Induction of Fluconazole Metabolism by Rifampin: <i>In Vivo</i> Study in Humans

Apseloff, Glen; Hilligoss, Donald M.; Gardner, Mark; Henry, Eugenia B.; Inskeep, Philip B.; Gerber, Nicholas; Lazar, Jeffrey D.

doi:10.1002/j.1552-4604.1991.tb03718.x

Cited by 65 publications

(13 citation statements)

References 12 publications

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“…Unlike ketoconazole, fluconazole is excreted mainly unchanged in the urine and so its elimination is not as markedly induced by rifampicin. Nevertheless, Apseloff et al (1991) have found a 19% decrease in the half-life of fluconazole, with no change in AUC, in 16 healthy male volunteers who received fluconazole on days 1 and 22 and rifampicin on days 8 to 27. The same workers have also suggested an increased dosage of fluconazole for the treatment of concomitant fungal infections in tuberculosis patients receiving rifampicin.…”

Section: Fluconazolementioning

confidence: 93%

Pharmacokinetic Drug Interactions with Rifampicin

Venkatesan

1992

Clinical Pharmacokinetics

123

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Rifampicin, an antituberculosis drug, is usually administered for 4 to 12 months with other antituberculosis drugs or medications from other classes. A potential for drug interactions often exists because rifampicin is a potent inducer of hepatic drug metabolism, as evidenced by a proliferation of smooth endoplasmic reticulum and an increase in the cytochrome P450 content in the liver. The induction is a highly selective process and not every drug metabolised via oxidation is affected. Case reports and studies have demonstrated enhanced metabolism of several drugs; most of these interactions are clinically important. At the start of rifampicin treatment, and again at the end, clinicians must check the dosages of any accompanying medications with which rifampicin may potentially interact. Monitoring of clinical response and blood drug concentrations is essential to adjust the drug dosage during rifampicin therapy. Rifampicin also interacts with cholephils such as bilirubin and bromosulphthalein. Its pharmacokinetics are reported to be altered by ethambutol, p-aminosalicylic acid (through its excipient component), ketoconazole, cyclosporin, clofazimine, probenecid and phenobarbital through one or other of the following mechanisms--impaired absorption of rifampicin, competition between the drug and rifampicin for hepatic uptake and altered hepatic metabolism of rifampicin. Most interactions affecting rifampicin have been relatively minor or are not expected to alter its therapeutic efficacy.

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Section: Fluconazolementioning

confidence: 93%

Pharmacokinetic Drug Interactions with Rifampicin

Venkatesan

1992

Clinical Pharmacokinetics

123

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“…Concomitant administration of rifampicin (and possibly rifabutin) with ketoconazole, itraconazole and, to a lesser extent, fluconazole, increase the metabolic clearance and decrease the AVC of the azoles; therapeutic failures of fungal infection have been reported (Apseloff et al 1991;Brass et al 1982;Doble et al 1988;Tucker et al 1992). Presumably, because ketoconazole is a substrate for CYP3A4 (table 11), rifampicin and other inducers increase ketoconazole metabolism.…”

Section: Rifampicin and Rifabutinmentioning

confidence: 99%

Pharmacokinetic Drug Interactions with Antimicrobial Agents

Gillum

Israel

Polk

1993

Clinical Pharmacokinetics

129

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As new classes of antimicrobial drugs have become available, and new uses found for older drugs, pharmacokinetic drug interactions with antimicrobials have become more common. Macrolides, fluoroquinolones, rifamycins, azoles and other agents can interact adversely with commonly used drugs, usually by altering their hepatic metabolism. The mechanisms by which antimicrobial agents alter the biotransformation of other drugs is increasingly understood to reflect inhibition or induction of specific cytochrome P450 enzymes. Macrolides inhibit cytochrome P450IIIA4 (CYP3A4), which appears to be the most common metabolic enzyme in the human liver and is involved in the metabolism of many drugs, including cyclosporin, warfarin and terfenadine. Some quinolones preferentially inhibit CYP1A2, which is partially responsible for methylxanthine metabolism. Azoles appear to be broad spectrum inhibitors of cytochromes P450. Within each of these antibiotic classes, there is a rank order of inhibitory potency towards specific cytochrome P450 enzymes. By contrast, rifampicin (rifampin) and rifabutin induce several cytochromes P450, including CYP3A4, and hence can enhance the metabolism of many other drugs. By using in vitro preparations of human enzymes it is increasingly possible to predict those antibiotics that will adversely affect the metabolism of other drugs. In addition, between-patient variability in frequency of interaction may relate to differences in the activities of these enzymes. Although the mechanisms and scope of these interactions are becoming well characterised, the remaining challenge is how to best inform the clinician so that the undesirable consequences of interactions may be prevented.

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“…Posaconazole is primarily metabolised via UGT pathways (phase II enzymes), and therefore it is likely that induction of UGT pathways and CYP3A4 by phenytoin contributed to the interaction 137 . Although fluconazole undergoes little CYP‐mediated metabolism, drugs such as rifampin and its derivatives can accelerate its biotransformation, which significantly reduces its systemic exposure 160 …”

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confidence: 99%

Clinically relevant drug interactions of current antifungal agents

Gubbins

Heldenbrand

2010

Mycoses

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SummaryAntifungal agents are often prescribed in critically ill patients who are receiving many other medications. When using systemic antifungals, clinicians may possess susceptibility data and they are typically aware of the potential toxicity of these agents. However, the myriad of potential drugs that antifungal agents can interact with is daunting and can be confusing. This article reviews the pharmacokinetic properties of antifungal agents and their clinically relevant drug interactions. The antifungal agents differ markedly in their pharmacokinetic properties and in how they interact with other medicines. The amphotericin B formulations interact with other medicines primarily by reducing their renal elimination or producing additive toxicities. The azoles interact with other medicines primarily by inhibiting biotransformation or by affecting drug distribution and elimination. The echinocandins have the lowest propensity to interact with other medicines. The clinical relevance of antifungal-drug interactions varies substantially. While certain interactions are benign and result in little or no untoward clinical outcomes, others can produce significant toxicity or compromise efficacy if not properly managed through monitoring and dosage adjustment. However, certain interactions produce significant toxicity or compromise efficacy to such an extent that they cannot be managed and the particular combination of antifungal and interacting medicine should be avoided.

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Induction of Fluconazole Metabolism by Rifampin: In Vivo Study in Humans

Cited by 65 publications

References 12 publications

Pharmacokinetic Drug Interactions with Rifampicin

Pharmacokinetic Drug Interactions with Rifampicin

Pharmacokinetic Drug Interactions with Antimicrobial Agents

Clinically relevant drug interactions of current antifungal agents

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