J. F. M. Nouws

Pharmacokinetics, hydroxylation and acetylation of sulphadimidine in mammals, birds, fish, reptiles and molluscs

Plasma disposition, plasma protein binding, recovery in urine and renal clearance of sulphadimidine (SDM), its N4-acetyl (N4-SDM), its 6-hvdroxymethyl (SCH2OH), its 5-hydroxy (SOH) and its glucuronide (SOH-gluc) metabolites were studied in man, ruminants, horses, pigs, laying-hens and the carp. The elimination half-life depended mainly on the extent of metabolism and the renal excretion rate of the metabolites. N4-SDM, SCH2OH and SOH metabolites exhibited higher renal clearance values than SDM. Hydroxylation of SDM predominated over acetylation in horses, ruminants, poultry, turtles and snails. The main metabolite in horses was SOH: in cows, calves, goats, turtles and snails it was SCH2OH. In ruminants a capacity-limited hydroxylation of SDM to SCH2OH was observed at dosages of 100–200 mg/kg. Also in laying-hens a capacity-limited elimination-like pattern was obtained following an intravenous SDM dosage of 100 mg/kg. In man and pigs the acetylation pathway was predominant and the elimination half-life in the latter species depended on the position of the acetylation-deacetylation equilibrium. Fish are able to hydroxylate and acetylate SDM.

The effect of tick-borne fever on metabolism and renal clearance of sulfadimidine in goats

The tick-borne fever (TBF) model was used to study the effect of fever on the metabolism of sulfadimidine in goats. During TBF the elimination half-lives were prolonged, and the renal clearance values of sulfadimidine and the majority of its metabolites were markedly diminished compared with those in the uninfected state. During TBF the steady-state levels of the hydroxy metabolites were markedly increased. TBF reduced the extent of hydroxymethylation of the pyrimidine side chain; TBF did not affect acetylation of sulfadimidine. In one goat a progressive accumulation of the metabolites was noticed.

Tickborne fever: efficacy and effects on pharmacokinetics of some chemotherapeutic agents in the goat

The tickborne fever model developed in dwarf goats and used in this study has an acute character: fever, dullness, anorexia, tachycardia, a moderate inhibition of rumen contractions, leucopenia and a decreased serum alkaline phosphatase activity. The model can be of great value in testing the therapeutic efficacy and pharmacokinetics of chemotherapeutic agents in rickettsial infections. The dwarf goats receiving oxytetracyc1ine. chloramphenicol or trimethoprim (plus sulphonamides) showed improvement, whereas ampicillin and spiramycin were ineffective. Furthermore, marked changes in drug metabolism were observed in tickborne fever-infected goats treated with chloramphenicol or sulphadimidine; the elimination half-life values of these drugs and of oxytetracycline were significantly prolonged. The pharmacokinetics of ampicillin, spiramycin and sulpha-methylphenazole did not show marked differences between healthy and tickborne fever-infected animals.