Metabolite Of Metronidazole Research Articles

Metronidazole: an update on metabolism, structure-cytotoxicity and resistance mechanisms.

Metronidazole, a nitroimidazole, remains a front-line choice for treatment of infections related to inflammatory disorders of the gastrointestinal tract including colitis linked to Clostridium difficile. Despite >60 years of research, the metabolism of metronidazole and associated cytotoxicity is not definitively characterized. Nitroimidazoles are prodrugs that are reductively activated (the nitro group is reduced) under low oxygen tension, leading to imidazole fragmentation and cytotoxicity. It remains unclear if nitroimidazole reduction (activation) contributes to the cytotoxicity profile, or whether subsequent fragmentation of the imidazole ring and formed metabolites alone mediate cytotoxicity. A molecular mechanism underpinning high level (>256 mg/L) bacterial resistance to metronidazole also remains elusive. Considering the widespread use of metronidazole and other nitroimidazoles, this review was undertaken to emphasize the structure-cytotoxicity profile of the numerous metabolites of metronidazole in human and murine models and to examine conflicting reports regarding metabolite-DNA interactions. An alternative hypothesis, that DNA synthesis and repair of existing DNA is indirectly inhibited by metronidazole is proposed. Prokaryotic metabolism of metronidazole is detailed to discuss new resistance mechanisms. Additionally, the review contextualizes the history and current use of metronidazole, rates of metronidazole resistance including metronidazole MDR as well as the biosynthesis of azomycin, the natural precursor of metronidazole. Changes in the gastrointestinal microbiome and the host after metronidazole administration are also reviewed. Finally, novel nitroimidazoles and new antibiotic strategies are discussed.

Determination and confirmation of metronidazole, dimetridazole, ronidazole and their metabolites in bovine muscle by LC-MS/MS

Nitroimidazoles are a class of veterinary drugs used for the treatment and prevention of certain bacterial and protozoal diseases in poultry, swine dysentery and genital trichomoniasis in cattle. Since the safety assessment of nitroimidazoles showed them to be genotoxic, carcinogenic and mutagenic, a number of nitroimidazoles have been banned for therapeutic purposes in different countries. Moreover, nitroimidazoles have also been extensively used as growth promoters in food-producing animals. Due to their efficacious improvement in meat production and feed conversion, deliberate use still exists. Therefore, the illegal use of nitroimidazoles in animal husbandry must be monitored. A sensitive method based on LC-MS/MS for the simultaneous determination and confirmation of five banned nitroimidazole drugs including metronidazole, ronidazole, dimetridazole, metronidazole-OH (metabolite of metronidazole), and 2-hydroxymethyl-1-methyl-5-nitroimidazole (metabolite of ronidazole and dimetridazole) in bovine muscle, using ronidazole-d3 as an internal standard, was developed and validated. After extraction with ethyl acetate and evaporation, the nitroimidazoles were reconstituted in petroleum ether and purified, and LC-MS/MS analysis was performed. The method was validated according to Brazilian Regulation 24/2009 (equivalent to European Union Decision 2002/657/EC). Parameters such as decision limit (CCα), detection capability (CCβ), precision, accuracy, uncertaincy and ruggedness were determined. Average accuracy of the five nitroimidazoles from bovine muscle fortified at 5 levels (0.5, 1.0, 1.5, 2.0 and 2.5 μg kg–1) ranged from 96% to 103%. The calculated CCα ranged from 0.0 to 0.17 μg kg–1; CCβ ranged from 0.08 to 0.41 μg kg–1. A complete statistical analysis was performed and the results indicate that the method is robust when subjected to day-to-day analytical variations.

Trichomonas vaginalis: metronidazole and other nitroimidazole drugs are reduced by the flavin enzyme thioredoxin reductase and disrupt the cellular redox system. Implications for nitroimidazole toxicity and resistance

