Intravenous disposition kinetics, oral and intramuscular bioavailability and urinary excretion of norfloxacin nicotinate in donkeys

An aqueous solution of norfloxacin nicotinate (NFN) was administered to donkeys (Aquus astnus) intravenously (once at 10 mg/kg), intramuscularly and orally (both routes once at 10 and 20 mg/kg, and for 5 days at 20 mg/kg/day). Blood samples were collected at predetermined times after each treatment and urine was sampled after intravenous drug administration. Serum NFN concentrations were determined by microbiological assay. Intravenous injection of NFN over 45–60 s resulted in seizures, profuse sweating and tachycardia. The intravenous half-life (t_1/2β was 209 ± 36 min, the apparent volume of distribution (V_d(area)) was 3.34 ± 0.58 L/kg, the total body clearance (Cl_E) was 1.092 ± 0.123 ± 10^--²mL/min/kg and the renal clearance (C1_R) was 0.411 ± 0.057 ± 10^--²mL/min/kg. Oral bioavailability was rather poor (9.6% and 6.4% for the 10 and 20 mg/kg doses respectively). Multiple oral treatments did not result in any clinical gastrointestinal disturbances. After intramuscular administration (20 mg/kg), serum NFN concentrations > 0.25 μg/mL (necessary to inhibit the majority of gram-negative bacteria isolated from horses) were maintained for 12 h. The intramuscular bioavailability was 31.5% and 18.8% for the 10 and 20 mg/kg doses respectively. After multiple dosing some local swelling was observed at the injection site. About 40% of the intravenous dose was recovered in the urine as parent drug. The results of comprehensive haematological and blood biochemistry tests indicated no abnormal findings except elevation in serum CPK (creatine phosphokinase) values after multiple intramuscular dosing. On the basis of the in vitro-determined minimum inhibitory concentrations of the drug and serum concentrations after multiple dosing, the suggested intramuscular dosage schedules for the treatment of gram-negative bacterial infections in Equidae are 10 mg/kg every 12 h or 20 mg/kg every 24 h.     

The kinetics of triclabendazole disposition in sheep

To investigate whether the disposition of triclabendazole (TCBZ) and its metabolites in blood or bile influenced its flukicidal potency, TCBZ was administered intraruminally at 10 mg kg-1 to sheep surgically fitted with a permanent re-entrant bile duct cannula. The profiles of TCBZ metabolites in peripheral plasma and bile were determined using high performance liquid chromatography. In plasma, only TCBZ sulphoxide (TCBZ-SO) and TCBZ sulphone were present and reached their maximum concentrations (greater than 13 micrograms ml-1) at 18 and 36 h, respectively, after administration. TCBZ metabolites were specifically bound to plasma albumin, which is believed to exert a major influence on the duration of plasma TCBZ metabolite concentrations and consequent exposure of liver fluke. In bile, the major TCBZ metabolites were hydroxylated in the 4' position and secreted predominantly as sulphate esters with lesser proportions as glucuronide conjugates. The major biliary metabolite was conjugated hydroxy TCBZ-SO which reached a maximum concentration in excess of 40 micrograms ml-1 and contributed almost half the total conjugated metabolites. The major free biliary metabolite was TCBZ-SO. Of the administered TCBZ dose, 9.7% was secreted as free metabolites in bile whereas 35.8% was secreted as conjugated metabolites. Approximately 6.5% of the dose was excreted in urine.     

