Comparative aspects and sex differentiation of plasma sulfamethazine elimination and metabolite formation in rats, rabbits, dwarf goats, and cattle

R. F. Witkamp From the Departments of Veterinary Pharmacology (Witkamp, Yun, van't Klooster, van Miert), Internal Medicine and Nutrition (van Mosel, van Mosel), Large Animal Surgery (Ensink), and the Research Institute for Toxicology (Noordhoek), Faculty of Veterinary Medicine, University of Utrecht, PO Box 80176, 3508 TD Utrecht, The Netherlands.

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H-I. Yun From the Departments of Veterinary Pharmacology (Witkamp, Yun, van't Klooster, van Miert), Internal Medicine and Nutrition (van Mosel, van Mosel), Large Animal Surgery (Ensink), and the Research Institute for Toxicology (Noordhoek), Faculty of Veterinary Medicine, University of Utrecht, PO Box 80176, 3508 TD Utrecht, The Netherlands.

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G. A. E. van't Klooster From the Departments of Veterinary Pharmacology (Witkamp, Yun, van't Klooster, van Miert), Internal Medicine and Nutrition (van Mosel, van Mosel), Large Animal Surgery (Ensink), and the Research Institute for Toxicology (Noordhoek), Faculty of Veterinary Medicine, University of Utrecht, PO Box 80176, 3508 TD Utrecht, The Netherlands.

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J. F. van Mosel From the Departments of Veterinary Pharmacology (Witkamp, Yun, van't Klooster, van Miert), Internal Medicine and Nutrition (van Mosel, van Mosel), Large Animal Surgery (Ensink), and the Research Institute for Toxicology (Noordhoek), Faculty of Veterinary Medicine, University of Utrecht, PO Box 80176, 3508 TD Utrecht, The Netherlands.

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M. van Mosel From the Departments of Veterinary Pharmacology (Witkamp, Yun, van't Klooster, van Miert), Internal Medicine and Nutrition (van Mosel, van Mosel), Large Animal Surgery (Ensink), and the Research Institute for Toxicology (Noordhoek), Faculty of Veterinary Medicine, University of Utrecht, PO Box 80176, 3508 TD Utrecht, The Netherlands.

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J. M. Ensink From the Departments of Veterinary Pharmacology (Witkamp, Yun, van't Klooster, van Miert), Internal Medicine and Nutrition (van Mosel, van Mosel), Large Animal Surgery (Ensink), and the Research Institute for Toxicology (Noordhoek), Faculty of Veterinary Medicine, University of Utrecht, PO Box 80176, 3508 TD Utrecht, The Netherlands.

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J. Noordhoek From the Departments of Veterinary Pharmacology (Witkamp, Yun, van't Klooster, van Miert), Internal Medicine and Nutrition (van Mosel, van Mosel), Large Animal Surgery (Ensink), and the Research Institute for Toxicology (Noordhoek), Faculty of Veterinary Medicine, University of Utrecht, PO Box 80176, 3508 TD Utrecht, The Netherlands.

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A. S. J. P. A. M. van Miert From the Departments of Veterinary Pharmacology (Witkamp, Yun, van't Klooster, van Miert), Internal Medicine and Nutrition (van Mosel, van Mosel), Large Animal Surgery (Ensink), and the Research Institute for Toxicology (Noordhoek), Faculty of Veterinary Medicine, University of Utrecht, PO Box 80176, 3508 TD Utrecht, The Netherlands.

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SUMMARY

Plasma disposition and urinary recovery of sulfamethazine (smz), its N4-acetylated metabolite (N4AcSMZ), and 2 of its hydroxylated metabolites—5-hydroxysulfamethazine (5OHSMZ) and 6-hydroxymethylsulfamethazine (6CH2OHSMZ)—were determined in either sex of 4 animal species: rats, dwarf goats, rabbits, and cattle. Rats, rabbits, and dwarf goats had significant (P < 0.01) sex difference in smz plasma clearance. Male rats had higher plasma clearance than did female rats, and excreted higher amounts of the hydroxy metabolites and lower amounts of N4AcSMZ. The N4AcSMZ metabolite was predominant in plasma and urine of rabbits. Male rabbits had higher plasma clearance than did female rabbits, but differences in metabolite profile were not apparent. With regard to plasma smz elimination, the situation in goats was opposite to that in rats. Male goats had considerably lower clearance than did female goats. This was associated with a lower hydroxylation rate in males. Plasma half-life of smz in cows was lower than that in bulls, probably because of a smaller distribution volume in cows. Compared with elimination via urine, elimination via milk was negligible in cows. Significant differences in metabolite profiles were not found between bulls and cows. Similar to those in rats and mice, hormone-dependent xenobiotic metabolic pathways may exist in other species. Depending on species and xenobiotic compound residue concentrations of xenobiotics, their metabolites, or both may differ with sex of the animal, or may be altered after treatment with anabolic hormones.

SUMMARY

Plasma disposition and urinary recovery of sulfamethazine (smz), its N4-acetylated metabolite (N4AcSMZ), and 2 of its hydroxylated metabolites—5-hydroxysulfamethazine (5OHSMZ) and 6-hydroxymethylsulfamethazine (6CH2OHSMZ)—were determined in either sex of 4 animal species: rats, dwarf goats, rabbits, and cattle. Rats, rabbits, and dwarf goats had significant (P < 0.01) sex difference in smz plasma clearance. Male rats had higher plasma clearance than did female rats, and excreted higher amounts of the hydroxy metabolites and lower amounts of N4AcSMZ. The N4AcSMZ metabolite was predominant in plasma and urine of rabbits. Male rabbits had higher plasma clearance than did female rabbits, but differences in metabolite profile were not apparent. With regard to plasma smz elimination, the situation in goats was opposite to that in rats. Male goats had considerably lower clearance than did female goats. This was associated with a lower hydroxylation rate in males. Plasma half-life of smz in cows was lower than that in bulls, probably because of a smaller distribution volume in cows. Compared with elimination via urine, elimination via milk was negligible in cows. Significant differences in metabolite profiles were not found between bulls and cows. Similar to those in rats and mice, hormone-dependent xenobiotic metabolic pathways may exist in other species. Depending on species and xenobiotic compound residue concentrations of xenobiotics, their metabolites, or both may differ with sex of the animal, or may be altered after treatment with anabolic hormones.

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