Infections with the microaerophilic parasite Trichomonas vaginalis are treated with the 5-nitroimidazole drug metronidazole, which is also in use against Entamoeba histolytica, Giardia intestinalis and microaerophilic/anaerobic bacteria. Here we report that in T. vaginalis the flavin enzyme thioredoxin reductase displays nitroreductase activity with nitroimidazoles, including metronidazole, and with the nitrofuran drug furazolidone. Reactive metabolites of metronidazole and other nitroimidazoles form covalent adducts with several proteins that are known or assumed to be associated with thioredoxin-mediated redox regulation, including thioredoxin reductase itself, ribonucleotide reductase, thioredoxin peroxidase and cytosolic malate dehydrogenase. Disulphide reducing activity of thioredoxin reductase was greatly diminished in extracts of metronidazole-treated cells and intracellular non-protein thiol levels were sharply decreased. We generated a highly metronidazole-resistant cell line that displayed only minimal thioredoxin reductase activity, not due to diminished expression of the enzyme but due to the lack of its FAD cofactor. Reduction of free flavins, readily observed in metronidazole-susceptible cells, was also absent in the resistant cells. On the other hand, iron-depleted T. vaginalis cells, expressing only minimal amounts of PFOR and hydrogenosomal malate dehydrogenase, remained fully susceptible to metronidazole. Thus, taken together, our data suggest a flavin-based mechanism of metronidazole activation and thereby challenge the current model of hydrogenosomal activation of nitroimidazole drugs.

Validated Method for Determination of Eight Banned Nitroimidazole Residues in Natural Casings by LC/MS/MS with Solid-Phase Extraction

A sensitive method based on solid-phase extraction-liquid chromatography-tandem mass spectrometry interfaced with electrospray ionization (SPE-LC-MS/MS-ESI) was developed for the simultaneous determination of 8 banned nitroimidazole (NOZ) drugs including metronidazole (MNZ), ronidazole (RNZ), dimetridazole (DMZ), tinidazole, ornidazole, secnidazole, metronidazole-OH (MNZOH, the metabolite of MNZ), and 2-hydroxymethyl-1-methyl-5-nitroimidazole (HMMNI, the metabolite of RNZ and DMZ) in natural casings. After extraction with ethyl acetate and evaporation, the NOZs were reconstituted in ethyl acetate and purified on a strong cation-exchange SPE column, and then LC/MS/MS analysis was performed by positive ESI applying multiple reaction monitoring of 2 transition reactions for each compound. The method was validated according to the European Union requirements (Commission Decision 2002/657/EC). Specificity, linearity, decision limit (CCalpha), detection capability (CCbeta), accuracy, and precision were determined. Average recoveries of the 8 NOZs from natural animal casing fortified at 3 levels (0.1, 0.5, and 1 microg/kg) ranged from 87.3 to 116.5%. The calculated CCalpha for NOZs ranged from 0.029 to 0.049 microg/kg, and CCbeta ranged from 0.049 to 0.083 microg/kg. Repeatability was in the range of 3.35-10.1%, and within-laboratory reproducibility was <10.3%.

Nitroimidazole Action in Entamoeba histolytica: A Central Role for Thioredoxin Reductase

Metronidazole, a 5-nitroimidazole drug, has been the gold standard for several decades in the treatment of infections with microaerophilic protist parasites, including Entamoeba histolytica. For activation, the drug must be chemically reduced, but little is known about the targets of the active metabolites. Applying two-dimensional gel electrophoresis and mass spectrometry, we searched for protein targets in E. histolytica. Of all proteins visualized, only five were found to form adducts with metronidazole metabolites: thioredoxin, thioredoxin reductase, superoxide dismutase, purine nucleoside phosphorylase, and a previously unknown protein. Recombinant thioredoxin reductase carrying the modification displayed reduced enzymatic activity. In treated cells, essential non-protein thiols such as free cysteine were also affected by covalent adduct formation, their levels being drastically reduced. Accordingly, addition of cysteine allowed E. histolytica to survive in the presence of otherwise lethal metronidazole concentrations and reduced protein adduct formation. Finally, we discovered that thioredoxin reductase reduces metronidazole and other nitro compounds, suggesting a new model of metronidazole activation in E. histolytica with a central role for thioredoxin reductase. By reducing metronidazole, the enzyme renders itself and associated thiol-containing proteins vulnerable to adduct formation. Because thioredoxin reductase is a ubiquitous enzyme, similar processes could occur in other eukaryotic or prokaryotic organisms.

