Hepatic. Of the five metabolites that have been identified, 25-O-desacetyl and 31-hydroxy are the most predominant. The former metabolite has an activity equal to the parent drug and contributes up to 10% to the total antimicrobial activity.
... Like rifampin rifabutin induces its own metabolism during multiple dosing. Rifabutin is extensively metabolized. The two major metabolites of rifabutin contribute to its antimicrobial activity. Rifabutin induces hepatic metabolism but is not as potent an inducer as is rifampin. ...
Because of its limited use, the effects of rifabutin on the liver have been less well defined than those of rifampin, but they are likely to be similar. Thus, studies on the prevention of MAC in HIV infected patients with rifabutin, minor, transient elevations in serum aminotransferase levels occurred in 3% to 8% of patients, but these abnormalities rarely required dose adjustment or discontinuation. Clinically apparent liver injury due to rifabutin has not been reported, but it is likely to be similar to rifampin in its potential for causing acute liver injury. Because rifabutin is usually given in combination with other agents used to treat HIV infection, the cause of the acute liver injury in patients on rifabutin-containing regimens may be difficult to relate to a single agent. Typically, the onset of injury due to rifampin is within 1 to 6 weeks and the serum enzyme pattern is usually hepatocellular at the onset of injury, but can cholestatic and mixed in contrast to isoniazid and pyrazinamide. Extrahepatic manifestations due to rifampin hepatotoxicity such as fever, rash, arthralgias, edema and eosinophilia are uncommon as is autoantibody formation. This potential for hepatotoxicity has not been demonstrated specifically for rifabutin, and some patients with apparent hepatotoxicity attributed to rifampin have tolerated rifabutin without recurrence of liver injury.
Rifampin is structurally related to rifabutin; rifampin is known to reduce the activity of many drugs /including aminophylline; coumarin- or indandione-derivative anticoagulants; oral antidiabetic agents; barbiturates; systemic beta-adrenergic blocking agents; chloramphenicol; clofibrate; oral estrogen-containing contraceptive; glucocorticoid and mineralocorticoid corticosteriods; cyclosporine; dapsone; diazepam; digitalis glycoside; disopyramide; estramustine; estrogens; ketoconazole; mexiletine; oxtriphylline; phenytoin; qiunidine; theophylline; tocainide; oral verapamil/ due to its hepatic enzyme inducer of the hepatic cytochrome p450 system that rifampin. Drug interaction data are unavailable for rifabutin itself; therefore, it is recommended that patients taking rifabutin concurrently with these medications be monitored since the significance of possible drug interactions is not known.
Pharmacokinetic studies with fluconazole and rifabutin show that fluconazole appears to increase the serum concentration of rifabutin; however, this is not thought to have clinical significance and rifabutin dosing does not need to be modified in patients receiving fluconazole; in addition, the pharmacokinetics of fluconazole were unchanged.
Concurrent administration with rifabutin has no significant effect on the pharmacokinetics of methadone; however, a few patients may require methadone dosage modifications if symptoms or narcotic withdrawal occur.
A mass-balance study in three healthy adult volunteers with 14C-labeled rifabutin showed that 53% of the oral dose was excreted in the urine, primarily as metabolites. About 30% of the dose is excreted in the feces.
Highly lipophilic; widely distributed with extensive intracellular tissue uptake. Rifabutin crosses the blood-brain barrier; cerebrospinal fluid concentrations are approximately 50% of the corresponding serum concentration.
