Showing papers in "Journal of Veterinary Pharmacology and Therapeutics in 2000"

Ochratoxin A from a toxicological perspective.

Abstract: Ochratoxin A (OTA) is a widespread mycotoxin which is produced mainly by the mould fungi Aspergillus ochraceus and Penicillum verrucosum during the storage of cereals, cereal products and other plant-derived products such as herbs, spices, grapes, etc. By carry over from mouldy fodder, ochratoxin A is also found in pork meat, offal and sausages containing pork blood. When ingested as a food contaminant, OTA is very persistent in human beings with a blood half-life of 35 days after a single oral dosage due to unfavourable elimination toxicokinetics. This renders the toxin among the most frequent mycotoxin contaminants in human blood in the EU, the US, Canada, and elsewhere, where it has been investigated. OTA is neither stored nor deposited in the body, but heterogeneous body distribution may impose serious damage to the kidneys. The toxin was classified a 2B cancer compound, being possibly carcinogenic for humans. It was among the strongest carcinogenic compounds in rats and mice. As the toxicological profile also includes teratogenesis, nephrotoxicity, and immunotoxicity, legislation authorities are currently discussing maximal residue levels (MRL) for OTA in various foodstuffs. In the present article arguments are presented which suggest an acceptable daily intake (ADI) of 1.5 ng OTA/kg body weight and a much lower MRL than 5 microgram OTA/kg cereals and cereal products as has been postulated by the EU commission.

Clinical effects and pharmacokinetics of medetomidine and its enantiomers in dogs.

Abstract: The clinical effects and pharmacokinetics of medetomidine (MED) and its enanti-omers, dexmedetomidine (DEX) and levomedetomidine (LEVO) were compared in a group of six beagle dogs. The dogs received intravenously (i.v.) a bolus of MED (40 microg/kg), DEX (20 and 10 microg/kg), LEVO (20 and 10 microg/kg), and saline placebo in a blinded, randomized block study in six separate sessions. Sedation and analgesia were scored subjectively, and the dogs were monitored for heart rate, ECG lead II, direct blood pressure, respiratory rate, arterial blood gases, and rectal body temperature. Blood samples for drug analysis were taken. Peak sedative and analgesic effects were observed at mean (+/- SD) plasma levels of 18.5 +/- 4.7 ng/mL for MED40, 14.0 +/- 4.5 ng/mL for DEX20, and 5.5 +/- 1.3 ng/mL for DEX10. The overall level of sedation and cardiorespiratory effects did not differ between MED40, DEX20 and DEX10 during the first hour, apparently due to a ceiling effect. However, the analgesic effect of DEX20 lasted longer than the effect of the corresponding dose of racemic medetomidine, suggesting greater potency for dexmedetomidine in dogs. Levomedetomidine had no effect on cardio-vascular parameters and caused no apparent sedation or analgesia. The pharmacokinetics of dexmedetomidine and racemic medetomidine were similar, but clearance of levomedetomidine was more rapid (4.07 +/- 0.69 L/h/kg for LEVO20 and 3.52 +/- 1.03 for LEVO10) than of the other drugs (1.26 +/- 0.44 L/h/kg for MED40, 1.24 +/- 0.48 for DEX20, and 0.97 +/- 0.33 for DEX10).

Pharmacokinetics and metabolic effects of triamcinolone acetonide and their possible relationships to glucocorticoid-induced laminitis in horses.

Abstract: Experiments were performed to establish the pharmacokinetics of triamcinolone acetonide and the effects of the glucocorticoid on glucose metabolism in horses. The pharmacokinetics after intravenous (i.v.) dosing was best described by a three-compartment open model. There was rapid distribution from the central compartment followed by two phases of elimination. The half-life of the rapid elimination phase was 83.5 min and of the slower phase was 12 h. The term (V-ss/V-c) - 1 was 12.3 indicating extensive distribution into the tissues. Triamcinolone acetonide given i.v. or intramuscularly (i.m.) induced a prolonged period of hyperglycaemia, hyperinsulinaemia and hypertriglyceridaemia. Significant changes in plasma glucagon and serum non-esterified fatty acids were not observed. These observations suggest that the hyperglycaemia was a result of decreased glucose utilization by tissues and increased gluconeogenesis. The effects on glucose metabolism persisted for 3-4 days after triamcinolone was given i.m. at 0.05 mg/kg, the upper limit of the recommended dose range, and for 8 days when given at 0.2 mg/kg. These observations, together with recent evidence implicating inhibition of glucose metabolism in the pathogenesis of equine laminitis, indicated that triamcinolone-induced laminitis may be associated with the long duration of action of the glucocorticoid when higher than recommended doses or when repeated doses are given.

