Urinary Metabolites of Rifabutin, a New Antimycobacterial Agent, in Human Volunteers

Cocchiara, G; Benedetti, Μ. Strolin; Vicario, Gian Piero; Ballabio, Marzia; Gioia, B.; Vioglio, Sergio; Vigevani, A.

doi:10.3109/00498258909042314

Cited by 28 publications

(10 citation statements)

References 11 publications

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“…The precise metabolic pathways for rifabutin are controversial, with in vitro data supporting both microsomal 22 and nonmicrosomal metabolism. 23 In this study, we found that indinavir increased 25-desacetyl rifabutin concentrations more than rifabutin concentrations (Table II).…”

Section: Discussionmentioning

confidence: 99%

“…However, rifampin is a potent inducer of cytochrome P450 (CYP) enzymes [9][10][11][12][13][14] and is therefore contraindicated in patients taking HIV protease inhibitors because it may reduce protease inhibitor concentrations by as much as 80% to 90%. 22 The primary routes of metabolism are desacetylation and oxidation; however, the CYP450 enzymes involved (in vitro) have not been elucidated, and metabolism may be nonmicrosomal. [15][16][17][18] In 3 large placebo-controlled trials in HIV-infected patients, rifabutin substantially decreased the incidence of MAC bacteremia and reduced the signs and symptoms associated with disseminated disease.…”

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confidence: 99%

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Steady‐state pharmacokinetic interaction of modified‐dose indinavir and rifabutin

Hamzeh

2003

Clin Pharma and Therapeutics

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Increasing indinavir's dose to 1000 mg every 8 hours when coadministered with rifabutin at a reduced dose of 150 mg daily compensates for rifabutin induction of indinavir metabolism. Rifabutin concentrations were still higher than with rifabutin alone despite a 50% reduction of rifabutin dose, which is the current recommendation when these 2 drugs are combined. The clinical significance of the increase in rifabutin and 25-desacetyl rifabutin concentrations is not known.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Steady‐state pharmacokinetic interaction of modified‐dose indinavir and rifabutin

Hamzeh

2003

Clin Pharma and Therapeutics

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“…Autoinduction Properties ofRifibutin and Rifampicin in Humans RIB is metabolized in humans to more than 20 compounds (44). Besides the unchanged drug, 25-O-deacetyl RIB has been identified in human urine together with four metabolites produced by oxidative pathways: 31-OH-RIB, 32-OH-RIB, 32-OH-25-O-deacetyl-RIB and 25-0-deacetyl-RIB-piperidine-N-oxide.…”

Section: Inducton Properties Of Rifampicin and Rifabutin In Animalsmentioning

confidence: 99%

Induction and autoinduction properties of rifamycin derivatives: a review of animal and human studies.

Benedetti¹,

Dostert²

1994

Environ Health Perspect

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Animal studies have demonstrated that the mouse and rabbit are far more responsive to the inductive properties of rifamycin derivatives than the rat and guinea pig. The rat hepatic cytochrome P450 system seems to be resistant to the action of rifampicin unless very high doses are used. Mouse hepatic microsomal mixed-function oxidase activity is markedly increased by repeated dosing with rifampicin, whereas administration of rifabutin may be ineffective. In humans, both rifampicin and rifabutin are extensively metabolized and induce their own metabolism. The induced metabolic pathways remain essentially unknown. Under autoinduction conditions, the elimination half-life of rifampicin decreases, whereas that of rifabutin is not altered. Although the effects of repeated administration of rifampicin and rifabutin on the various forms of cytochrome P450 in humans have not been extensively examined, there is convincing evidence that the P4503A subfamily is induced by either drug, whereas the P4501 A subfamily and P4502D6 do not appear to be affected by rifampicin. Limited reliable information is available concerning the induction of human glucuronyltransferase activities by rifampicin and rifabutin which, however, do not seem to influence zidovudine glucuronide formation in healthy subjects.

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“…!3] These are 25-0-deacetylrifabutin and 31-hydroxy-rifabutin. In addition to these 2 metabolites, at least 4 other metabolites have been identified in the urine:[58,59] 32-hydroxyrifabutin, 32-hydroxy-25-0-deacetyl-rifabutin, 25-0-deacetyl-rifabutin-N-oxide, and 30-hydroxy-rifabutin. In addition, other metabolites of undetermined structure have been isolated.…”

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confidence: 98%

Clinical Pharmacokinetics of Rifabutin

Skinner

Blaschke

1995

Clinical Pharmacokinetics

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The clinical effectiveness of rifabutin for prophylaxis of disseminated Mycobacterium avium complex infection has recently been demonstrated in HIV-positive patients with low CD4 counts. Rifabutin is a newly marketed, semisynthetic antimycobacterial agent similar to rifampicin (rifampin) in structure and activity. However, rifabutin has important pharmacokinetic differences compared with rifampicin. Rifabutin has relatively low oral bioavailability; about 20% after single dose administration. With long term administration rifabutin induces its own metabolism and the metabolism of some other drugs. The elimination half-life of rifabutin is long (45 hours) but, as a result of a very large volume of distribution (> 9 L/kg), average plasma concentrations remain relatively low after repeated administration of standard doses. In vitro rifabutin is more active against M. avium-intracellulare complex and at least as active against M. tuberculosis as rifampicin. In vivo the advantage of rifabutin is less apparent due to its lower plasma concentrations at equivalent doses. Adverse effects are unusual at the recommended oral dosage of 300 mg/day, but become common as the total daily dose approaches 1 g. Dose-limiting toxicity consists of a polyarthralgia/arthritis syndrome, possibly complicated by uveitis. More clinical studies are needed to establish the role of rifabutin in combination therapy for M. avium-intracellulare complex and other mycobacterial infections.

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Urinary Metabolites of Rifabutin, a New Antimycobacterial Agent, in Human Volunteers

Cited by 28 publications

References 11 publications

Steady‐state pharmacokinetic interaction of modified‐dose indinavir and rifabutin

Steady‐state pharmacokinetic interaction of modified‐dose indinavir and rifabutin

Induction and autoinduction properties of rifamycin derivatives: a review of animal and human studies.

Clinical Pharmacokinetics of Rifabutin

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