Clinical pharmacokinetics of metronidazole: a systematic review and meta-analysis

Abstract

Metronidazole (MTZ) is used in various clinical settings; however, its pharmacokinetics may vary across patient populations due to physiological and pathological differences. Understanding these variations is important for personalized dosing and optimization of therapeutic outcomes. This study aimed to systematically review clinical pharmacokinetic studies of MTZ and perform a meta-analysis of the area under the concentration-time curve (AUC). AUC was selected for meta-analysis as it provides a direct and comprehensive measure of total drug exposure over time, facilitating standardized comparisons across populations. Four databases, including PubMed, ScienceDirect, Cochrane Library, and Google Scholar, were screened for pharmacokinetic studies on MTZ using systematic search strategies until July 2024. Out of 1,882 articles identified in the literature search, only 67 studies that fulfilled eligibility criteria were included in this systematic review. A meta-analysis of AUC was performed using random-effects models, with heterogeneity assessed by I² statistic. Effect sizes (pooled AUC) were compared across populations and visually presented with their corresponding 95% confidence intervals. Meta-analysis revealed significant differences in AUC across populations, with substantial heterogeneity among studies. This study provides a comprehensive evaluation of the MTZ pharmacokinetic profile across diverse patient populations. The findings emphasize the importance of tailored dosing strategies and support evidence-based clinical decision-making for optimizing the safety and efficacy of MTZ.

Keywords: AUC; Cmax; clearance; metronidazole; pharmacokinetics.

Fig 1

Literature search strategy.

Fig 2

PRISMA flow diagram.

Fig 3

Forest plot of AUC for MTZ 250 mg single dose. The figure displays the mean of AUC and sample size (black square and its size) and 95% CI (the horizontal lines) for adult healthy population across studies, with the blue diamond at the bottom showing the overall pooled AUC estimate and its CI. The vertical red dashed line is a reference for the overall pooled AUC estimate, allowing for a visual comparison across studies. In this figure, the pooled AUC for the 250 mg single dose is 48.27 (95% CI: 41.09–55.45), and I² of 0% indicates low heterogeneity across the studies.

Fig 4

Forest plot of AUC for MTZ 400 mg single dose. The figure displays the mean of AUC and sample size (black square and its size) and 95% CI (the horizontal lines) for adult healthy population across studies, with the blue diamond at the bottom showing the overall pooled AUC estimate and its CI. The vertical red dashed line is a reference for the overall pooled AUC estimate, allowing for a visual comparison across studies. In this figure, the pooled AUC for the 400 mg single dose is 92.83 (95% CI: 83.99–101.67), and I² of 79.3% indicates moderate heterogeneity across the studies.

Fig 5

Forest plot of AUC for MTZ 500 mg single oral dose. The figure displays the mean of AUC and sample size (black square and its size) and 95% CI (the horizontal lines) for adult healthy population across studies, with the blue diamond at the bottom showing the overall pooled AUC estimate and its CI. The vertical red dashed line is a reference for the overall pooled AUC estimate, allowing for a visual comparison across studies. In this figure, the pooled AUC for the 500 mg single dose is 110.43 (95% CI: 92.81–128.04), and I² of 94.1% indicates high heterogeneity across the studies.

Fig 6

Forest plot of AUC for MTZ 500 mg single IV dose. The figure displays the mean of AUC and sample size (black square and its size) and 95% CI (the horizontal lines) for adult healthy population across studies, with the blue diamond at the bottom showing the overall pooled AUC estimate and its CI. The vertical red dashed line is a reference for the overall pooled AUC estimate, allowing for a visual comparison across studies. In this figure, the pooled AUC for the 500 mg single dose is 116.69 (95% CI: 99.34–134.05), and I² of 79.2% indicates moderate heterogeneity across the studies.

Fig 7

Forest plot of AUC for MTZ 1000 mg single dose. The figure displays the mean of AUC and sample size (black square and its size) and 95% CI (the horizontal lines) for adult healthy population across studies, with the blue diamond at the bottom showing the overall pooled AUC estimate and its CI. The vertical red dashed line is a reference for the overall pooled AUC estimate, allowing for a visual comparison across studies. In this figure, the pooled AUC for the 1,000 mg single dose is 254.63 (95% CI: 220–289.3), and I² of 72.3% indicates moderate heterogeneity across the studies.

Fig 8

Forest plot of AUC for MTZ 1,500 mg (Soreide and Solhaug) and 2,000 mg (Loft and Lau) single dose. The figure displays the mean of AUC and sample size (black square and its size) and 95% CI (the horizontal lines) for adult healthy population across studies, with the blue diamond at the bottom showing the overall pooled AUC estimate and its CI. The vertical red dashed line is a reference for the overall pooled AUC estimate, allowing for a visual comparison across studies. In this figure, the pooled AUC is 528.9 (95% CI: 445.54–612.27), and I² of 89.7% indicates moderate heterogeneity across the studies.

Fig 9

Forest plot of AUC for MTZ 500 mg single dose in Schistosomiasis-induced liver disease (45, 50) and class A and B Child-Pugh liver cirrhosis (50). The figure displays the mean of AUC and sample size (black square and its size) and 95% CI (the horizontal lines) for adult healthy population across studies, with the blue diamond at the bottom showing the overall pooled AUC estimate and its CI. The vertical red dashed line is a reference for the overall pooled AUC estimate, allowing for a visual comparison across studies. In this population, the pooled AUC is 127.73 (95% CI: 116.95–138.5), and I² of 0% indicates low heterogeneity across the studies.

Fig 10

Forest plot of AUC for MTZ 500 mg single dose in severe liver impairment. The figure displays the mean of AUC and sample size (black square and its size) and 95% CI (the horizontal lines) for adult healthy population across studies, with the blue diamond at the bottom showing the overall pooled AUC estimate and its CI. The vertical red dashed line is a reference for the overall pooled AUC estimate, allowing for a visual comparison across studies. In this population, the pooled AUC is 199.29 (95% CI: 138.63–259.94), and I² of 83% indicates moderate heterogeneity across the studies.

Fig 11

Forest plot of dose-normalized AUC for MTZ in patients with moderate to severe renal impairment.

Fig 12

Forest plot of dose-normalized AUC for MTZ in patients with renal impairment on dialysis.

Fig 13

Forest plot of dose-normalized AUC for MTZ in pregnant women.

Fig 14

Forest plot of dose-normalized AUC values for each population subgroup. The figure displays dose-normalized AUC values (and 95% confidence intervals [CIs]) for individual population groups: Healthy, Enteric Diseases, Hepatic Impairment, Pregnant Women, Renal Impairment, and Renal Impairment on Dialysis. Each effect size is represented by a circle. The horizontal lines indicate the 95% CIs for each population’s AUC estimate. The vertical dashed line represents the overall pooled AUC estimate of the healthy population, allowing for a visual comparison across populations. Non-overlapping or minimally overlapping CIs suggest meaningful differences between populations. This visual comparison allows for an intuitive assessment of variability across groups.