Comparison of fluoroquinolone pharmacokinetic parameters after treatment with marbofloxacin, enrofloxacin, and difloxacin in dogs.

Abstract: Plasma, urine, and skin drug concentrations were determined for dogs (n=12) given five daily oral doses of marbofloxacin (MAR) (2.75 mg/kg), enrofloxacin (ENR) (5.0 mg/kg) or difloxacin (DIF) (5.0 mg/kg). Concentrations of the active metabolite of ENR, ciprofloxacin (CIP), were also determined. The three-period, three-treatment crossover experimental design included a 21-day washout period between treatments. Area under the plasma drug concentration vs. time curve (AUC0-last, microg/mLxh of MAR was greater than for ENR, CIP, ENR/CIP combined, and DIF. Maximum concentration (Cmax) of MAR was greater than ENR, CIP, and DIF. Time of maximum plasma concentration (Tmax) was similar for MAR and DIF; Tmax occurred earlier for ENR and later for CIP. Plasma half-life (t1/2) of MAR was longer than for ENR, CIP, and DIF. Urine concentrations of DIF were less than MAR or ENR/CIP combined, but urine concentrations of MAR and ENR/CIP combined did not differ. DIF skin concentrations were less than the concentrations of MAR or ENR/CIP combined 2 h after dosing, but skin concentrations of MAR and ENR/CIP combined did not differ.

Correlation between serum concentrations following continuous intravenous infusion of dexmedetomidine or medetomidine in cats and their sedative and analgesic effects.

Abstract: Dexmedetomidine (DEX) may have some therapeutic advantages over the racemate medetomidine (MED). Here we have examined how serum concentrations of DEX correlate with some of its anaesthetic effects. Cats (n = 6) were administered with a continuous stepwise intravenous (i.v.) infusion of DEX or MED on different occasions in a cross-over design. Maintenance infusion rates (mg/kg/min) used were: DEX = 0.25 (MED = 0.50); DEX = 1 (MED = 2) and DEX = 4 (MED = 8) for infusion steps 1, 2 and 3, respectively. Each maintenance infusion lasted at least 50 min and was preceded with a loading dose. There was no significant difference between serum DEX and 0.5 serum MED concentrations at any dose level nor was there a significant difference between serum DEX and the (entire) serum MED concentrations. There was no significant difference between DEX and MED for sedation, analgesia, muscular relaxation and heart and respiratory rates. For both DEX and MED, serum drug concentration and analgesia were dose-dependent and sedation increased until the end of infusion step 2 (dose level 2) and decreased at the end of step 3 (dose level 3). Muscular relaxation was not dose-dependent. We conclude that increasing the blood concentration of DEX or MED beyond a certain level decreases the level of sedation instead of increasing it even though analgesia increases. The rate at which DEX and MED are metabolized in cats may not be the same.

The pharmacokinetics and effects of intravenously administered carprofen and salicylate on gastrointestinal mucosa and selected biochemical measurements in healthy cats

Abstract: The pharmacokinetics of carprofen, a propionic acid-derived nonsteroidal anti-inflammatory (NSAID), and its effect on gastrointestinal mucosa, complete blood counts (CBC) and biochemical indicators of liver and renal function were investigated in healthy cats using a randomized crossover design A single dose of 4 mg/kg of carprofen (Zenecarp(R) Injection), normal saline, or 20 mg/kg of DL-lysine acetyl salicylate (Vetalgine(R)) was given intravenously (iv) to each of five cats with a washout period of 2 weeks between treatments Endoscopy of the stomach and duodenum 8 h postinjection revealed one acetyl salicylate-(aspirin)-treated cat with minor pinpoint erosions None of the other cats in the three treatment groups had evidence of bleeding or ulceration Serum biochemistry measurements of blood urea nitrogen (BUN), alanine transferase (ALT) and alkaline phosphatase (ALP) and complete blood counts (CBC) were not significantly altered from pretreatment values by the single dose of salicylate or carprofen (P < 005) Early and extended sample time points suggest that the pharmacokinetics of carprofen in the cat fit a 2-compartment model, with a long elimination half-life (t1/2) of 201 +/- 166 h, an area under the plasma concentration-time curve (AUC) of 637 (+/- 237) microgrammL/h and a volume of distribution (Vdss) of 014 +/- 005 L/kg Intravenously administered aspirin fit a 2-compartment model and had a long elimination half-life (t1/2) of 222 +/- 31 h, an AUC of 38242 +/- 5067 microgrammL/h and a volume of distribution (Vdss) of 017 +/- 0 01 L/kg

