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

Abstract

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.

Comparative Study of the Effects of Antituberculosis Drugs and Antiretroviral Drugs on Cytochrome P450 3A4 and P-Glycoprotein

“…Additionally, there was no inhibitory effect on P-gp even at a concentration of 500 M in both the in vitro screening and P-gp-expressing MDCK cells (see Table S4 in the supplemental material). These results support a previous report using human primary hepatocytes (52). We also assessed the effect of LZD on CYP2B6 using an in vitro screening kit, but no inhibition was observed at 500 M (data not shown).…”

Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients

“…Rifampicin, a well-known inducer of P-glycoprotein and cytochrome P450 enzymes, decreases linezolid serum levels in critically ill patients [25]. Another study confirmed this finding in healthy volunteers [26,27]. GEBHART et al [25] suggest the interaction to be mediated by Pglycoprotein, since an in vitro study has shown that linezolid is not metabolised by cytochrome P450 enzymes [28].…”

“…P-glycoprotein polymorphism could explain some of the interpatient variation that we observed. However, in a recent study GANDELMAN et al [27] refer to unpublished data on file from Pfizer suggesting that linezolid is not a P-glycoprotein substrate. Their hypothesis for the observed interaction between linezolid and rifampicin is that a large increase in expression of CYP3A, which typically has a small contribution (0.7-10.5%) to linezolid clearance, could cause a small decrease in linezolid exposure [27].…”

Linezolid plus Rifampin as a Salvage Therapy in Prosthetic Joint Infections Treated without Removing the Implant

“…The mean (SD) durations of linezolid treatment were 77.5 (31.9) and 84. 4 (6). Therefore, use of this combination requires increasing the linezolid dosages in order to obtain the pharmacodynamic parameter that predicts the efficacy of linezolid (AUC/MIC Ͼ 80).…”