Oxidative degradation of triazine derivatives in aqueous medium: a radiation and photochemical study.

Pulse and steady state radiolysis techniques have been used to determine the bimolecular rate constants and to investigate the spectral nature of the intermediates and the degradation induced by hydroxyl radicals ((*)OH) with 1,3,5-triazine (T), 2,4, 6-trimethoxy-1,3,5-triazine (TMT), and 2,4-dioxohexahydro-1,3, 5-triazine (DHT) in aqueous medium. A competitive kinetic method with KSCN as the (*)OH scavenger was used to determine the rate constants for the reaction of (*)OH with T, TMT, and DHT. The bimolecular rate constants are 3.4 x 10(9), 2.06 x 10(8), and 1.61 x 10(9) dm(3) mol(-)(1) s(-)(1) respectively, for T, TMT, and DHT at pH approximately 6. The transient absorption spectra obtained from the reaction of (*)OH with T, TMT, and DHT have single absorption maxima at 320, 300, and 300 nm, respectively, and were found to undergo a second-order decay. The formation of TOH(*) [C(6)OH-N(5)-yl radical], TMTOH(*) [N(5)OH-C(6)-yl radical], and DHT(*) [C(6)-yl radical] is proposed from the initial attack of (*)OH with T, TMT, and DHT, respectively. A complete degradation of TMT (10(-3) mol dm(-3)) was obtained after absorbed doses of 5 kGy in N(2)O-saturated solutions and 16 kGy in aerated solutions. A similar degradation pattern was obtained with DHT in N(2)O-saturated solutions. Complete degradation was observed with an absorbed dose of 7 kGy. On the basis of the results from both pulse and steady state radiolysis, a possible reaction mechanism involving (*)OH-mediated oxidative degradation is proposed. A complete photodecomposition of DHT was also observed in the presence of ferric perchlorate using ultraviolet light at low pH. Photoinduced electron transfer between Fe(III) and DHT in the Fe(III)-DHT complex and subsequent formation of DHT(*) are proposed to be the major processes that lead to the complete degradation of DHT at pH 3.

Comparative metabolic disposition of ivermectin in fat tissues of cattle, sheep, and rats.

In the study of the metabolic disposition of ivermectin in cattle, sheep, and rats, a group of nonpolar metabolites was detected in the fat tissues of these animals. Upon saponification or esterase treatment, these nonpolar metabolites gave rise to polar products that were similar to the ivermectin metabolites present in the liver. A hypothesis was thus proposed that the polar ivermectin metabolites produced in the liver were esterified and stored in the fat as nonpolar entities, which can be reconverted back to the polar metabolites chemically or enzymatically. To substantiate this hypothesis, the regeneration of polar metabolites from the nonpolar metabolites was studied and hydrolysis products were characterized to establish the basic structure of the alcohol portion of the metabolites. Furthermore, chromatographic comparisons were made between radiolabeled in vivo metabolites and synthetic fatty acid ester samples. These results established the general structural class of the ivermectin nonpolar metabolites and also confirmed the unusual metabolic pathway of ivermectin disposition in fat tissue.

Dermal penetration of avermectin B1a in the rhesus monkey.

Forearms of rhesus monkeys were treated with [3H]avermectin B1a in three different vehicles and concentrations so that the penetration of avermectin B1a through skin could be determined. In order to simulate exposure of farm workers, such as mixer-loaders, applicators, and harvesters, to this pesticide, avermectin B1a was applied to the forearms of the monkeys as an emulsifiable concentrate (300 micrograms/monkey), a diluted emulsifiable concentrate (4.5 micrograms/monkey), and as a suspension in water (216 micrograms/monkey). After 1 or 10 hr of exposure, the treatment area was washed. The levels of radioactivity were determined in the urine, feces, plasma, and wash. On the basis of the amounts of radioactivity excreted in the urine and feces and the levels of radioactivity in the plasma after dermal application compared to those found after intravenous administration of the compound, less than 1% of the doses was absorbed. These data indicate that avermectin B1a would not readily penetrate the skin of farm workers exposed to it. Therefore, the hazard to farm workers exposed to this compound would be substantially mitigated.

Metabolic disposition of ivermectin in tissues of cattle, sheep, and rats.

