Disposition of ronidazole by swine. I. Radiocarbon content of tissues

Abstract

The antiparasitic and antibacterial compound, ronidazole (( l-methyl-5-nitroimidazol-2-yl)methyl carbamate), was rapidly absorbed and excreted by the pig after oral administration of 14CH3-labeled drug. Of the total excreted, less than half of the radioactivity was present in the urine. Radioactive residues were ubiquitously distributed in all tissues analyzed. Radioactive residues were present in edible tissues 42 days after dosing and were associated with tissue proteins. The relative depletion rates of different tissues is suggestive of the incorporation of endogeneous metabolites. Liberation of labeled methylamine by acid hydrolysis indicated that as much as 20-30% of the persistent residues retain some chemical relationship to the drug. As the fraction of the persistent residues which liberate methylamine declined with time, at least two general types of residues are present. Further studies using nitric acid oxidation of the residues showed that the fraction containing an intact 1-methyl-5-nitroimidazole nucleus was about 1% of the total residue.Ronidazole [ (l-methyl-5-nitroimidazol-2-yl)methyl carbamate] is a nitroimidazole useful in animal husbandry. Metabolic studies in the turkey have been reported (Rosenblum et al., 1972). These studies showed extensive metabolic degradation with resultant persistent radioactivity in various tissues, especially muscle. Since evolution of 14C02 was reported as 2.5% when the label was at the 2-ring atom and only 0.8% when the CH3 was labeled, 14CH3-labeled ronidazole was used in the current studies except that one animal was dosed with 2-ring-labeled ronidazole. The current studies were designed to determine the distribution of drug and metabolites in edible tissues of the pig, the depletion of radioactive residues with time, and the macromolecular nature of the tissue residue due to ronidazole. Chemical degradation studies designed to determine if the radioactive residues were due exclusively to metabolic degradation to single carbon fragments were carried out. MATERIALS AND METHODS Chemicals.Radiolabeled ronidazole was synthesized in the Merck Sharp & Dohme Research Laboratories. All lots were analyzed for radiochemical purity by paper or thin-layer chromatography and had a radiochemical purity of greater than 98% when used. No single impurity was present in a quantity greater than 0.5%. The specific activity was adjusted for each experiment to a suitable level by dissolving unlabeled and labeled material and either dosing the resultant solution or crystallizing the product before use.14CH3-Labeled ronidazole was synthesized from 14CH30H by treatment with methanesulfonic acid anhydride. The methyl methanesulfonate reacted with 4-nitroimidazole to yield predominantly [methyP4C]-lmethyl-5-nitroimidazole. Reaction with formaldehyde followed by transesterification with methylcarbamate yielded [methyl-14C] ronidazole.Ring 2-labeled ronidazole was synthesized from [2-l4CIimidazole obtained by reaction of ethylenediamine and [14C]formic acid at 500 "C via the usual steps of ...

Neurotoxicosis in 4 Cats Receiving Ronidazole

“…8,9 It is readily absorbed from the gastrointestinal tract and biodegraded, and is found in its intact form only in muscle. 10,11 The primary mechanism of action of most nitroimidazoles (including ronidazole) is thought to be related to production of nitro anion radicals, 12,13 leading to destabilization of deoxyribonucleic acid. Hydrogenosomes are specialized double-membrane-bound organelles responsible for the production of adenosine triphosphate (ATP) by a process that involves generating hydrogen and are found in some eukaryotic microbes that inhabit oxygen-deficient environments.…”

Tissue residue studies with ronidazole. Effect of label site on total radioactivity content of rat tissues

“…Treatment of N-methyl-5-nitroimidazoles and the 5acetylamino compound derived from ronidazole with 6 N hydrochloric acid at 120 °C degrades the imidazole nucleus and liberates IV-methylamine (Wolf et al, 1983b). It seems likely that all metabolites containing an IV-methylimidazole nucleus would respond similarly.…”

“…It seems likely that all metabolites containing an IV-methylimidazole nucleus would respond similarly. When uCH3-labeled ronidazole was dosed to swine, a portion of the tissue residue was found to liberate UCH3NH2 on strong acid hydrolysis (Wolf et al, 1983b). Consequently, the protein fraction of rat muscle and liver was examined for 14CH3NH2 liberation.…”

“…Previously reported studies (Rosenblum et al, 1972) have shown that significant metabolic degradation of radioactive ronidazole occurs in the turkey, and studies in swine using [mef/iy/-14C]ronidazole (Figure 1) gave evidence for persistent residues due to incorporation of metabolites possibly derived from methylamine as well as residues that may contain an intact imidazole nucleus. (Wolf et al, 1983b).…”

Pharmaco‐Toxicological Mode of Action of Antimicrobial5‐Nitroimidazole Derivatives

“…as seen with ronidazole etc. These fragments are incorporated into endogenous proteins and nucleic acids in the turkey as well as in the pig (Rosenblum et al, 1972;Wolf et al, 1983). They have polar properties due to oxidized side chains (Assandri et al, 1978;Voogd, 1981) and are rapidly excreted.…”