAZANAVIR i efficacy of efavirenz t CYP3A4-mediated metabolism of efavirenz Recommended dose of atazanavir is 400 mg when given with efavirenz 600 mg. Optimal suggested treatment is this combination plus ritonavir 100 mg daily... 

PROTEASE INHIBITORS ANTIHISTAMINES-ASTEMIZOLE, CHLORPHENAMINE, TERFENADINE Possibly t adverse effects with amprenavir, atazanavir, indinavir, ritonavir (with or without lopinavir), saquinavir and tipranavir Inhibition of CYP3A4-mediated metabolism of astemizole the risk is greatest in patients who are slow CYP2D6 metabolizers because chlorphenamine and terfenadine are also metabolized by this route Avoid co-administration... 

ATAZANAVIR INDINAVIR t efficacy and t adverse effects of indinavir t adverse effects of atazanavir, e.g. hyperbilirubinaemia t bioavailability. Inhibition of metabolism via CYP3A4 by atazanavir inhibition of UDGPT by indinavir Avoid co-administration... 

ATAZANAVIR SAQUINAVIR t efficacy and t adverse effects of saquinavir Inhibition of CYP3A4-mediated metabolism of saquinavir Monitor more closely... 

HIV-1 infection. Like indinavir, atazanavir frequently causes unconjugated hyperbilirubinemia, although this is mainly a cosmetic side effect and is not associated with other hepatotoxicity. Because atazanavir is metabolized by cytochrome (CYP3A4), concomitant administration of agents that induce this enzyme (e.g., rifampin) is contraindicated. 

Lamivudine metabolism does not involve the cytochrome P450 isoenzyme CYP3A4. Therefore it is unlikely that it will interact with drugs, such as the protease inhibitors, whieh are metabolised by this system. No pharmacokinetic interaction appears to oeeur between lamivudine and amprenavir, - atazanavir, -" indinavir, and nelfinavir. The manufacturer of lopinavir/ritonavir notes that lamivudine did not alter the pharmacokinetics of lopinavir, - and tipranavir plus low-dose ritonavir did not cause a signifieant ehange in the AUC of lamivudine. - ... 

The UK manufacturer of indinavir states that a normal (acidic) gastric pH may be necessary for optimum absorption of indinavir. Any drug that increases the gastric pH could therefore potentially reduce absorption. Altered gastric pH may also account for the interaction with atazanavir. Cimetidine probably boosts saquinavir levels by inhibiting the first-pass metabolism of saquinavir. It is not understood why ranitidine and omeprazole increase saquinavir levels. 

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