Pharmacokinetics of sulfadimethoxine and sulfamethoxazole in combination with trimethoprim after intravenous administration to healthy and pneumonic pigs

The pharmacokinetics of two sulfonamide/trimethoprim combinations were investigated after intravenous administration to clinically healthy pigs and to the same pigs following a challenge with Actinobacillus pleuropneumoniae toxins. Endobronchial challenge with A.pleuropneumoniae toxins resulted in fever, increased white blood cell counts and decreased water and feed consumption. Healthy, as well as febrile, pigs were given sulfadimethoxine (SDM) or sulfamethoxazole (SMX) intravenously at a dose of 25 mg/kg b.w. in combination with 5 mg trimethoprim (TMP) per kg body weight. The pharmacokinetic parameters of the sulfonamides as well as their main metabolites (acetyl sulfonamides) were not significantly different in healthy and febrile pigs. In healthy and pneumonic pigs, the mean elimination half-lives of SDM were 12.9 h and 13.4 h, respectively, those of SMX 2.5 h and 2.7 h, respectively, and those of TMP 2.8 h and 2.6 h, respectively. Distribution volumes in healthy and febrile pigs of SDM and SMX varied between 0.2 and 0.4 L/kg, and those of TMP between 1.1 and 1.6 L/kg. The mean AUC of TMP was decreased and the volume of distribution and total body clearance of TMP were increased in febrile pigs. Protein binding of the drugs and metabolites studied were not significantly changed after toxin-induced fever. The extent of protein binding of SDM, SMX and TMP was in the range 94–99%, 45–56% and 40–50%, respectively. Based on knowledge of in vitro antimicrobial activity of the drug combinations against A.pleuropneumoniae it was concluded that after intravenous administration of the dose administered (30 mg/kg of the combination preparations) to healthy and pneumonic pigs, plasma concentrations of SMX and TMP were above the concentration required for growth inhibition of 50% of A., pleuropneumoniae strains for approximately 16 h, whereas bacteriostatic plasma concentrations of SDM were still present after TMP had been eliminated from plasma. Because of similar elimination half-lives of SMX and TMP in pigs this combination is preferred to the combination of SDM with TMP.     

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 administration, administration by nasogastric tube and administration with concentrate were determined in the horse. Eight adult horses were dosed at 1 week intervals in a sequentially designed study at a dose of 5 mg/kg trimethoprim (IMP) and 25 mg/kg sulphachlorpyridazine (SCP) on all occasions. Plasma concentrations of both drugs were measured serially for 48 h. Pharmacokinetic parameters of clinical importance (distribution and elimination half-lives, clearance, bioavail-ability, volume of distribution) were determined both for TMP and SCP. Following intravenous administration, the volume of distribution at steady-state (V_d(33) was 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 significantly 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 SCP 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 combination preparation. Based on the pharmacokinetic data obtained and the published 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 sufficiently high plasma concentrations for effectiveness against susceptible bacteria. The single oral administration of TMP and SCP mixed with concentrate did not result in effective plasma concentrations. Further studies are needed to investigate whether higher plasma concentrations would be achieved by a multiple dosing scheme for several days.     

Pharmacokinetics of gamithromycin after intravenous and subcutaneous administration in pigs

The aim of this study was to investigate the pharmacokinetic properties of gamithromycin in pigs after an intravenous (i.v.) or subcutaneous (s.c.) bolus injection of 6 mg/kg body weight. The plasma concentrations of gamithromycin were determined using a validated high-performance liquid chromatography–tandem mass spectrometry method, and the pharmacokinetics were noncompartmentally analysed.     

