PHARMACOKINETICS OF TRIMETHOPRIM SULPHACHLORPYRIDAZINE IN HORSES AFTER ORAL, NASOGASTRIC AND INTRAVENOUS ADMINISTRATION

In the present study, the pharmacokinetic parameters of a trimethoprim /sulphachlorpyridazine preparation following intravenous administratio n, administration by nasogastric tube and administration with concentr ate were determined in the horse. Eight adult horses were dosed at 1 w eek intervals in a sequentially designed study at a dose of 5 mg/kg tr imethoprim (TMP) and 25 mg/kg sulphachlorpyridazine (SCP) on all occas ions. Plasma concentrations of both drugs were measured serially for 4 8 h. Pharmacokinetic parameters of clinical importance (distribution a nd elimination half-lives, clearance, bioavailability, volume of distr ibution) were determined both for TMP and SCP. Following intravenous a dministration, the volume of distribution at steady-state (V-d(ss)) wa s significantly larger for TMP (1.51 +/- 0.25 L/kg than for SCP (0.26 +/- 0.05 L/kg, The clearance was 7.73 +/- 2.26 mL/min-kg for TMP and 2 .64 +/- 0.48 mL/min kg for SCP. For both TMP and SCP, mean peak plasma concentrations (C-max) and the bioavailabilities (F) were reduced sig nificantly when the drugs were mixed with concentrate (ct) as compared with those after nasogastric administration (ngt) (F-ct = 44.3 +/- 10 .7% vs. F-ngt = 68.3 +/- 12.5% for TMP; F-ct = 46.3 +/- 8.9% vs. F-ngt = 67.3 +/- 13.7% for SCP). Following the administration of TMP and SC P mixed with concentrate, the plasma concentration-time curves showed a biphasic absorption pattern in all horses. The first peak occurred 1 -2 h and the second peak 8-10 h after administration of the combinatio n preparation. Based on the pharmacokinetic data obtained and the publ ished in vitro sensitivity data, it may be predicted that TMP and SCP given intravenously or by nasogastric tube at a dose of 5 mg/kg and 25 mg/kg respectively and a dosage interval of 8-12 h would result in su fficiently high plasma concentrations for effectiveness against suscep tible bacteria. The single oral administration of TMP and SCP mixed wi th concentrate did not result in effective plasma concentrations. Furt her studies are needed to investigate whether higher plasma concentrat ions would be achieved by a multiple dosing scheme for several days.