The behaviour of doramectin in the gastrointestinal tract, its secretion in bile and pharmacokinetic disposition in the peripheral circulation after oral and intravenous administration to sheep.

Abstract: Sheep were 'compartmentalized' by surgically implanting cannulae in the rumen, abomasum and terminal ileum with a re-entrant cannula inserted between the cystic duct and the duodenum to monitor bile secretion. Doramectin, containing a trace of [3H]-doramectin, was administered both intravenously (i.v.) and intraruminally (i.r.) at a dosage of 150 microg/kg. The pharmacokinetic behaviour of [3H]-labelled products was determined in these pools, and also in peripheral plasma, urine and faeces. Parent doramectin was also determined in plasma, abomasal digesta fluid and bile. Following i.r. administration, [3H] compounds were almost entirely associated with particulate digesta. A 14.5 h half-life in the rumen prolonged the presence of [3H] in the abomasum. Doramectin appeared to be degraded in abomasal digesta because only 24% of abomasal [3H] was attributed to the parent drug. Absorption of doramectin resulted in a systemic availability of 35%, of which 1.6 and 23.6% of the dose was contained in urine and biliary secretions, respectively. Following i.v. administration, almost negligible quantities of [3H] were secreted into the rumen or abomasum and only 2.7% of the dose was excreted in urine, whereas 132% was secreted in bile. This indicated that approximately one-third of biliary metabolites were enterohepatically recycled with biliary metabolites, elevating the proportion of [3H] in fluid digesta in the small intestine. Passage of the i.r.-administered drug through the gastrointestinal tract (GIT) resulted in virtually complete faecal excretion of [3H] within 5 days, whereas the continued secretion of i.v.-administered [3H] in bile prolonged the presence of [3H] in the GIT, with faecal clearance not being complete for at least 10 days. This multi-compartmental study has provided more information on the behaviour of doramectin than can be obtained from examining drug disposition in the peripheral circulation alone. With this knowledge, it is anticipated that opportunities for improving drug performance will be identified.

Pharmacokinetics of metronidazole in horses after intravenous, rectal and oral administration.

Abstract: Metronidazole pharmacokinetics in horses was studied after intravenous (i.v.), rectal (p.r.) and oral (p.o.) administration at 20 mg/kg using a triple crossover study design. Metronidazole mean+/-SD half-life was 196+/-39, 212+/-30 and 240+/-65 min after i.v., p.r. and p.o. administration, respectively. The metronidazole clearance was 2.8 (mL/min/kg) and the volume of distribution at steady state was 0.68 L/kg. The pharmacokinetic parameters calculated for metronidazole after administration of the drug by the various routes showed that bioavailability (74+/-18 vs. 30+/-9%) and maximum serum concentration (22+/-8 vs. 9+/-2 microg /mL) were significantly higher after p.o. administration compared with p.r. administration. There were no significant differences in mean absorption time (45+/-69 vs. 66+/-18 min) and the time to reach maximum serum concentration (65+/-36 vs. 58+/-18 min). The results indicated that p.r. administration of metronidazole to horses, although inferior to p.o. administration in terms of bioavailability, provides an alternative route of administration when p.o. administration cannot be used.

Effects of endotoxin-induced fever and probenecid on disposition of enrofloxacin and its metabolite ciprofloxacin after intravascular administration of enrofloxacin in goats