Validation of a method for the detection and confirmation of nitroimidazoles and the corresponding hydroxy metabolites in pig plasma by high performance liquid chromatography–tandem mass spectrometry

Nitroimidazoles (Ronidazole, Dimetridazole, Metronidazole, Ipronidazole) and their hydroxy metabolites are banned substances with antibiotic and anticoccidial activity. They are suspected to be carcinogenic and mutagenic. Since nitroimidazoles showed an inhomogeneous distribution and a rapid degradation in incurred muscle samples, plasma is the preferred target matrix for residue analysis. The analytical method of Polzer et al. [J. Polzer, C. Stachel, P. Gowik, Anal. Chim. Acta 521 (2004) 189] was adapted for liquid chromatography–tandem mass spectrometry detection and was validated in house according to the Commission Decision 2002/657/EC. The method is specific for all nitroimidazole except for Ipronidazole and its metabolite, due to interferences at their retention times in chromatograms of blank plasma and reagents samples. The absence of a matrix effect enables the use of a (linear) calibration curve in solution for quantitation. The apparent recovery (obtained after correction with a deuterated internal standard) is between 93% and 123%, except for the metabolite of Metronidazole (58–63%). The repeatability (CVr=2.49–13.39%) and intralaboratory reproducibility (CVRW=2.49–16.38%) satisfy the Horwitz equation. The obtained values for the detection capacity (CCβ) range from 0.25 to 1μgL−1, while values obtained for the decision limit (CCα) are below CCβ.

Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials.

Metronidazole, the prototype nitroimidazole antimicrobial, was originally introduced to treat Trichomonas vaginalis, but is now used for the treatment of anaerobic and protozoal infections. The nitroimidazoles are bactericidal through toxic metabolites which cause DNA strand breakage. Resistance, both clinical and microbiological, has been described only rarely. Metronidazole given orally is absorbed almost completely, with bioavailability > 90% for tablets; absorption is unaffected by infection. Rectal and intravaginal absorption are 67 to 82%, and 20 to 56%, of the dose, respectively. Metronidazole is distributed widely and has low protein binding (< 20%). The volume of distribution at steady state in adults is 0.51 to 1.1 L/kg. Metronidazole reaches 60 to 100% of plasma concentrations in most tissues studied, including the central nervous system, but does not reach high concentrations in placental tissue. Metronidazole is extensively metabolised by the liver to 5 metabolites. The hydroxy metabolite has biological activity of 30 to 65% and a longer elimination half-life than the parent compound. The majority of metronidazole and its metabolites are excreted in urine and faeces, with less than 12% excreted unchanged in urine. The pharmacokinetics of metronidazole are unaffected by acute or chronic renal failure, haemodialysis, continuous ambulatory peritoneal dialysis, age, pregnancy or enteric disease. Renal dysfunction reduces the elimination of metronidazole metabolites; however, no toxicity has been documented and dosage alterations are unnecessary. Liver disease leads to a decreased clearance of metronidazole and dosage reduction is recommended. Recent pharmacodynamic studies of metronidazole have demonstrated activity for 12 to 24 hours after administration of metronidazole 1 g. The post-antibiotic effect of metronidazole extends beyond 3 hours after the concentration falls below the minimum inhibitory concentration (MIC). The concentration-dependent bactericidal activity, prolonged half-life and sustained activity in plasma support the clinical evaluation of higher doses of metronidazole given less frequently. Metronidazole-containing regimens for Helicobacter pylori in combination with proton pump inhibitors demonstrate higher success rates than antimicrobial regimens alone. The pharmacokinetics of metronidazole in gastric fluid appear contradictory to these results, since omeprazole reduces peak drug concentration and area under the concentration-time curve for metronidazole and its hydroxy metabolite; however, concentrations remain above the MIC. Other members of this class include tinidazole, ornidazole and secnidazole. They are also well absorbed and distributed after oral administration. Their only distinguishing features are prolonged half-lives compared with metronidazole. The choice of nitroimidazole may be influenced by the longer administration intervals possible with other members of this class; however, metronidazole remains the predominant antimicrobial for anaerobic and protozoal infections.

Binding of 3H-metronidazole in olfactory, respiratory and alimentary epithelia in rats.