Influence of closure of the reticular groove on the bioavailability and disposition kinetics of meclofenamate in sheep

Sodium meclofenamate is a non-steroidal anti-inflammatory drug with anaphylactic protective activity in cattle. The objectives of this study were to describe the pharmacokinetic behaviour of sodium meclofenamate after intravenous and oral administration to sheep and to determine the influence of closure of the reticular groove on the bioavailability of the drug. Sodium meclofenamate was administered by the intravenous (2.2 mg/kg) and oral (20 mg/kg) routes to sheep (n = 6). During the oral study the reticular groove was closed by intravenous administration of lysine vasopressin (0.3 IU/kg) or left open (saline solution). The closure of the reticular groove was assessed by determination of the blood glucose curves after oral administration of a glucose solution. After intravenous administration of meclofenamate, the distribution and elimination half-lives of the drug were 7.2 min and 542 min respectively, V_ss was 1.68 L/kg and Cl_B was 2.47 mL/min kg. Two different patterns of the plasma concentration curves were observed after oral administration of sodium meclofenamate. When the reticular groove was closed, two peaks were observed ( t _max-2 12-15 min, C _max-1 3.30-24.01 μg/mL; and t _max-2', 52.50-75 min, C _max-2' 6.45-11.08 μg/mL).     

Altered disposition of propylthiouracil in cats with hyperthyroidism

The oral and intravenous disposition of the anti-thyroid drug propylthiouracil (PTU) was determined in six clinically healthy cats and four cats with naturally occurring hyperthyroidism. Compared with the normal cats, the mean plasma elimination half-life of PTU was significantly (P less than 0.001) shorter in the hyperthyroid cats (77.5 +/- 5.8 minutes compared with 125.5 +/- 3.7 minutes) and the total body clearance of PTU was significantly (P less than 0.05) more rapid in the cats with hyperthyroidism (5.1 +/- 0.8 ml kg-1 min-1 compared with 2.7 +/- 0.2 ml kg-1 min-1). Following oral administration, both the bioavailability (59.7 +/- 4.9 per cent compared with 73.3 +/- 3.7 per cent) and peak plasma concentrations (14.5 +/- 1.6 micrograms ml-1 compared with 18.9 +/- 0.9 micrograms ml-1) of PTU were significantly (P less than 0.05) lower in the hyperthyroid cats than in the control cats. No difference was noted, however, between the apparent volume of distribution for PTU in the two groups of cats. Overall, results of this study indicate that the oral bioavailability of PTU is decreased and PTU disposition is accelerated in cats with hyperthyroidism.     

The bioavailability, dispostion kinetics and dosage of sulphadimethoxine in dogs.

The disposition kinetics of sulphadimethoxine were studied in six normal beagle dogs after intravenous injection of a single dose (55 mg/kg). The median (range) distribution and elimination half times of the drug were 2.36 (2.06-3.35) hours and 13.10 (9.71-16.50) hours, respectively. Total body clearance of the drug had a median value of 21.7 ml/kg/h and a mean value of 21.4 ml/kg/h. While the overall tissue to plasma level ratio (k12/k21) of the drug was 0.55 after distribution equilibrium had been attained, analogue computer simulated curves showed that at 24 hours the fractions (percentage) of the dose in the central and tissue compartments were 12 and 11%, respectively. The drug was shown, by equilibrium dialysis method, to be highly bound to plasma proteins (greater than 75%) within the usual therapeutic range (50 to 150 mug/ml) of plasma levels. The systemic availability of sulphadimethoxine from the oral suspension was 32.8% (22.5-80.0). Since the absorption half time, 1.87 (0.86-3.22) hours, was considerably shorter than the half-life, 13.10 (9.71-16.50) hours, of the drug, the rate of absorption would have little influence on the dosage regimen. Based on the experimental data obtained, a satisfactory dosage regimen might consist of a priming dose of 55 mg/kg by the intravenous route and maintenance doses of either 27.5 mg/kg of sulphadimethoxine injection given intravenously or 55 mg/kg of the oral suspension administered at 24 hour intervals. The adequacy and duration of therapy will depend upon the clinical response obtained.     

