John H. Wedig

Identification of metabolites from salts of pyridine-2-thiol-1-oxide following intravenous and dermal administration to swine

Abstract Mature female Yorkshire swine were given 14C-labeled zinc pyrithione (ZPT), sodium pyrithione (NPT), and the magnesium sulfate adduct of 2,2′-dithio-bis(pyridine-1-oxide) (MDS) iv and by dermal application. The urine from the iv study contained one major and two minor metabolites. Analyses of these by gas chromatography-mass spectrometry indicated that the major metabolite was the S-glucuronide of 2-mercaptopyridine-N-oxide and one of the minor metabolites was the S-glucuronide of 2-mercaptopyridine. The metabolic pattern after the dermal application was considerably different. Chromatographic evidence indicated that the major metabolites were 2,2′-pyridyldisulfide and 2-(pyridyl-N-oxide) sulfonic acid.

Urinary excretion and metabolism of salts of 2-pyridinethiol-1-oxide following intravenous administration to female Yorkshire pigs.

A single dose of zinc pyridine-2-thiol-1-oxide (ZPT; 5 mg/kg; oil-in-water emulsion), sodium pyridine-2-thiol-1-oxide (SPT; 50 mg/kg; aqueous solution), or the magnesium sulfate adduct of 2,2′-dithio-bis-pyridine-1-oxide (MDS; 4 mg/kg; aqueous solution), which included 5 μCi/kg of 2,6-14C-labeled material, was injected via a jugular vein cannula into female Yorkshire pigs in order to study the plasma half-life, the urinary excretion rate, and the metabolism of these antimicrobial and antifungal agents during a 96-hr period. At the doses employed, all of these agents produced cholinergic effects (parasympathetic and somatomotor) which lasted for 30–60 min. Plasma decline in radioactivity was a biphasic exponential function for each compound. Half-lives for the initial phase of plasma disappearance (0.25 to 8 hr after injection) ranged from 2.0 to 2.9 hr and the slower, secondary phase was characterized by half-lives of 26.6 to 36.3 hr. The urinary excretion in terms of the percentage of total dose excreted within 96 hr, was 95 for SPT, 56 for ZPT, and 54 for MDS. The majority of total radioactivity was recovered in the urine within the first 24 hr postinjection. Thin-layer radiochromatographic analysis indicated that 2,2′-(pyridyl-N-oxide) disulfide was the primary metabolite of SPT whereas the primary metabolite for both ZPT and MDS appeared to be 2-(pyridyl-N-oxide) sulfonic acid.

Teratologic evaluation of dermally applied zinc pyrithione on swine

Abstract A teratologic study in Yorkshire pigs was performed by applying zinc pyrithione (30, 100, or 400 mg/kg prepared as a 50% ( w v ) suspension in Aquaphor cream) for 8 hr per day on the clipped dorsal surface from Days 8 through 32 of gestation. The design of the experiment also included a naive and a vehicle-treated control group. Piglets obtained by Caesarian section on gestation Day 100 were examined for external, soft tissue, and skeletal (X-ray) abnormalities. The number of implantation and resorption sites and viable fetuses among the test groups was not significantly different than the control groups. No evidence of any teratogenic or embryotoxic effect was observed in the fetuses from dams treated with zinc pyrithione.

Teratogenesis study of N-cyclohexyl-2-pyrrolidone in rats and rabbits

Teratogenesis studies were performed in rats and rabbits given N-cyclohexyl-2-pyrrolidone, an aprotic solvent used in chemical processing. Dosages of 0, 15, 50, 150, or 500 mg N-cyclohexyl-2-pyrrolidone/kg body wt/day were administered by gavage to groups of 25 pregnant Sprague-Dawley rats on Days 6 through 15 of gestation. Dosages of 0, 10, 30, 100, or 300 mg/kg/day were administered by gavage to groups of at least 15 pregnant Dutch-Belted rabbits on Days 6 through 18 of gestation. Animals were killed and subjected to uterine examination on Day 20 of gestation for rats and on Day 29 for rabbits. There were no significant differences between the vehicle control and N-cyclohexyl-2-pyrrolidone-treated groups for implantation numbers or live or dead fetuses, resorptions, and fetal body weight in rats and rabbits. Dam body weight gain during gestation was comparable among groups. External gross visual examination of the fetus as well as examination of skeletal and soft tissues revealed no effects related to treatment with N-cyclohexyl-2-pyrrolidone.

