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Comparative Study
. 2025 Jun;25(2):127-140.
doi: 10.1007/s40268-025-00504-x. Epub 2025 May 13.

Safety Evaluation of Contezolid (MRX-I) Versus Linezolid in Sprague-Dawley Rats

Liping Wei #  1   2   3 , Min Hong #  2   3 , Min Lu  3 , Yimin Qian  2   3 , Qingmei Li  3 , Naping Tang  2 , Hua Li  2 , Yan Chang  4 , Yunliang Qiu  5
Affiliations
Comparative Study

Safety Evaluation of Contezolid (MRX-I) Versus Linezolid in Sprague-Dawley Rats

Liping Wei et al. Drugs R D. 2025 Jun.

Abstract

Background & objectives: Contezolid (MRX-I) is a novel ortho-fluorophenyl dihydropyridone developed by MicuRx Pharmaceuticals, Inc. It has been approved for the treatment of drug-resistant Gram-positive bacterial infections with relatively lower toxicity than other oxazolidinones such as linezolid. However, the toxicity profile has not yet been completely revealed. The aim of this study was to disclose the toxicity of contezolid in Sprague-Dawley (SD) rats and compare its toxicity profile with linezolid in a standard 4-week toxicity study.

Methods: In this study, SD rats were orally administered with contezolid at doses of 20, 100, or 200/300 mg/kg/day for 28 consecutive days followed by a 28-day recovery period. Linezolid at doses of 100 or 200 mg/kg/day served as a comparator. Clinical observations, body weight, food consumption, hematology, clinical chemistry, urinalysis, and histopathological examinations were conducted.

Results: All females in the 200 mg/kg/day linezolid group were subjected to unscheduled death due to myelosuppression within the first 2 weeks. No abnormalities were noted in the 200 mg/kg/day contezolid group, and the dose level was escalated to 300 mg/kg/day from day 15. Myelosuppression or myelosuppression-associated effects were comparable between the 300-mg/kg/day contezolid group and the 100-mg/kg/day linezolid group. The 'no observed adverse effect level' (NOAEL) of contezolid was determined to be 100 mg/kg/day (with an average AUC0-24 h of 268.4 μg*h/mL). At the same dose levels, the toxicity of contezolid was significantly lower than that of linezolid.

Conclusion: These findings demonstrate that contezolid exhibits a favorable safety profile compared with linezolid in this 4-week repeated-dose toxicity study in rats.

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Conflict of interest statement

Declarations. Funding: This study was sponsored by MicuRx Pharmaceuticals Inc. The funder had no role in the study design, data analysis, or interpretation of results. Conflict of Interest: InnoStar was contracted by MicuRx Pharmaceuticals Inc. to conduct this study. However, the authors declare that this contractual relationship did not influence the study design, data collection, analysis, or interpretation of results. The authors also confirm that they have no financial investments in MicuRx Pharmaceuticals Inc. Ethics Approval: All protocols and procedure were ethically approved and monitored by the Institutional Animal Care and Use Committee (IACUC) in Shanghai Innostar Bio-tech Co., Ltd. (reference number: IACUC-2009-r-008). Consent to Participate: Not applicable. Consent for Publication: Not applicable. Data Availability Statement: All data supporting the findings are included in the article. The detailed datasets and raw records are available from Shanghai Innostar Bio-tech Co., Ltd upon reasonable request. Code Availability Statement: Not applicable. Authors’ Contributions: Conception and study design: YC and YLQ. Data acquisition: NPT and HL. Analysis and interpretation: ML, YMQ, and QML. Drafting of the manuscript: LPW and MH. All authors read and approved the final version of the manuscript.

Figures

Fig. 1
Fig. 1
Changes of body weights and food consumption in Sprague-Dawley rats treated with MRX-I or linezolid. The results are expressed as the mean ± standard deviation. Data were statistically analyzed using a one-way ANOVA followed by Dunnett T test for pairwise comparison. *p ≤ 0.05, **p ≤ 0.01 when compared with vehicle control group
Fig. 2
Fig. 2
Organ weights of spleen and thymus in Sprague-Dawley rats treated with MRX-I or linezolid. The results are expressed as the mean ± standard deviation. Data were statistically analyzed using a one-way ANOVA followed by Dunnett T test for pairwise comparison. *p ≤ 0.05, **p ≤ 0.01 when compared with vehicle control group
Fig. 3
Fig. 3
Histological changes after hematoxylin–eosin (H–E) staining of target organs in Sprague-Dawley rats. The organs were fixed with 10% neutral formalin and subjected to paraffin embedding, sectioning, H–E staining, and histopathological examination. A Typical images of sternal bone marrow from vehicle control animal and linezolid-treated animals are presented in the left panel and right panels, respectively. The arrows indicate inhibition in the sternal bone marrow proliferation. B Typical images of thymus from vehicle control animal and linezolid-treated animals are presented in the left panel and right panels, respectively. The arrows indicate thymus atrophy with lymphocytes necrosis. C Typical images of mesentery lymph node from vehicle control animal and linezolid-treated animals are presented in the left panel and right panels, respectively. The arrows indicate mesentery lymph node atrophy. D Typical images of hair follicle from vehicle control animal and linezolid-treated animals are presented in the left panel and right panels, respectively. The arrows indicate follicular atrophy
Fig. 4
Fig. 4
Toxicokinetic (TK) profile of MRX-I in Sprague-Dawley rats over a 4-week treatment period. Plasma concentrations of MRX-I were determined using a validated LC-MS/MS method with a linearity range of 10.0–10,000 ng/mL. Toxicokinetic parameters were derived using noncompartmental methods with Phoenix WinNonlin software. A TK profile of MRX-I-treated groups on day 1; B TK profile of MRX-I-treated groups on day 14; C TK profile of MRX-I-treated groups on day 28; D AUC0–24 h values and dose levels of 200, 100, and 20 mg/kg/day on day 1 were subjected to logarithmic transformation followed by linear regression analysis. Regression equation was calculated as y = 1.1538x + 7.1403, with correlation coefficient (r2) of 0.8727
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