Pharmacokinetics of a novel amoxicillin/colistin suspension after intramuscular administration in pigs

He, J., Tang, S., Li, L., Zhang, C., Li, X., Xia, X., Xiao, X. Pharmacokinetics of a novel amoxicillin/colistin suspension after intramuscular administration in pigs. J. vet. Pharmacol. Therap. 34 , 42–50. An amoxicillin (AMO) or colistin (COS) oil suspension was developed and corresponding pharmacokinetics studies were conducted in pigs after i.m. injection. The combination product is a white‐ to cream‐colored oil suspension which is easy to be re‐dispersed. Settling volume ratio, syringeability and flowability of the product is well consistent with the technical standards set by the Ministry of Agriculture of People’s Republic of China. Two studies were conducted to investigate the pharmacokinetics of the combination product in swine. First, the pharmacokinetics of the combination product was compared with those of the same products merely removing either AMO or COS. No significant change in the major pharmacokinetic parameters (C_max, T_max, MRT, t_1/2λ, AUC and AUMC) was observed when either component was removed from the combination product, indicating that AMO and COS do not interfere with each other in their absorption and distribution in the tissue when used as a combination. Second, the pharmacokinetics of the combination product was compared with that of their respective single products. It was found that the apparent elimination half‐lives (t_1/2λ) of AMO and COS in combination product were 6.38 and 8.09 h, which were 2.40 and 2.38 times longer than the single products, respectively. Thus, the novel AMO/COS suspension extended significantly the half‐life of both drugs to maintain a longer drug residence time in pigs when compared to their single products.     

Pharmacokinetics of moxifloxacin in rabbits after intravenous, subcutaneous and a long-acting poloxamer 407 gel formulation administration

The pharmacokinetics (PK) of moxifloxacin in healthy white New Zealand rabbits was studied following intravenous (IV) and subcutaneous (SC) administration routes as well as a SC long-acting poloxamer 407 gel formulation (SC-P407). Moxifloxacin concentrations were determined by high-performance liquid chromatography assay with fluorescence detection. Mean half-life for IV, SC and SC-P407 routes was 2.15, 5.41 and 11.09 h. Clearance value after IV dosing was 0.78 l/kg/h. After SC administration, the mean absolute bioavailability was 117% and the C(max) was 1.61 +/- 0.49 mg/l. After SC-P407 administration, the bioavailability was 44% and the C(max) 1.83 was +/-0.62 mg/l. No adverse effects were observed in any of the rabbits following IV, SC and SC-P407 administration of moxifloxacin. Minimal inhibitory concentrations of moxifloxacin against different strains of Staphylococcus aureus from different european countries were used to compute the main pharmacodynamic (PD) surrogate markers of efficacy. The high tolerability of this SC-P407 formulation and the favourable PK behaviour such as the long half-life, acceptable bioavailability and excellent PK-PD ratios achieved indicate that it is likely to be effective in rabbits.     

Pharmacokinetics of cefonicid in lactating goats after intravenous,intramuscular and subcutaneous administration,and after a long-acting formulation for subcutaneous administration

The single-dose disposition kinetics of cefonicid were determined in clinically normal lactating goats (n = 6) after intravenous (IV), intramuscular (IM) and subcutaneous (SC) administration of a conventional formulation, and after subcutaneous administration of a long-acting formulation (SC-LA). Cefonicid concentrations were determined by high performance liquid chromatography with ultraviolet detection. The concentration–time data were analysed by noncompartmental pharmacokinetic methods. Steady-state volume of distribution (V_ss) and clearance (Cl) of cefonicid after IV administration were 0.14 ± 0.03 L/kg and 0.51 ± 0.07 L/h·kg, respectively. Following IM, SC and SC-LA administration, cefonicid achieved maximum plasma concentrations of 14.46 ± 0.82, 11.98 ± 1.92 and 17.17 ± 2.45 mg/L at 0.26 ± 0.13, 0.42 ± 0.13 and 0.83 ± 0.20 hr, respectively. The absolute bioavailabilities after IM, SC and SC-LA routes were 75.34 ± 11.28%, 71.03 ± 19.14% and 102.84 ± 15.155%, respectively. After cefonicid analysis from milk samples, no concentrations were found above LOQ at any sampling time. From these data, cefonicid administered at 20 mg/kg each 12 hr after SC-LA could be effective to treat bacterial infections in lactating animals not affected by mastitis problems.     

