Pharmacokinetics of imidocarb dipropionate in white-tailed deer (Odocoileus virginianus) after single intramuscular administration.

This study was designed to investigate the pharmacokinetics of imidocarb, a carbanilide derivative, in white-tailed deer (Odocoileus virginianus). The pharmacokinetic properties of a single intramuscular (IM) dose of imidocarb were determined in 10 deer. A single IM injection of 3.0 mg/kg imidocarb dipropionate was administered, and blood samples were collected prior to, and up to 48 hr after imidocarb administration. Plasma imidocarb concentrations were determined by high-performance liquid chromatography with ultraviolet detection. The disposition of plasma imidocarb was best characterized by a two-compartment open model. The mean ± SE maximal imidocarb concentration in deer was 880.78 ± 81.12 ng/ml at 38.63 ± 5.30 min postinjection. The distribution phase had a half-life (t1/2α ) of 25.90 ± 10.21 min, and plasma imidocarb concentration declined with a terminal elimination half-life (t1/2ß ) of 464.06 ± 104.08 min (7.73 ± 1.73 hr). Apparent volume of distribution based on the terminal phase (VZ /F) was 9.20 ± 2.70 L/kg, and apparent total body clearance (Cl/F) was 15.97 ± 1.28 ml min-1  kg-1 .

Pharmacokinetics and bioavailability of imidocarb dipropionate in swine.

A two-way crossover study was performed in eight healthy young pigs to determine the pharmacokinetics of imidocarb dipropionate (IMDP) following intravenous (2 mg/kg b.w.) and intramuscular (2 mg/kg b.w.) administrations. Each animal received one intravenous and one intramuscular injection with a 30-day washout period between the two-treatments. Plasma concentrations were measured by high-performance liquid chromatography (HPLC) assay with UV detector at regular intervals for up to 24 h post-injection. Intravenous plasma concentration profiles best fit a three-compartmental model yielding a mean system clearance (Cl((s))) of 558 mL/kg.h and a mean half-life of 13.91 h. Mean imidocarb AUC((0-infinity)) (microg.h/mL), V(c) (L/kg), V(d(area))(L/kg) and MRT((0-t)) (h) values were 3.58, 0.11, 14.36 and 1.46, respectively. Compartmental modeling of imidocarb, after intramuscular administration produced best fit for two-compartmental model yielding mean Kalpha (h(-1)), Cmax (microg/mL), tmax (h), and bioavailability (%) of 3.89, 2.02, 0.54, and 86.57 for the 2 mg/kg dose level. The present studies showed that IMDP was rapidly absorbed, widely distributed, and slowly eliminated. No adverse effects were observed in any of the pigs after i.v. and i.m. administrations of IMDP. The favorable PK behavior, such as the long half-life, acceptable bioavailability indicated that it is likely to be effective in pigs.

A cellular mechanism for imidocarb retention in edible bovine tissues.

Imidocarb dipropionate, formulated as Imizol, is used for the treatment and prophylaxis of bovine babesiosis. Several studies have shown that imidocarb remains detectable in edible ovine and bovine tissues for several months after dosing but the mechanism of retention remains unknown. In this study, the mechanism of imidocarb retention was investigated by measuring the binding of [14C]imidocarb to bovine hepatocytes, erythrocytes, sub-cellular fractions and isolated bovine macromolecules. The proportion of [14C]imidocarb (10 microM) bound to cells in suspension culture (1 x 10(7) cells.ml-1) was found to be substantially greater to hepatocytes (56.5%) than to erythrocytes (4.6%). Studies with washed erythrocytes reconstituted in plasma indicated that approximately 70% of the [14C]imidocarb was bound to plasma proteins, 10% to erythrocytes, and 20% remained free. Measurement of [14C]imidocarb binding to sub-cellular fractions prepared from bovine liver revealed preferential accumulation in the nuclear, rather than in the mitochondrial, microsomal or cytosolic fractions. Binding capacities of selected bovine macromolecules for [14C]imidocarb were in the order deoxy-ribonucleic acid (DNA) = ribonucleic acid (RNA) > > alpha 1-acid glycoprotein (AGP) > serum albumin (BSA) > haemoglobin (Hb). DNA binding sites for imidocarb remained unsaturated over the concentration range 0-100 microM [14C]imidocarb. Competitive binding studies between imidocarb and pentamidine or spermidine provided evidence for common DNA binding sites. These studies indicated that preferential binding of [14C]imidocarb to hepatocytes compared with erythrocytes observed in vitro was a result of substantial reversible binding to nucleic acids and that the same cellular mechanism may be implicated in the slow elimination of imidocarb from edible tissues in vivo.

Paired-ion extraction and high-performance liquid chromatographic determination of diminazene in cattle plasma: a modified method.