Pharmacokinetics,oral bioavailability and tissue distribution of azithromycin in cats

Azithromycin is the first of a class of antibiotics classified as azalides. In an initial experiment four cats were given a single dose of azithromycin 5 mg/kg orally (p.o.), followed 2 weeks later by a single intravenous bolus (i.v.) dose of 5 mg/kg. Subsequently, six cats were given [¹⁴C]azithromycin p.o. in a single dose of 5.4 mg/kg for the study of tissue distribution and metabolism. In both experiments, serial blood samples were collected and the plasma assayed for unchanged azithromycin to determine various pharmacokinetic parameters. After p.o. administration, bioavailability was 58% and absorption rapid with a t_max of 0.85±0.72 h and a C_max of 0.97 ± 0.65 μg/mL The harmonic mean terminal t_1/2 after i.v. administration was 35 h. Tissue half-lives varied from 13 h in fat to 72 h in cardiac muscle. Three metabolites were identified in bile. Unchanged azithromycin accounted for 100% of the total radioactivity in lung and skin tissues when assayed. In comparison with other species, the bioavailability in cats is higher than in humans but lower than in dogs. As in the dog, > 50% of the azithromycin-related material in feline bile was unchanged azithromycin.     

Oral clindamycin disposition after single and multiple doses in normal cats

Eighteen normal cats were randomly allocated into three treatment groups and dosed with clindamycin aqueous solution for 10 days at a dosage rate of: (1) 5.5 mg/kg b.i.d.; (2) 11 mg/kg b.i.d.; or (3) 22 mg/kg once daily. Serum disposition of clindamycin was determined after the first and last dose of clindamycin was given, and was analyzed using model-independent pharmacokinetics by both the trapezoidal rule method and the predictive equation method. Complete blood counts and clinical chemistries were determined before and after the study. The trapezoidal rule method produced similar mean results with much less variance than the predictive equation method. Mean residence time was longer (P less than 0.05) after the high dose (393 +/- 77 min) than after either the low or medium doses (276 +/- 51 and 274 +/- 45 min, respectively). Oral volume of distribution (Vd(ss)/F) after the high dose (3.06 +/- 0.92 l/kg) was larger (P less than 0.05) than that after the low or medium doses (1.62 +/- 0.30 and 1.76 +/- 0.53 l/kg, respectively). Oral Vd(ss)/F was significantly smaller (P less than 0.001) after the last dose than after the first dose when analyzed by treatment group. Significant (P less than 0.01) decreases in the leukogram and erythrogram were observed, due to the large amount of blood collected for drug analysis. No clinical signs of drug intoxication were observed, and no drug-related necropsy findings were found.     

Kinetic disposition, systemic bioavailability and tissue distribution of apramycin in broiler chickens

Apramycin was administered to chickens orally, intramuscularly and intravenously to determine blood concentration, kinetic behaviour, bioavailability and tissue residues. Single doses of apramycin at the rate of 75 mg kg⁻¹ body weight were given to broiler chickens by intracrop, i.m. and i.v. routes. The highest serum concentrations of apramycin were reached 0·20 and 0·76 hours after the oral and i.m. doses with an absorption half-life () of 0·10 and 0·19 hours and an elimination half life () of 1·22 and 2·31 hours respectively. The systemic bioavailability was 2·0 and 58 per cent after intracrop and i.m. administration, respectively, indicating poor absorption of the drug when given orally.Following i.v. injection, the kinetics of apramycin was described by a two-compartment open model with a () of 1·5 hours, () of 2·1 hours, V_d(ss) (volume of distribution) of 4·82 litre kg⁻¹ and C1_(B) (total body clearance) of 1·88 litre kg⁻¹ hour⁻¹. The serum protein-binding of apramycin was 26 per cent.The highest tissue concentrations of apramycin were present in the kidneys and liver. No apramycin residues were detected in tissues after six hours except in the liver and kidneys following intracrop dosing and kidneys following i.m. administration.     