Abstract: Pharmacokinetics of enrofloxacin and its active metabolite ciprofloxacin were investigated in normal, febrile and probenecid-treated adult goats after single intravenous (i.v.) administration of enrofloxacin (5 mg/kg). Pharmacokinetic evaluation of the plasma concentration-time data of enrofloxacin and ciprofloxacin was performed using two- and one-compartment open models, respectively. Plasma enrofloxacin concentrations were significantly higher in febrile (0.75-7 h) and probenecid-treated (5-7 h) goats than in normal goats. The sum of enrofloxacin and ciprofloxacin concentrations in plasma > or =0.1 microg /mL was maintained up to 7 and 8 h in normal and febrile or probenecid-treated goats, respectively. The t1/2beta, AUC, MRT and ClB of enrofloxacin in normal animals were determined to be 1.14 h, 6.71 microg .h/mL, 1.5 h and 807 mL/h/kg, respectively. The fraction of enrofloxacin metabolized to ciprofloxacin was 28.8%. The Cmax., t1/2beta, AUC and MRT of ciprofloxacin in normal goats were 0.45 microg /mL, 1.79 h, 1.84 microg .h/mL and 3.34 h, respectively. As compared with normal goats, the values of t1/2beta (1.83 h), AUC (11.68 microg ? h/mL) and MRT (2.13 h) of enrofloxacin were significantly higher, whereas its ClB (430 mL/h/kg) and metabolite conversion to ciprofloxacin (8.5%) were lower in febrile goats. The Cmax. (0.18 microg /mL) and AUC (0.99 microg .h/mL) of ciprofloxacin were significantly decreased, whereas its t1/2beta (2.75 h) and MRT (4.58 h) were prolonged in febrile than in normal goats. Concomitant administration of probenecid (40 mg/kg, i.v.) with enrofloxacin did not significantly alter any of the pharmacokinetic variables of either enrofloxacin or ciprofloxacin in goats.

The effects of medetomidine and its reversal with atipamezole on plasma glucose, cortisol and noradrenaline in cattle and sheep.

Abstract: In the present study, we report the effect of medetomidine followed by atipamezole on plasma glucose, cortisol and noradrenaline in calves, cows and sheep. Eight calves, eight lactating dairy cows and eight adult female sheep were included in a crossover trial. The animals were injected i.v. with medetomidine (40 microg/kg), followed 60 min later by atipamezole i.v. (200 microg/kg) or saline. The wash-out period between experiments was 1 or 2 weeks. In every animal, medetomidine induced a marked hyperglycaemia, which was reversed by atipamezole. Cortisol levels increased significantly in cows and sheep, reaching levels 4-8-fold higher than the baseline levels 25-45 min after injection of medetomidine. Atipamezole did not affect the cortisol levels, except in sheep where an increase was observed. Plasma levels of noradrenaline decreased in cows and sheep after medetomidine injection, reflecting the inhibition of sympathetic activity by the drug. After injection of the antagonist, there was a large increase in noradrenaline levels. In conclusion, a high dose of medetomidine does not seem to reduce the overall endocrine stress response in cattle and sheep, which has previously been reported in other species.

Comparison of plasma pharmacokinetics and bioequivalence of ceftiofur sodium in cattle after a single intramuscular or subcutaneous injection

Abstract: Ceftiofur sodium, a broad-spectrum cephalosporin, is active against gram-positive and gram-negative pathogens of veterinary importance. This study was designed to compare the bioequivalence of the sodium salt in cattle after a single intramuscular (i.m.) or subcutaneous dose (s.c.) of 2.2 mg ceftiofur equivalents/kg body weight. The criteria used to evaluate bioequivalence were (1) the area under the curve from time of injection to the limit of quantitation (LOQ) of the assay (AUC0-LOQ), and (2) time concentrations remained above 0.2 microg/mL (t>0.2). Twelve crossbred beef cattle were enrolled in a three-period, two-treatment crossover trial, with a minimum 2-week washout period between doses of 2.2 mg ceftiofur equivalents/kg. Blood samples were collected serially for up to 72 h post-injection. Plasma samples were then analyzed using a validated assay that measures ceftiofur, and all desfuroylceftiofur-related metabolites, by high-performance liquid chromatography (HPLC) as the stable derivative, desfuroylceftiofur acetamide. A maximum plasma concentration (Cmax) of 13.9+/-3.55 microg/mL was observed from 0. 67-2.0 h after i.m. administration, whereas a Cmax of 13.6+/-3.85 microg/mL was observed from 0.67-3.0 h after s.c. administration. The AUC0-LOQ was 108+/-35.0 microg. h/mL after i.m. dosing, compared with 105+/-29.8 microg. h/mL after s.c. dosing. The pre-established criterion for equivalence of the AUC0-LOQ for the i.m. and s.c. routes of administration was satisfied. The t>0.2 was 49.2+/-8.55 h after i.m. administration, compared with 47.0+/-9.40 h after s.c. administration. The pre-established criterion for equivalence of the t>0.2 for i.m. and s.c. administration was satisfied. The equivalence of AUC0-LOQ and t>0.2 for i.m. and s.c. administration of 2.2 mg ceftiofur equivalents (CE)/kg doses of ceftiofur sodium suggest similar therapeutic efficacy and systemic safety for the two routes of administration.