The metabolic disposition of ivermectin, a new antiparasitic drug, has been studied in cattle, sheep, and also in rats dosed with the drug labeled with tritium in the C-22,23 positions. In the edible tissues of these animals, the unaltered drug was the major tissue residue component and was quantitated by HPLC-reverse isotope dilution assay. The depletion half-lives of the drug ranged between 1 and 6 days, similar to those of the total tissue residue in these species. Most metabolites present in the liver tissues were more polar than the parent drug. Based on spectral (NMR, mass spectrometric) analysis and chromatographic comparison with authentic compounds prepared by in vitro rat or steer microsomal incubations, three of these metabolites have been isolated and identified as the hydroxylation derivatives of ivermectin, i.e. 24-hydroxymethyl-H2B1a, its monosaccharide, and 24-hydroxymethyl-H2B1b.

Ivermectin: a potent new antiparasitic agent.

Ivermectin is the 22,23-dihydro derivative of avermectin B1, a macrocyclic lactone produced by an actinomycete, Streptomyces avermitilis. It is active at extremely low dosage against a wide variety of nematode and arthropod parasites, apparently by virtue of its action on the mediation of neurotransmission by gamma-aminobutyric acid. It is now in commercial use in various countries for the treatment and control of parasites in cattle, horses, and sheep, and is expected to become available for use in swine and dogs. Since studies with the drug in man are in a preliminary stage, it is not yet known whether ivermectin will be useful in human medicine.

The metabolism of avermectins B1a, H2B1a, and H2B1b by liver microsomes.

The avermectins area a new class of structurally related antiparasitic agents isolated from Streptomyces avermitilis. The major polar metabolites isolated from in vitro incubations of [3H]avermectins B1a, H2B1a, and H2B1b with either rat or steer liver microsomes have been isolated and identified as the C24-methyl alcohols of the parent compounds. A smaller quantity of a more polar metabolite has also been identified as the monosaccharide of the C24-methyl alcohols of avermectin H2H1b from rat liver microsomal incubation and avermectin H2B1a from steer liver microsomal incubation. The mass spectra and 300-MHz 1H-NMR spectra permitted assignment of structures to these metabolites. Together these two metabolites represent 50-80% of the total radioactivity more polar than the parent compounds. The metabolite profiles on reverse-phase HPLC demonstrate that the rat and steer are qualitatively similar in the production of these two polar metabolites.

Identification of a glutathione conjugate of cambendazole formed in the presence of liver microsomes.

The incubation of multiply labeled (2H, 3H, 13C, 14C) cambendazole and glutathione with hepatic microsomes from phenobarbital-dosed hamsters results in the formation of polar metabolites. The major metabolite has been characterized by a variety of isotopic, spectrometric, chromatographic, and degradative/synthetic techniques as a glutathione conjugate of cambendazole in which substitution is on the 4-position of the benzimidazole nucleus. The same metabolite is produced by hepatic microsomes from the rat.

Cambendazole and nondrug macromolecules in tissue residues.

The anthelmintic cambendazole is rapidly metabolized to at least 13 urinary metabolites. Radioactivity was found in liver for weeks after a single dose in cattle, but even at 3 days' withdrawal, cambendazole and metabolites previously identified in urine accounted for only a small fraction of liver radioactivity. The radioactivity was ubiquitously distributed in protein and nucleic acid fractions, and [14C] glutamic acid was identified, indicating incorporation of 14C into the endogenous pool. Part of the residual liver radioactivity at 7 days was convertible chemically to 5-nitrobenzimidazole, indicating a drug-related macromolecular residue. However, data from rats fed radiolabeled steer liver indicate that the residue is minimally bioavailable and therefore of substantially less toxicological concern than cambendazole itself.

Production of guanosine-5'-monophosphate and inosine-5'-monophosphate by fermentation.

A biotin-requiring coryneform bacterium which produces glutamic acid was mutated to adenine dependency. The adenine-requiring strain, which excreted insoine-5'-monophosphate (IMP), was further mutated to xanthine dependency. As expected, IMP was also excreted by this mutant. The mutant strain was reverted to xanthine independence in an attempt to obtain a culture with an altered IMP dehydrogenase which would be less sensitive to feedback inhibition by guanosine-5'-monophosphate (GMP). A revertant was obtained which produced GMP and IMP, each at 0.5 g per liter. The reversion to xanthine independence had resulted in a concomitant requirement for isoleucine, leucine, and valine. Further mutation to increased nutritional requirements led to culture MB-1802, which accumulated 1 g per liter each of GMP and IMP. Both nucleotides were isolated in pure form. The concentrations of GMP and IMP produced by MB-1802 were four times that of cytidylate, uridylate, or adenylate, indicating that the mechanism of GMP and IMP production was direct and not via ribonucleic acid breakdown.