Reproductive Toxicological Evaluation of Omadine MDS

Reproductive toxicology studies with Omadine MDS were conducted using rats and rabbits, and plasma levels of the metabolite, 2-methylsulfonylpyridine (2-MSP), were assayed. In phase I (treated males, untreated females) of the fertility study, the no-effect level, for oral dosing, was 3.0 mg/kg; 7.5 mg/kg caused a decrease in male weight gain. In phase II (treated females, untreated males), the no-effect oral dose level was 1.0 mg/kg. At 3.0 mg/kg, decreases were seen in maternal body weight gain, the fertility index, and in total implantations and viable embryos at the 13-day uterine examination. Severe maternal toxicity including impaired motor function of limbs, decrease in weight gain, and mortality occurred at 7.5 mg/kg. In the perinatal/postnatal study, the no-effect level was 3.0 mg/kg. At 7.5 mg/kg, mortality was high, with a majority of animals dying during mid lactation. In the rat teratology study, the high dosage level, 30 mg/kg, dermally administered on Gestation Days 6 through 15 caused slight maternal toxicity, whereas 10 mg/kg produced none. These dosage levels corresponded to peak plasma levels on Gestation Day 10 of 470 and 1950 ng/ml 2-MSP at the 10- and 30-mg/kg dosage levels, respectively. In the rabbit, 5 mg/kg topically applied on Gestation Days 6 through 18 produced slight maternal toxicity while 1.5 mg/kg produced no maternal effects. The plasma levels of 2-MSP peaked on Days 12 and 15 of gestation. At 1.5 mg/kg these levels were 155 and 148 ng/ml; at 5.0 mg/kg, levels were 513 and 573 ng/ml. There was no teratogenic response seen in either species.

Teratogenesis study of o-toluenediamine in rats and rabbits.

o-Toluenediamine in corn oil was administered po to Sprague-Dawley rats at dosages of 10, 30, 100, or 300 mg/kg body wt/day during Days 6 through 15 of gestation. All animals were killed on Day 20 of gestation. A similar study was conducted with Dutch-Belted rabbits dosed po daily at 3, 10, 30, or 100 mg of o-toluenediamine/kg body wt/day from Days 6 through 18 of gestation. Rabbits were killed on Day 29 of gestation. Maternal toxicity was indicated at 300 mg/kg in rats and 100 mg/kg in rabbits by reduced body weight gain during gestation. Fetal body weight was reduced at the highest dosage in both rats and rabbits. In addition, at the high dosage, an increase in the number of resorption sites in rabbits were noted. Skeletal examination of rats showed increased incidence of missing sternebrae at 300 mg/kg and incompletely ossified vertebrae at 100 and 300 mg/kg in comparison to control fetuses. The effects on the fetus could be the result of maternal toxicity. There was no evidence of teratogenic effects or effects on the dams at dosages through 30 mg/kg body wt.

Pyrithione: Plasma Metabolite in Man

2-Methylsulfonylpyridine (2-MSP) has been identified as the terminal plasma pyrithione metabolite in rats, rabbits, dogs, and monkeys (W. B. Gibson, A. R. Jeffcoat, P. D. Rodriguez, T. S. Turan, P. F. Hughes, and M. E. Twine, Toxicol. Appl. Pharmacol. 62, 237-250 (1982); C. Mitoma, T. Steeger, J. Rogers, D. Thomas, and J. H. Wedig, Fundam. Appl. Toxicol. 3, 256-263 (1983]. This metabolite was detected in the systemic circulation of humans involved in the chemical manufacturing process. This confirms that the terminal pyrithione metabolite in plasma is identical among rat, rabbit, dog, monkey, and man.