Hepatic. Seven metabolites have been identified, one glucuronide conjugate and six oxidative metabolites. In vitro studies indicate that cytochrome P-450 3A4 (CYP3A4) is the major enzyme responsible for formation of the oxidative metabolites.
Indinavir has known human metabolites that include 1-[4-Benzyl-2-hydroxy-5-[(2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino]-5-oxopentyl]-N-tert-butylpiperazine-2-carboxamide, 1-[4-benzyl-2-hydroxy-5-[(2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino]-5-oxopentyl]-N-tert-butyl-4-[(1-oxidopyridin-1-ium-3-yl)methyl]piperazine-2-carboxamide, 1-[4-benzyl-5-[(2,3-dihydroxy-2,3-dihydro-1H-inden-1-yl)amino]-2-hydroxy-5-oxopentyl]-N-tert-butyl-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide, and N-tert-butyl-1-[2-hydroxy-5-[(2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino]-4-[(4-hydroxyphenyl)methyl]-5-oxopentyl]-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide.
Some degree of serum aminotransferase elevations occur in a high proportion of patients taking indinavir containing antiretroviral regimens. Moderate-to severe elevations in serum aminotransferase levels (>5 times the upper limit of normal) are found in 3% to 10% of patients, although rates may be higher in patients with HIV-HCV coinfection. These elevations are usually asymptomatic and self-limited and can resolve even with continuation of the medication. Indinavir therapy also causes increases in unconjugated (indirect) and total serum bilirubin that can manifest as jaundice in up to 10% of patients. These elevations are due to the inhibition of UDP glucuronyl transferase, the hepatic enzyme responsible for conjugation of bilirubin that is deficient in Gilbert syndrome. The hyperbilirubinemia is usually mild, the increases averaging 0.3-0.5 mg/dL, but can be more marked in patients with Gilbert syndrome with increases of 1.5 mg/dL or more and clinical jaundice. The jaundice, however, is not indicative of hepatic injury. Clinically apparent acute liver injury due to indinavir is rare. The few cases that have been reported have arisen after 1 to 8 weeks of starting indinavir, and the pattern of serum enzyme elevations has varied from hepatocellular to cholestatic. Signs of hypersensitivity (fever, rash, eosinophilia) are rare as is autoantibody formation. The acute liver injury due to indinavir is usually self-limited, but it can be severe, and isolated cases of acute liver failure have been reported. In addition, initiation of indinavir based highly active antiretroviral therapy can lead to exacerbation of an underlying chronic hepatitis B or C in coinfected individuals, typically arising 2 to 12 months after starting therapy and associated with a hepatocellular pattern of serum enzyme elevations and increases in serum levels of hepatitis B virus (HBV) DNA or hepatitis C virus (HCV) RNA. Indinavir therapy has not been clearly linked to lactic acidosis and acute fatty liver that is reported in association with several nucleoside analogue reverse transcriptase inhibitors.
