Effect of coadministration of rifampicin on the pharmacokinetics of linezolid: clinical and animal studies
Abstract Background Combination therapy of linezolid (LZD) and rifampicin (RFP) may be more effective than monotherapy for treating gram-positive bacterial infections, but several studies have suggested that RFP decreases LZD exposures, thereby increasing the risk of therapeutic failure and emergenc...
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doaj-a8e9927bbe194dd084a21c054444aed22020-11-25T02:51:58ZengBMCJournal of Pharmaceutical Health Care and Sciences2055-02942018-11-01411910.1186/s40780-018-0123-1Effect of coadministration of rifampicin on the pharmacokinetics of linezolid: clinical and animal studiesSatsuki Hashimoto0Kyoko Honda1Kohei Fujita2Yuka Miyachi3Kazuya Isoda4Ko Misaka5Yukio Suga6Satoshi Kato7Hiroyuki Tsuchiya8Yukio Kato9Masaki Okajima10Takumi Taniguchi11Tsutomu Shimada12Yoshimichi Sai13Department of Hospital Pharmacy, University Hospital, Kanazawa UniversityDepartment of Hospital Pharmacy, University Hospital, Kanazawa UniversityDepartment of Hospital Pharmacy, University Hospital, Kanazawa UniversityDepartment of Hospital Pharmacy, University Hospital, Kanazawa UniversityDepartment of Hospital Pharmacy, University Hospital, Kanazawa UniversityDepartment of Hospital Pharmacy, University Hospital, Kanazawa UniversityFaculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Science, Kanazawa UniversityDepartment of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa UniversityDepartment of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa UniversityFaculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Science, Kanazawa UniversityIntensive Care Unit, University Hospital, Kanazawa UniversityIntensive Care Unit, University Hospital, Kanazawa UniversityDepartment of Hospital Pharmacy, University Hospital, Kanazawa UniversityDepartment of Hospital Pharmacy, University Hospital, Kanazawa UniversityAbstract Background Combination therapy of linezolid (LZD) and rifampicin (RFP) may be more effective than monotherapy for treating gram-positive bacterial infections, but several studies have suggested that RFP decreases LZD exposures, thereby increasing the risk of therapeutic failure and emergence of LZD-resistant strains. However, the mechanism of the drug-drug interaction between LZD and RFP is unknown. Methods We conducted a prospective, open-label, uncontrolled clinical study in Japanese patients receiving LZD and RFP to evaluate the effect of coadministered RFP on the concentration of LZD. In animal study in rats, the influence of coadministered RFP on the pharmacokinetics of LZD administered intravenously or orally was examined. Intestinal permeability was investigated with an Ussing chamber to assess whether coadministered RFP alters the absorption process of LZD in the intestine. Results Our clinical study indicated that multiple doses of RFP reduced the dose-normalized trough concentration of LZD at the first assessment day by an average of 65%. In an animal study, we found that multiple doses of RFP significantly decreased the area under the concentration-time curve, the maximum concentration and the bioavailability of orally administered LZD by 48%, 54% and 48%, respectively. In contrast, the pharmacokinetics of intravenously administered LZD was unaffected by the RFP pretreatment. However, investigation of the intestinal permeability of LZD revealed no difference in absorptive or secretory transport of LZD in the upper, middle and lower intestinal tissues between RFP-pretreated and control rats, even though RFP induced gene expression of multidrug resistance protein 1a and multidrug resistance-associated protein 2. Conclusions Therapeutic drug monitoring may be important for avoiding subtherapeutic levels of LZD in the combination therapy. The drug-drug interaction between LZD and RFP may occur only after oral administration of LZD, but is not due to any change of intestinal permeability of LZD. Trial registration UMIN, UMIN000004322. Registered 4 October 2010.http://link.springer.com/article/10.1186/s40780-018-0123-1LinezolidRifampicinDrug-drug interactionTherapeutic drug monitoringPharmacokineticsAdverse event |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Satsuki Hashimoto Kyoko Honda Kohei Fujita Yuka Miyachi Kazuya Isoda Ko Misaka Yukio Suga Satoshi Kato Hiroyuki Tsuchiya Yukio Kato Masaki Okajima Takumi Taniguchi Tsutomu Shimada Yoshimichi Sai |