Whole-body autoradiography of 3H-metronidazole in rats showed retention of bound metabolites in the epithelia lining the olfactory part of the nose, the tongue, the gingiva, the palate, the pharynx, the oesophagus and the forestomach. In vitro microautoradiography in O2- and N2-atmosphere with some of these tissues indicated reductive formation of bound metabolites in specific cells of the epithelia. Studies with subcellular fractions of the nasal olfactory mucosa showed formation of DNA- and protein-bound metronidazole metabolites. A lower bioactivating capacity was found in experiments with the liver. The bioactivation was dependent on N2-atmosphere, and presence of the P450-inhibitor metyrapone or GSH in the incubation media depressed the protein-binding of metronidazole both in the nasal olfactory mucosa and the liver. These data indicate that the bioactivation is partly P450-dependent and GSH may play an important role in scavaging the bioactivated drug. The epithelial cells with a capacity to bioactivate metronidazole may be potential targets for negative effects of the drug. Whole-body autoradiography also showed a strong binding of radioactivity in the contents of caecum and colon. This can be considered to be due to reductive bioactivation of metronidazole by the intestinal microorganisms and reflects the principal site of action of the drug.

Effects of metronidazole and its metabolites on histamine immunosuppression activity

We have previously reported that metronidazole treatment increases human lymphocyte proliferation showing individual differences. This drug and its metabolites are imidazole compounds like histamine and cimetidine. The first is an endogenous amine that inhibits T-helper lymphocyte proliferation, and the second is a histamine antagonist. We presently report the in vitro effects of histamine, cimetidine, imidazole, metronidazole and its two principal metabolites (the acetic acid and hydroxy forms), on the mitogenic response to phytohemagglutinin (PHA) stimulation of human peripheral blood lymphocytes. Histamine decreased lymphocyte proliferation while (in order of potency) cimetidine, the hydroxy metabolite of metronidazole, imidazole and metronidazole, increased the mitogenic response to PHA in a dose-response fashion. The acetic acid metabolite lacked immunomodulatory effects. Competitive studies showed that cimetidine, metronidazole, and the hydroxy metabolite blocked the inhibitory effect of histamine on lymphocyte proliferation in a dose-related manner. This blockage was non-competitive, suggesting that the target of the imidazole compounds was not the active site of the H 2 receptor.

Separation of metronidazole, its major metabolites and their conjugates using dynamically modified silica

Metronidazole has previously been used as a probe when investigating cytochrome P450 isoenzymes and thus the pattern of metabolism of this drug has been extensively studied. However, in previous investigations the conjugates were determined by indirect methods. In this paper we present a high-performance liquid chromatographic (HPLC) system for the simultaneous determination of metronidazole, its major metabolites and their glucuronic acid conjugates in biological fluids. The separation is performed using bare silica dynamically modified with N-cetyl-N,N,N-trimethylammonium bromide contained in the mobile phase. The separation of the acidic metabolites of metronidazole is greatly improved with this system compared to other published reversed-phase HPLC systems intended for the same purpose. Glucuronides of metronidazole and its hydroxy metabolites have been synthesized in vitro using rat liver microsomes and preparative HPLC. The method developed makes it possible to determine the intact glucuronic acid conjugates of metronidazole and the hydroxy metabolite in human urine.

ChemInform Abstract: A Facile Synthesis of the Major Urinary Metabolite of Metronidazole.

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Non-induction of extrahepatic antipyrine and metronidazole metabolism evaluated from partially hepatectomized rats.

1. The effect of beta-naphthoflavone (BNF), given i.p. (n = 9) and orally (n = 9), on the metabolism of antipyrine and metronidazole was investigated in rats. 2. The clearances of antipyrine and metronidazole were determined on a single saliva sample. The rates of formation of antipyrine and metronidazole metabolites were determined from a 20 h urine sample and saliva clearance. 3. Administration of beta-naphthoflavone i.p. was significantly more effective than oral dosage on the induction of antipyrine and metronidazole metabolism (p < 0.05). 4. The capacity of extrahepatic tissues to metabolize antipyrine and metronidazole was quantitatively assessed in rats with and without pretreatment with beta-naphthoflavone immediately after sham operation or 70% partial hepatectomy (n = 40). 5. Antipyrine and metronidazole clearances correlated with liver weight in induced and non-induced rats. Linear regression of antipyrine and metronidazole clearances did show a non-significant Y-intercept (p > 0.05), indicating a negligible extrahepatic metabolism in both induced and in non-induced rats. 6. From a quantitative point of view this study indicates that induction of extrahepatic cytochrome P450 metabolism of antipyrine and metronidazole is negligible.

A Facile Synthesis of the Major Urinary Metabolite of Metronidazole

Abstract An efficient synthesis of diol 9, a urinary metabolite of Metronidazole 5, is described.