The high-performance liquid chromatographic method published by Aliu & Odegaard (1983) was found to give poor peak separation when used to determine plasma diminazene concentrations in cattle. Before bioequivalence studies could be carried out, the method had to be modified. Solid-phase extraction with acetonitrile/0.025 M Na-octane sulphonate and 2% acetic acid as eluent, followed by sample concentration, gave recoveries of > 90% for diminazene and the internal standard. A mobile phase of acetonitrile/0,005 M Na-octane sulphonate, 0.1% triethylamine, pH 3.2 with acetic acid on a Nova Pak C18 column was used for the analysis. Wavelength switching was used to determine the internal standard (imidocarb) and diminazene at their respective wavelengths of maximum absorbance, resulting in a fivefold increase in the limit of detection for diminazene. The modified method attained a detection limit of 2 ng.m.-1 (peak 4x baseline noise), limit of quantitation of 10 ng.m.-1 (coefficient of variation < 15%) and an accuracy of > 96% over the range from 10-5000 ng.m.-1.

Influence of Escherichia coli endotoxin-induced fever on pharmacokinetics of imidocarb in dogs and goats.

The pharmacokinetics of imidocarb, administered as an IV bolus dose (4 mg/kg), was studied in normal and Escherichia coli endotoxin-induced febrile dogs and goats. In the febrile group, the drug was administered 1 hour after injection of the endotoxin. The plasma and urine concentrations of imidocarb were measured by spectrophotometry. The decline in plasma drug concentrations in both species was analyzed, using a 2-compartment open model. With the exception of the coefficient A and the volume of central compartment, E coli endotoxin-induced fever produced the same changes in kinetic determinants in both species. Fever significantly decreased the distribution rate constant in both dogs (P less than 0.05) and goats (P less than 0.01). The elimination rate constant and, in turn, the half-life were not altered by the endotoxin-induced fever in either species. The volume of distribution at steady-state was significantly lower (P less than 0.01) in the febrile dogs and goats. The body clearance of imidocarb was also significantly lower in the febrile dogs (P less than 0.05) and goats (P less than 0.01). The decreased apparent volume of distribution and lower body clearance of imidocarb could explain the higher plasma values of the drug in the febrile, compared with normal, animals.

Pharmacokinetics of imidocarb in normal dogs and goats.

The pharmacokinetics of imidocarb were studied in seven mongrel dogs and eight crossbred goats. An intravenous bolus dose (4 mg/kg) of 12% imidocarb dipropionate solution was injected into the cephalic vein in dogs and the jugular vein in goats. The plasma concentration of imidocarb was measured by spectrophotometry. The experimental data were analysed using a two-compartment open model. The apparent volume of the central compartment was significantly higher (P less than 0.01) in dogs than in goats. The significantly larger (P less than 0.05) apparent specific volume of distribution in goats than in dogs may be attributed to passive diffusion followed by ion trapping of the drug in rumen fluid. Neither the half-life nor body clearance differed significantly between dogs (t1/2, 207 +/- 45 min; ClB, 1.47 +/- 0.38 ml/min kg) and goats (t1/2, 251 +/- 94 min; ClB, 1.62 +/- 0.50 ml/min kg). While almost 80% of the dose had been eliminated at 8 h in both species, the high ratio of the imidocarb level in the peripheral-to-central compartment in goats suggests that a prolonged period may be required for complete elimination of the drug.

Absorption, distribution, and excretion of imidocarb dipropionate in sheep.

Spectrophotometric and thin-layer chromatographic methods for determination of imidocarb in biological specimens are described. Following intravenous injection of imidocarb (2.0 mg/kg) into 3 sheep, plasma concentrations, initially averaging 10.8 microgram/ml, decreased to an average of 1.9 microgram/ml within 1 hour and then to less than 1 microgram/ml within the next 4 hours. When imidocarb (4.5 mg/kg) was injected intramuscularly (IM) into 7 sheep, peak plasma concentrations averaging 7.9 microgram/ml were achieved within 4 hours and then rapidly decreased to 4.6 microgram/ml within the next 2 hours. Plasma values then decayed very slowly by first-order kinetics and trace amounts were still present 4 weeks after treatment. Imidocarb was bound to plasma proteins and the apparent volume of distribution was estimated to be slightly higher than the total body water. The concentrations of the drug in the plasma and in the erythrocytes were approximately equal. Detectable amounts were present in all examined tissues 4 weeks after IM administration Twenty-four hours after IM administration, the highest concentrations were in kidney, liver, and brain. The 14C-labeled imidocarb could be detected in all regions of the central nervous system examined, in the hypophysis, and in the pineal body. Metabolic or biotransformation products were not detected by the methods used. Of the administered IM dose, 11 to 17% was excreted in the urine within 24 hours; thereafter, the excretion rate was low, and detectable amounts were still present in the urine for 4 weeks. Renal clearance of imidocarb was less than glomerular filtration rate, indicating net tubular reabsorption. The relatively high concentration of imidocarb in the bile suggests that the bile is an important route of excretion. High concentrations were also found in the mild of lactating ewes, but the drug could not be detected in the plasma of lambs fed milk from these ewes.