Comparison of the disposition of carbimazole and methimazole in clinically normal cats

The oral disposition of the antithyroid drugs methimazole and carbimazole were compared in nine clinically normal cats. After the administration of 5 mg of methimazole, serum concentrations of methimazole increased in all the cats, with mean drug concentrations reaching peak values (1·37 μg ml⁻¹) at 30 minutes. After administration of 5 mg carbimazole, serum concentrations of carbimazole remained low, but serum methnnazole became readily measurable, with mean drug concentrations reaching peak values (0·79 μg ml⁻¹) at 120 minutes. When serum concentrations of methimazole attained after administration of the two antithyroid drugs were compared, the mean maximum serum methimazole concentration achieved after administration of methimazole was approximately two-fold higher than peak concentrations measured after administration of carbimazole. In addition, the mean area under the serum concentration curve (AUC) after administration of methimazole was approximately two-fold higher than the mean AUC determined after administration of carbimazole. When the differences in molecular weight between the two drugs was taken into consideration, however, these methimazole:carbimazole ratios of 2:1 were nearly equivalent to the molar ratio of the 5 mg doses of the drugs given (1·63). Results of this study indicate that carbimazole is nearly totally converted to methimazole after oral administration to cats, similarly to the findings in man. The finding of less available serum methimazole after administration of a 5 mg tablet of carbimazole than after methimazole is also consistent with published antithyroid drug dosages needed to control hyperthyroidism in cats.     

Oestradiol and genistein reduce food intake in male and female overweight cats after gonadectomy

AIM: To determine if exogenous oestradiol or the phyto-oestrogen genistein could reduce food intake in male and female cats fed ad libitum that had been allowed to accrue excessive bodyfat following neutering. METHODS: Sixteen adult (eight female, eight male) cats were neutered and allowed to increase their bodyweight (BW) through feeding ad libitum of a complete and balanced dry diet. Oestradiol was injected subcutaneously for 5-day periods in incremental doses (0.25-4 microg per cat), then food intake was recorded, and vaginal cytological changes were observed in females. Similarly, genistein was administered orally for 5-day periods in incremental doses (5-100 mg/kg). RESULTS: In males and females, both oestradiol (p<0.001) and genistein (p=0.037) significantly reduced food intake during treatment, and the minimum daily doses that produced a significant effect were 0.5 mug and 100 mg/kg, respectively. The minimum daily dose of oestradiol that produced a significant effect on food intake was not associated with changes in vaginal cytology over the 5-day treatment period. CONCLUSIONS AND CLINICAL RELEVANCE: Gonadal oestradiol appeared to be a key modulator of food intake in both male and female cats, and replacement of oestrogen to neutered cats via oestradiol or an oestrogen surrogate such as genistein has potential for reducing the prevalence of obesity in neutered cats.     

The disposition kinetics,urinary excretion and dosage regimen of amikacin in cross-bred bovine calves

The disposition kinetics, urinary excretion and dosage regimen of amikacin after a single intravenous administration of 10 mg/kg was investigated in six cross-bred bovine calves. At 1 min, the concentration of amikacin in the plasma was 116.9±3.16 µg/ml and the minimum therapeutic concentration was maintained for 8 h. The elimination half-life and volume of distribution were 3.09±0.27 h and 0.4±0.03 L/kg, respectively. The total body clearance (Cl_B) and T/P ratio were 0.09±0.002 L/kg/h and 4.98±0.41, respectively. Approximately 50% of the total dose of amikacin was recovered in the urine within 24 h after administration. Amikacin in concentrations ranging from 5 to 150 µg/ml bound to plasma proteins to the extent of 6.32%±0.42%. A satisfactory intravenous dosage regimen of amikacin in bovine calves would be 13 mg/kg followed by 12 mg/kg at 12 h intervals.     

