AGE AND DOSAGE DEPENDENCY IN THE PLASMA DISPOSITION AND THE RENAL CLEARANCE OF SULFAMETHAZINE AND ITS N4-ACETYL AND HYDROXY METABOLITES IN CALVES AND COWS

Abstract

Plasma disposition, protein binding, urinary recovery, and renal clearance of sulfamethazine (SMZ), its N4-acetylsulfamethazine (N4-SMZ) and its 2 hydroxy metabolites-6 hydroxymethylsulfamethazine (SCH2OH) and 5-hydroxysulfamethazine (SOH)- and the glucuronide of the latter were studied in 7 cows and 7 calves to determine the relationship between these values and the age of the animal and dosage applied. A capacity-limited hydroxylation of SMZ into SCH2OH was observed in cows and calves given dosages of 100 to 200 mg/kg. A biphasic SMZ elimination curve and steady state in SCH2OH plasma concentration (6 to 15 .mu.g/ml) were observed. The N4-SMZ plasma concentration-time curve was parallel to that of SMZ at the dosages and in all animals. The total body clearance and the cumulative urinary recovery (expressed as percentage of the dose) for SMZ and its metabolites depended on drug dosage and age of the animals. At dosages of SMZ < 25 mg/kg, the main metabolite in the urine of calves and cows was SCH2OH (23% to 55.2%), whereas in calves given a larger dosage (100 mg/kg), the N4-SMZ and SOH percentages increased. The plasma protein binding of SMZ and its metabolites depended on the SMZ plasma concentration. Hydroxylation lowered the protein binding (from 75-80%) to 50%. The renal clearance of SMZ was dependent on urine flow in all animals. The renal clearance of the SCH2OH metabolite was 2 to 3 times greater than the creatinine clearance value; thus, this compound was excreted by glomerular filtration and partly by tubular secretion. Both N4-SMZ and SOH were predominantly excreted by tubular secretion; at dosages of SMZ of 100 to 200 mg/kg, and N4-SMZ clearance was diminished. Intravenous administration of N4-SMZ to a calf resulted in deacetylation and a subsequent hydroxylation of the formed SMZ into the 2-hydroxy metabolites. It was concluded that the elimination half-life of SMZ in ruminants depended mainly on the extent of the metabolism, which was dose related, and on the renal clearance of its metabolites.