Pharmacokinetics of levamisole in sheep after intravenous administration

The pharmacokinetics of levamisole at doses of 5, 7.5 and 10 mg/kg were determined after its intravenous administration to eighteen healthy Merino sheep. Using compartmental analysis, the disposition of the drug best fitted a two-compartmental open model. The mean values for the compartmental volume of distribution at steady state (Vss) were 2.034 +/- 0.23 I, 2.347 +/- 0.720 and 2.001 +/- 0.367 I/kg for each dose, respectively, and values obtained using the statistical moment theory were 2.141 +/- 0.269,2.390 +/- 0.536 and 2.140 +/- 0.345 l/kg for each dose, respectively. There were no dose-related differences (one-way ANOVA) in the constants describing distribution and elimination phases (alpha and beta) or Vss, but significant differences were detected in the total body clearance (Cl) and the area under the plasma concentration-time curve (AUC). After non-compartmental analysis, no significant differences were found when the parameters lambda (the linear terminal slope) and Vss were compared, but significant differences were detected in Cl and AUC. There were no significant differences between the values obtained using the compartmental and non-compartmental analysis when lambda -beta, Cl, Vss, and AUC were compared.     

Pharmacokinetics of levamisole in rabbits after intravenous administration

A compartmental and non-compartmental pharmacokinetic study was carried out on rabbits after intravenous (i.v.) administration of levamisole at the three dose rates: 12.5, 16.0 and 20.0 mg/kg body weight. Using compartmental analysis, the disposition of levamisole best fitted a two-compartmental open model with mean values of alpha = 0.1278, 0.1019 and 0.1282 min-1; beta = 0.0139, 0.0126 and 0.0124 min-1; A = 6.24, 5.27 and 10.58 micrograms/ml and B = 2.14, 3.83 and 5.08 micrograms/ml for each dose, respectively. The statistical moment theory was mainly used for non-compartmental analysis. Values for mean residence time (MRT) of 69.2, 71.7 and 73.1 min were obtained for each dose. The mean values for volume of distribution at steady state (Vd(ss)), determined by compartmental analysis, were 3879, 3279 and 2735 ml/kg for each dose, and values obtained using the statistical moment theory were 3760, 3015 and 2943 ml/kg; there were no statistically significant differences using Student's paired t-test. Identical conclusions were obtained using both methods when the parameters beta, AUC and Cl were compared.     

Pharmacokinetics of fenbendazole following intravenous and oral administration to pigs

OBJECTIVE: To determine pharmacokinetics and metabolic patterns of fenbendazole after IV and oral administration to pigs. ANIMALS: 4 mixed-breed female pigs weighing 32 to 45 kg. PROCEDURE: Fenbendazole was administered IV at a dose of 1 mg/kg. One week later, it was administered orally at a dose of 5 mg/kg. Blood samples were collected for up to 72 hours after administration, and plasma concentrations of fenbendazole, oxfendazole, and fenbendazole sulfone were determined by use of high-pressure liquid chromatography. Plasma pharmacokinetics were determined by use of noncompartmental methods. RESULTS: Body clearance of fenbendazole after IV administration was 1.36 L/h/kg, volume of distribution at steady state was 3.35 L/kg, and mean residence time was 2.63 hours. After oral administration, peak plasma concentration of fenbendazole was 0.07 microg/ml, time to peak plasma concentration was 3.75 hours, and mean residence time was 15.15 hours. Bioavailability of fenbendazole was 27.1%. Oxfendazole was the major plasma metabolite, accounting for two-thirds of the total area under the plasma concentration versus time curve after IV and oral administration. Fenbendazole accounted for 8.4% of the total AUC after IV administration and 4.5% after oral administration. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate that fenbendazole was rapidly eliminated from plasma of pigs. The drug was rapidly absorbed after oral administration, but systemic bioavailability was low.     

