Unexpected Effect of Rifampin on the Pharmacokinetics of Linezolid: In Silico and In Vitro Approaches to Explain Its Mechanism

The effect of rifampin on the steady‐state pharmacokinetics of linezolid was evaluated in an open‐label, multiple‐dose, crossover study in 16 healthy subjects. When coadministered with rifampin, area under the plasma concentration‐time curve over the dosing interval and maximum concentration values...

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Bibliographic Details
Published in:	Journal of clinical pharmacology Vol. 51; no. 2; pp. 229 - 236
Main Authors:	Gandelman, Kuan, Zhu, Tong, Fahmi, Odette A., Glue, Paul, Lian, Kenny, Obach, R. Scott, Damle, Bharat
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Publishing Ltd 01-02-2011 SAGE Publications Wiley Subscription Services, Inc
Subjects:	Acetamides - adverse effects Acetamides - pharmacokinetics Adult Anti-Infective Agents - adverse effects Anti-Infective Agents - pharmacokinetics Antibiotics, Antitubercular - adverse effects Antibiotics, Antitubercular - pharmacology Area Under Curve Bioavailability Cells, Cultured Computer Simulation Cross-Over Studies Cytochrome Cytochrome P-450 CYP3A - drug effects Cytochrome P-450 CYP3A - metabolism drug interaction Drug Interactions Enzyme Induction - drug effects Half-Life Hepatocytes - metabolism Humans Ketoconazole - pharmacology Linezolid Male Metabolism Oxazolidinones - adverse effects Oxazolidinones - pharmacokinetics pharmacokinetics rifampin Rifampin - adverse effects Rifampin - pharmacology Testosterone - metabolism Tissue Distribution Young Adult
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Summary:	The effect of rifampin on the steady‐state pharmacokinetics of linezolid was evaluated in an open‐label, multiple‐dose, crossover study in 16 healthy subjects. When coadministered with rifampin, area under the plasma concentration‐time curve over the dosing interval and maximum concentration values for linezolid were reduced approximately 32% and 21%, respectively. Time to maximum concentration and apparent volume of distribution were generally similar between treatments. The mean half‐life and apparent oral clearance were decreased for the combination treatment compared with linezolid alone. In vitro and in silico approaches were used to evaluate this interaction. In human hepatocytes, the metabolism of linezolid was increased by 1.3‐ to 1.6‐fold when the cells were pretreated with rifampin, compared with a 19‐ to 40‐fold increase in testosterone metabolism, a positive control for cytochrome P4503A activity. This increase in linezolid and testosterone metabolism was partially inhibited (∼50%) by ketoconazole. Modeling of these data using Simcyp suggested that rifampin inducible drug metabolizing enzymes, such as cytochrome P4503A, have a very minor contribution to linezolid clearance, which increases when rifampin is coadministered. The clinical significance of the decreased linezolid levels is unclear. Linezolid and rifampin administered alone or in combination was generally safe and well tolerated.
Bibliography:	ArticleID:JCPH5108 ark:/67375/WNG-V8TVN813-2 istex:D4A60233FA028539888222A3B853DECDD689C8AD ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0091-2700 1552-4604
DOI:	10.1177/0091270010366445