Effect of coadministration of rifampicin on the pharmacokinetics of linezolid: clinical and animal studies
| Autor: | Satoshi Kato, Tsutomu Shimada, Ko Misaka, Yoshimichi Sai, Yukio Suga, Satsuki Hashimoto, Kohei Fujita, Hiroyuki Tsuchiya, Takumi Taniguchi, Yuka Miyachi, Masaki Okajima, Kazuya Isoda, Kyoko Honda, Yukio Kato |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Adverse event Combination therapy 030106 microbiology lcsh:RS1-441 Pharmacology (nursing) Pharmacology Therapeutic drug monitoring lcsh:Pharmacy and materia medica 03 medical and health sciences chemistry.chemical_compound Pharmacokinetics Oral administration medicine Pharmacology (medical) Adverse effect Rifampicin Intestinal permeability medicine.diagnostic_test business.industry lcsh:RM1-950 fungi Linezolid medicine.disease lcsh:Therapeutics. Pharmacology chemistry business medicine.drug Research Article Drug-drug interaction |
| Zdroj: | Journal of Pharmaceutical Health Care and Sciences Journal of Pharmaceutical Health Care and Sciences, Vol 4, Iss 1, Pp 1-9 (2018) |
| ISSN: | 2055-0294 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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