Pharmacokinetics of sulphamethoxazole and trimethoprim administered intravenously and orally to Japanese quails

The pharmacokinetic behaviour of sulphamethoxazole and trimethoprim was studied after combined intravenous (i.v.) administration at doses of 20 mg/kg and 4 mg/kg, respectively, and after oral administration at doses of 50 mg/kg and 10 mg/kg. The serum concentration versus time data after i.v. administration were best described by the biexponential equations C = 34.77.e^-2.655.t+ 39.03.e^-0.241.t for sulphamethoxazole and C = 3.29.e^-3.878.t+ 0.83.e^-0.306.t for trimethoprim. Mean biological half-lives of the drugs were 2.89 ± 0.11 and 2.38 ± 0.33 h, respectively. The distribution volumes (V_area) were 0.475 ± 0.026 l/kg (sulphamethoxazole) and 3.89 ± 0.61 I/kg (trimethoprirn). Orally administered sulphamethoxazole and trimethoprim were rapidly absorbed. The maximum serum concentrations were reached 0.5-1 h after administration. The bioavailability was 8 1% for sulphamethoxazole and 41% for trimethoprim.     

Pharmacokinetics of a new ivermectin/praziquantel oil suspension after intramuscular administration in pigs

A new oil suspension containing 0.15% ivermectin and 15% praziquantel for intramuscular injection was developed, and corresponding pharmacokinetics studies were conducted in swine. The combination product is a white- to cream-colored oil suspension and its physical properties such as settling volume ratio, redispersibility, syringeability and flowability are well consistent with the Technical Standards by the Ministry of Agriculture of the People's Republic of China. The pharmacokinetic study consists of two parts. First, the experiments were carried out to compare the pharmacokinetic parameters of the combination product and those same products with praziquantel or ivermectin removed merely. The results showed that no significant change in the major pharmacokinetic parameters (t(1/2z), T(max), C(max), AUC(INF), TimeDur) was observed when either of the component was removed from the combination product, indicating that ivermectin and praziquantel do not interfere with each other when being used together. Second, the pharmacokinetics of the combination product were compared with those of their respective single product. The results showed that the C(max) (15.94 ng/mL) of ivermectin in combination product was 9.01 times higher than the single product, while the AUC(INF) (1925.61 ng h/mL) was 6.02 times higher. Meanwhile, the C(max) (1.48 μg/mL), AUC(INF) (17.08μgh/mL), t(1/2z) (20.25 h), TimeDur3 (42.01 h) and TimeDur4 (16.60 h) of praziquantel in combination product were improved with a factor of 5.48, 13.66, 8.58, 10.10 and 7.31 times when compared with the single product, respectively. Therefore, the efficacy of the combination product was significantly prolonged, especially for praziquantel, so that comprehensive efficacy of controlling parasites sensitive to ivermectin and praziquantel can be achieved with one-single use of it.     

Pharmacokinetics of a novel formulation of ivermectin after administration to goats

OBJECTIVE: To evaluate the pharmacokinetics of a novel commercial formulation of ivermectin after administration to goats. ANIMALS: 6 healthy adult goats. PROCEDURE: Ivermectin (200 microg/kg) was initially administered IV to each goat, and plasma samples were obtained for 36 days. After a washout period of 3 weeks, each goat received a novel commercial formulation of ivermectin (200 microg/kg) by SC injection. Plasma samples were then obtained for 42 days. Drug concentrations were quantified by use of high-performance liquid chromatography with fluorescence detection. RESULTS: Pharmacokinetics of ivermectin after IV administration were best described by a 2-compartment open model; values for main compartmental variables included volume of distribution at a steady state (9.94 L/kg), clearance (1.54 L/kg/d), and area under the plasma concentration-time curve (AUC; 143 [ng x d]/mL). Values for the noncompartmental variables included mean residence time (7.37 days), AUC (153 [ng x d]/mL), and clearance (1.43 L/kg/d). After SC administration, noncompartmental pharmacokinetic analysis was conducted. Values of the variables calculated by use of this method included maximum plasma concentration (Cmax; 21.8 ng/mL), time to reach Cmax (3 days), and bioavailability (F; 91.8%). CONCLUSIONS AND CLINICAL RELEVANCE: The commercial formulation used in this study is a good option to consider when administering ivermectin to goats because of the high absorption, which is characterized by high values of F. In addition, the values of Cmax and time to reach Cmax are higher than those reported by other investigators who used other routes of administration.