The role of plasma protein binding on the metabolism and renal excretion of sulphadimethoxine and its metabolite N4-acetylsulphadimethoxine in pigs.
The effects of plasma protein binding on the elimination of sulphadimethoxine (SDM) were examined after intravenous administration of 6.25, 12.5, 25, 50, 100 and 150 mg/kg to pigs. At an early stage of the experiment, the animals were anaesthetised by inhalation of enflurane to obtain a more exact relationship between plasma concentration and the renal excretion. SDM and its acetylated conjugate, N4-acetylsulphadimethoxine (N4-SDM) were detected in plasma and urine of all animals, and the recovery of the doses was almost complete in two animals with negligible renal excretion of SDM. The percentages of plasma protein binding of SDM and N4-SDM were almost similar, and ranged from 30 to 95%, depending on the plasma concentration. The metabolic clearance of SDM by acetylation increased when the plasma protein binding decreased. These results suggested that the main elimination route of SDM in pigs is acetylation, and that the plasma protein binding can have a large effect on the elimination of SDM in pigs. The effect of plasma protein binding on the renal clearance of SDM was not so evident, because urine pH had a much greater effect on it. The deacetylation of N4-SDM was detected after 25 mg/kg intravenous administration of N4-SDM, which suggests that the metabolic clearance of SDM is part of an acetylation-deacetylation equilibrium. Saturation of the active tubular reabsorption of SDM and of the active tubular secretion of N4-SDM was also suggested after higher doses of SDM.
Shimoda
M
M
Department of Clinical Pharmacy, St. Radboud Hospital, Nijmegen, The Netherlands.
Vree
T B
TB
Beneken Kolmer
E W
EW
Arts
T H
TH
D000107:Acetylation; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D003404:Creatinine / Q000652:urine; D005260:Female; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D013412:Sulfadimethoxine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D013552:Swine / Q000378:metabolism*
D001798:Blood Proteins; C038180:N(4)-acetylsulfadimethoxine; D013412:Sulfadimethoxine; D003404:Creatinine