Modulation of innate and acquired immunity by an estrogenic dose of genistein in gonadectomized cats

Dietary genistein has potential as a surrogate estrogen to restore normal control of food intake in cats following gonadectomy. However, since genistein affects immunological responses in other species it is important to determine if there is any immunological effect of genistein in cats, before long-term feeding of it could be considered. It was hypothesized that the minimum estrogenic dose of genistein (peak serum concentration 0.276+/-0.055 microg/mL) would be associated with altered innate and acquired immunity in cats. Cats (n=8 per group) were surgically neutered then treated daily with either 0.5 microg estradiol subcutaneously, 100mg/kg genistein orally, or vehicle only for 38 days. Circulating CD4+ and CD8+ T cells, and CD21+ B cells were quantified using flow cytometry. Concanavalin-A induced lymphocyte proliferation was assayed using incorporation of tritiated thymidine. Indirect ELISA was used to assay serum IgG in response to a commercial vaccine. Neutrophil respiratory burst in response to opsonized zymosan was evaluated using flow cytometric detection of oxidized dihydrorhodamine. Delayed-type hypersensitivity was evaluated with formalin-killed Yersinia pseudotuberculosis. Genistein treatment decreased circulating CD8+ cells (P=0.006), increased neutrophil respiratory burst (P=0.034), and increased wheal formation at 24h (P=0.038) but decreased wheal formation at 72 h (P=0.012) following intradermal challenge with killed Y. pseudotuberculosis. There were no significant differences between genistein treated cats and the other treatment groups in any other parameters. It is concluded that the minimum estrogenic dose of genistein alters selected leukocyte responses in cats. Unexpected effects of genistein suggest that extrapolation from one species to other species may not be appropriate in regards to the effects of genistein on immunity.     

Bioavailability, disposition kinetics and dosage of sulfadimethoxine in dogs--a correction.

A reevaluation of the disposition kinetics and extent of absorption of sulfadimethoxine in normal dogs following intravenous and oral dosage has been made. The tissue to plasma level ratio at the peak tissue level (k12/k21) was 0.55, while the tissue to plasma level ratio after distribution equilibrium (k12/k21-beta) was 0.926. The systemic availability of sulfadimethoxine from the oral suspension was 48.8% (24.4-86.2) when corrections for intrasubject variability were made.     

Comparison of the oral bioavailability and tissue disposition of monensin and salinomycin in chickens and turkeys

Henri, J., Maurice, R., Postollec, G., Dubreil‐Cheneau, E., Roudaut, B., Laurentie, M., Sanders, P. Comparison of the oral bioavailability and tissue disposition of monensin and salinomycin in chickens and turkeys. J. Vet. Pharmacol. Therap.  35 , 73–81. The current study describes the pharmacokinetic parameters of two carboxylic polyether ionophores: monensin in turkeys and salinomycin in chickens. These data can be used to understand and predict the occurrence of undesirable residues of coccidiostats in edible tissues of these animal species. Special attention is paid to the distribution of residues between the different edible tissues during and at the end of the treatment period. For the bioavailability studies, monensin was administered to turkeys intravenously, in the left wing vein, at a dose of 0.4 mg /kg and orally at a dose of 20 mg /kg. Salinomycin was administered to chickens intravenously, in the left wing vein, at a dose of 0.25 mg /kg and orally at a dose of 2.5 mg /kg. Residue studies were carried out with supplemented feed at the rate of 100 mg /kg of feed for monensin in turkeys and 70 mg /kg for salinomycin in chickens, respectively. Coccidiostats had a low bioavailability in poultry (around 30% for monensin in chickens, around 1% for monensin in turkeys and around 15% for salinomycin in chickens). Monensin in chickens had a longer terminal half‐life (between 3.07 and 5.55 h) than both monensin in turkeys (between 1.36 and 1.55 h) and salinomycin in chickens (between 1.33 and 1.79 h). The tissue /plasma partition coefficients showed a higher affinity of both monensin and salinomycin for fat, followed by liver and muscle tissue. The depletion data showed a fairly rapid elimination of coccidiostats in all the tissues after cessation of treatment. According to the results of depletion studies, a withdrawal period of 1 day seems sufficient to avoid undesirable exposure of consumers.