spellingShingle |
Satsuki Hashimoto Kyoko Honda Kohei Fujita Yuka Miyachi Kazuya Isoda Ko Misaka Yukio Suga Satoshi Kato Hiroyuki Tsuchiya Yukio Kato Masaki Okajima Takumi Taniguchi Tsutomu Shimada Yoshimichi Sai Effect of coadministration of rifampicin on the pharmacokinetics of linezolid: clinical and animal studies Journal of Pharmaceutical Health Care and Sciences Linezolid Rifampicin Drug-drug interaction Therapeutic drug monitoring Pharmacokinetics Adverse event |
author_facet |
Satsuki Hashimoto Kyoko Honda Kohei Fujita Yuka Miyachi Kazuya Isoda Ko Misaka Yukio Suga Satoshi Kato Hiroyuki Tsuchiya Yukio Kato Masaki Okajima Takumi Taniguchi Tsutomu Shimada Yoshimichi Sai |
author_sort |
Satsuki Hashimoto |
title |
Effect of coadministration of rifampicin on the pharmacokinetics of linezolid: clinical and animal studies |
title_short |
Effect of coadministration of rifampicin on the pharmacokinetics of linezolid: clinical and animal studies |
title_full |
Effect of coadministration of rifampicin on the pharmacokinetics of linezolid: clinical and animal studies |
title_fullStr |
Effect of coadministration of rifampicin on the pharmacokinetics of linezolid: clinical and animal studies |
title_full_unstemmed |
Effect of coadministration of rifampicin on the pharmacokinetics of linezolid: clinical and animal studies |
title_sort |
effect of coadministration of rifampicin on the pharmacokinetics of linezolid: clinical and animal studies |
publisher |
BMC |
series |
Journal of Pharmaceutical Health Care and Sciences |
issn |
2055-0294 |
publishDate |
2018-11-01 |
description |
Abstract Background Combination therapy of linezolid (LZD) and rifampicin (RFP) may be more effective than monotherapy for treating gram-positive bacterial infections, but several studies have suggested that RFP decreases LZD exposures, thereby increasing the risk of therapeutic failure and emergence of LZD-resistant strains. However, the mechanism of the drug-drug interaction between LZD and RFP is unknown. Methods We conducted a prospective, open-label, uncontrolled clinical study in Japanese patients receiving LZD and RFP to evaluate the effect of coadministered RFP on the concentration of LZD. In animal study in rats, the influence of coadministered RFP on the pharmacokinetics of LZD administered intravenously or orally was examined. Intestinal permeability was investigated with an Ussing chamber to assess whether coadministered RFP alters the absorption process of LZD in the intestine. Results Our clinical study indicated that multiple doses of RFP reduced the dose-normalized trough concentration of LZD at the first assessment day by an average of 65%. In an animal study, we found that multiple doses of RFP significantly decreased the area under the concentration-time curve, the maximum concentration and the bioavailability of orally administered LZD by 48%, 54% and 48%, respectively. In contrast, the pharmacokinetics of intravenously administered LZD was unaffected by the RFP pretreatment. However, investigation of the intestinal permeability of LZD revealed no difference in absorptive or secretory transport of LZD in the upper, middle and lower intestinal tissues between RFP-pretreated and control rats, even though RFP induced gene expression of multidrug resistance protein 1a and multidrug resistance-associated protein 2. Conclusions Therapeutic drug monitoring may be important for avoiding subtherapeutic levels of LZD in the combination therapy. The drug-drug interaction between LZD and RFP may occur only after oral administration of LZD, but is not due to any change of intestinal permeability of LZD. Trial registration UMIN, UMIN000004322. Registered 4 October 2010. |
topic |
Linezolid Rifampicin Drug-drug interaction Therapeutic drug monitoring Pharmacokinetics Adverse event |
url |
http://link.springer.com/article/10.1186/s40780-018-0123-1 |
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