Pharmacokinetics of sulphamethoxazole in calves and cows

Abstract

SUMMARY The kinetics of sulphamethoxazole (SMZ) in plasma and milk, and its metabolism, protein binding and renal clearance were studied in three newborn calves and two dairy cows after intravenous administration. SMZ was predominantly acetylated; no hydroxy and glucuronide derivatives could be detected in plasma and urine. Age-dependent pharmacokinetics and metabolism of SMZ were observed. The plasma concentration-time curves of the N4-acetyl metabolite in the elimination phase were parallel to those of the parent drug; the No-acetyl metabolite plasma percentage depended on age and ranged between 100% (new-born) to 24.5% (cow). SMZ was rapidly eliminated (elimination half-lives: 2.0-4.7 It) and exhibited a relatively small distribution volume ( f/Darea: 0.44-0.571/kg). SMZ was excreted predominantly by glomerular filtration, while its No-acetyl metabolite was actively eliminated by tubular secretion.

Pharmacokinetics of a sulphamethoxazole/trimethoprim formulation in pigs after intravenous administration

“…For man similar low, urine-flow dependent renal clearance values for SMZ have been reported (19). It is noteworthy that in cows (alkaline pH and urine flow 6-13 ml/min) the renal clearance of SMZ is about 10 times higher and is not distinctly urine-flow dependent (14). Alkaline urine makes the renal clearance of SMZ maximal, while acidic pH makes the renal clearance of TMP maximal by reducing the tubular reabsorption (no urine-flow dependency).…”

“…In pigs both SMZ and TMP are rapidly eliminated, exhibiting similar elimination half-lives (which is also reported by Romvary and Horvay (17)), and therefore the synergistic effect between these two drugs (3) may be at the same magnitude all the time. But in other animal species (5,14,15,16,19) the SMZ and TMP plasma concentration-time curves diverge, and subsequently the synergistic effect between these two drugs gradually diminishes (3). Compared with cows, in pigs the SMZ elimination half-life is slightly longer, and its distribution volume and total body clearance similar (14).…”

“…But in other animal species (5,14,15,16,19) the SMZ and TMP plasma concentration-time curves diverge, and subsequently the synergistic effect between these two drugs gradually diminishes (3). Compared with cows, in pigs the SMZ elimination half-life is slightly longer, and its distribution volume and total body clearance similar (14). In pigs the elimination half-lives of TMP were in accordance with those reported (4,8,9,17), but we found a smaller distribution volume than reported (4,8,9).…”

“…The pharmacokinetics of SMZ differs between species, which can be related to the extent of metabolism and the renal clearance of the drug and its metabolites (19,20). For example, the elimination half-life of sulphamethoxazole (SMZ) varies largely between species: in man 9.5 h, horse 5 h, cow 2 h, sheep 2 h, pig 3 h, dog 8 h and cat 10 h (2,5,14,15,17,19,20). Data about SMZ metabolism and renal excretion in pigs are scarce (6).…”

“…The N4-acetyl and hydroxy metabolite of sulphamethoxazole were synthesised by Dr. Vree as described (19). The protein binding and deglucuronidation of samples were carried out as described (12,13,14,23) and the calculation of pharmacokinetic parameters was performed according to standard procedures (1). Because no plasma concentration data of the M4 metabolite and the glucuronide conjugates of MI and M4 were available, the quantification limit of the extraction method (0.08 pg/m1) was used in the estimation of their renal clearance values…”