Metronidazole and antipyrine metabolism in the rat: Clearance determination from one saliva sample

1. The applicability of a simple, non-invasive method for assessment of metronidazole and antipyrine metabolism in rats in vivo was investigated. 2. In 48 sample pairs of blood and pilocarpine-stimulated saliva from six rats the concentration of metronidazole was almost identical (r = 0.97). 3. In 26 rats the clearance could be determined from one sample without loss of precision and accuracy compared with conventional determinations (r = 0.99). If urine was collected for 24 h the fractional clearance representing each elimination pathway could be determined. 4. Pretreatment with phenobarbitone increased the fractional clearance of metronidazole by oxidation and glucuronidation 3.8-fold and 1.6-fold, respectively, whereas 3-methylcholanthrene pretreatment increased the rate of oxidation 10-fold and decreased the rate of glucuronidation 0.5-fold. 5. The clearance and fractional clearances of metronidazole and antipyrine administered in a mixture could be determined from the same saliva sample and urine collected for 24 h without drug-drug interactions. 6. Phenobarbitone pretreatment increased the formation rate of all metabolites of metronidazole and antipyrine administered in a mixture, whereas beta-naphthoflavone increased the formation rates of only the oxidative metronidazole metabolites, norantipyrine and 4-hydroxyantipyrine, but not metronidazole glucuronide or 3-hydroxymethylantipyrine. 7. A mixture of metronidazole and antipyrine and non-invasive sampling are recommendable for the study of the differential metabolism of foreign compounds in rats in vivo.

A CASE OF AMEBIC LIVER ABSCESS IN A PATIENT ON CHRONIC HEMODIALYSIS

We report a case of amebic liver abscess in a patient on chronic hemodialysis as well as its drug regimen. A 42-year-old single man who was undergoing long-term dialysis complained of fever and right hypochondralgia and was admitted to our hospital. A space-occupying lesion (10cm in diameter) was found on abdominal CT in the right lobe of the liver. He was diagnosed as having hepatic amebiasis because of a positive serologic test. Patients with amebic liver abscess were formerly more likely to have had recent travels to endemic areas, but recently this disease had become predominant among patients with depressed immune response. The immunological mechanism of resistance to infection is disturbed in patients on regular dialysis treatment and this disturbance interferes with the host-parasite equilibrium. Recently metronidazole or tinidazole is employed in the initial treatment of this disease. The metabolites of metronidazole, however, are slowly excreated and possibly accumulated in the patients with chronic renal failure, for which hemodialysis can efficiently remove. We successfully treated this patient with metronidazole 500mg daily, which corresponded to about one third of the usual dosage, without any toxic side

Metabolism of metronidazole and antipyrine in hepatocytes isolated from mouse and rat

1. In order to study species-related differences and select a model for the human metabolism of metronidazole and antipyrine, the Michaëlis-Menten kinetics of metabolite formation from the two compounds were investigated in freshly isolated mouse and rat hepatocytes. 2. The average Km values for the formation of the major metronidazole metabolites ranged from 0.6 to 3 mM. The intrinsic clearance values (Vmax/Km) of metronidazole to the acetic acid, hydroxy and glucuronide metabolites were 58 (36-125) and 21 (12-28; P less than 0.05), 156 (63-263) and 36 (19-56; P less than 0.05), and 269 (102-452) and 500 (389-1616; P less than 0.05) nl/min per 10(6) hepatocytes, for mouse and rat, respectively (median with range, n = 6). 3. The average Km values for the formation of antipyrine metabolites ranged from 2 to 10 mM. The intrinsic clearance values for production of 3-hydroxymethyl-, nor- and 4-hydroxyantipyrine were 232 (43-519) and 487 (296-793; P less than 0.05), 594 (168-813) and 93 (55-180; P less than 0.05), and 118 (23-505) and 239 (134-501; P greater than 0.05) nl/min per 10(6) hepatocytes, for mouse and rat, respectively (median with range, n = 6). 4. The results demonstrate that metronidazole and antipyrine are metabolized with quantitative, but not qualitative, differences in isolated hepatocytes from mice and rats. Neither species provided an ideal model for the human metabolism of the two compounds.

Susceptibility of Gardnerella vaginalis to metronidazole, its bioactive metabolites, and tinidazole.

The susceptibilities of 510 clinical isolates of Gardnerella vaginalis to metronidazole, its principal oxidative metabolites, and tinidazole were determined by an agar dilution method. The hydroxy metabolite was the most active, with an MIC90 value (minimum concentration that inhibited 90% of the strains) of 1.12 mg/L (5.51 mumol/L). Tinidazole and metronidazole were somewhat less active, with MIC90s of 4.09 mg/L (23.9 mumol/L) and 4.44 mg/L (18.0 mumol/L), respectively. The acid metabolite was inactive, with an MIC90 value of 226.55 mg/L (1.22 mmol/L). These results suggest that the hydroxy metabolite of metronidazole may contribute significantly to the antimicrobial effect of the parent drug in G. vaginalis-associated infections.

Influence of malnutrition on the disposition of metronidazole in rats.

The influence of dietary protein deficiency on the disposition of metronidazole and its two major metabolites was examined in male Sprague-Dawley rats fed for 4 weeks on a 23% (control-) or a 5% (low-) protein diet ad libitum. Following an intravenous bolus dose of 10 mg/kg metronidazole hydrochloride, blood samples were obtained serially for a period of 24 hr after drug administration. Serum concentration-time data were analyzed by nonlinear least-squares regression, as well as noncompartmental techniques. The average mean residence time (MRT) was significantly prolonged by 48%, while the systemic clearance (Cl) was decreased by 42% in the protein-deficient rats. Since there was no alteration in the apparent steady-state volume of distribution (V ss), the mean harmonic half-life was increased from 2.9 to 5.0 hr in the protein-deficient rats. Although the percentage of metronidazole recovered as total drug in the urine over 24 hr was not significantly different between the two groups of animals, rats on a low-protein diet excreted a significantly smaller percentage of the administered dose as unchanged metronidazole (mean ± SD, 24.6 ± 3.8 vs 36.5 ± 12%) and a larger percentage (16.7 ± 2.6 vs 8.3 ± 1.8%) as the hydroxylated metabolite. No significant difference in the partial metabolic clearance of the hydroxylated metabolite of metronidazole was seen between the two groups of animals; however, there was a significant decrease in the renal clearance of metronidazole (1.45 ± 0.68 vs 0.55 ± 0.06 ml/min/kg) in the rats fed a low-protein diet. We conclude that the decreased clearance of metronidazole in protein deficiency is a result primarily of the decreased glomerular filtration rate, decreased biliary excretion, and/or increased net tubular reabsorption of metronidazole.

1H nuclear magnetic resonance study of metronidazole metabolism by perfused rat liver.

High-resolution 1H nuclear magnetic resonance (NMR) spectroscopy at 300 MHz has been used to monitor the metabolism of metronidazole by the perfused rat liver. Samples of perfusate removed at various times during the perfusion show resonances from metronidazole and its major metabolites, as well as those from organic metabolites released from the liver. The major metabolite of metronidazole is shown to be its glucuronide conjugate. Metronidazole metabolism and glucuronide production are both stimulated in livers from rats pretreated with phenobarbitone.

Disposition and metabolism of metronidazole in patients with liver failure.

A pharmacokinetic study of metronidazole disposition was performed in 10 patients with severe liver disease, the majority of whom also had impaired renal function. Following a single intravenous dose, systemic clearance of metronidazole was decreased by 66% in patients compared with healthy controls (p less than 0.001). The apparent volume of distribution for metronidazole was also decreased in patients (by 21%), but the greater effect on clearance resulted in the elimination half-life being prolonged 152%. Total urinary excretion of unaltered metronidazole was not reduced in patients compared with controls, and systemic clearance of metronidazole did not correlate with creatinine clearance. Hepatic production of hydroxymetronidazole [1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole], the major oxidative metabolite of metronidazole, was significantly lowered in patients with liver failure. Peak plasma levels of this metabolite were lower, the time taken to achieve peak levels was longer and the area under the plasma concentration approximately time curve (AUC0-25h) was reduced in patients compared to controls (p less than 0.05). Similarly, urinary recovery of hydroxymetronidazole was lower in patients with liver disease while excretion of the other major oxymetabolite, 1-acetic acid-2-methyl-5-nitroimidazole, appeared reduced to an even greater extent. Thus, while the presence of renal function impairment in a patient with cirrhosis indicates that metronidazole elimination is likely to be abnormal, the principal mechanism for delayed elimination is impaired hepatic drug metabolism rather than reduced renal clearance of metronidazole and its major metabolites.