Serum pharmacokinetics of oxytetracycline in sheep and calves and tissue residues in sheep following a single intramuscular injection of a long-acting preparation.

Abstract: The pharmacokinetics of a long-acting oxytetracycline (OTC) formulation (Liquamycin LA-200) injected intramuscularly (i.m.) at a dose of 20 mg/kg were determined in four calves and 24 sheep to determine if the approved label dose for cattle provided a similar serum time/concentration profile in sheep. The AUC for the calves was 168+/-14.6 (microg ? h/mL) and was significantly less than the AUC for sheep (209+/-43 microg ? h/mL). Using the standard two-stage approach and a one-compartment model, the mean Cmax for the calves was 5.2+/-0.8 microg /mL, and for the sheep was 6.1+/-1.3 microg /mL. The mean terminal phase rate constants were 0.031 and 0.033 h, and the Vdss were 3.3 and 3.08 L/kg for the calves and sheep respectively. Analysis of the data using the standard two-stage approach, the naive pooled-data approach and a population model gave very similar results for both the cattle and sheep data. Sheep tissue residues of OTC in serum, liver, kidney, fat, muscle and injection site were measured at 1, 2, 3, 5, 7 and 14 days after a single i.m. injection of 20 mg/kg OTC. Half-lives of OTC residues in the tissues were 38.6, 33.4, 28.6, 25.4, 21.3, and 19.9 h for injection site, kidney, muscle, liver, mesenteric fat and renal fat, respectively. The ratio of tissue to serum concentration was fairly consistent at all slaughter times, except for the fat and injection sites. The mean ratios were 1.72, 4.19, 0.11, 0.061, 0.84 and 827 for the liver, kidney, renal fat, mesenteric fat, muscle and injection sites, respectively. The tissue concentrations of OTC residues were below the established cattle tolerances for OTC in liver (6 p.p.m.), muscle (2 p.p.m.) and kidney (12 p.p.m.) by 48 h, and in injection site muscle by 14 days after the single i.m. injection of 20 mg/kg.

Chiral inversion of R(-) fenoprofen and ketoprofen enantiomers in cats.

Abstract: The chiral inversion process is a characteristic metabolic pathway for different aryl-2-propionic acids or profens. Important variations have been observed between these individual compounds as well as between animal species. In this study, R(-) fenoprofen [R(-)FPF] and R(-) ketoprofen [R(-) KTF] were used to investigate their comparative stereoconversion in cats. After intravenous (i.v.) administration of R(-) FPF, the percentage of chiral inversion was 93.20+/-13.70%. A highly significant correlation (r: 0.978) was observed between the clearance of R(-) FPF and the chiral inversion process. After i.v. administration of R(-) KTF, the percentage of inversion was only 36.73+/-2.8%. No correlation between the clearance of R(-) KTF and this process was observed. R(-) FPF was metabolized by the pathways of thioesterification - chiral inversion processes. For R(-) KTF, the competitive metabolic pathways, glucuronidation and hydroxylation may be involved. However, these metabolic steps are saturable or less functional in cats. Moreover, the thioesterification of R(-) KTF in in vitro studies has been shown to be important in carnivores. The lack of correlation between clearance and chiral inversion process of R(-) KTF may be finally explained by deviation of thioesterification to other metabolic pathways of lipids and/or aminoacid conjugation, particulary glicine derivatives.

Pharmacokinetics of gentamicin in mares in late pregnancy and early lactation.

Abstract: The disposition of drugs may differ between pregnant and nonpregnant animals, necessitating a change in dosage. We hypothesized that volume of distribution or clearance may be different for aminoglycoside antibiotics in pregnant mares vs. nonpregnant lactating mares. To examine this hypothesis, we administered gentamicin sulfate to seven Thoroughbred and Quarterhorse mares on two occasions, followed by plasma drug gentamicin assay and pharmacokinetic analysis. The first dose was administered 1-4 weeks before parturition (mean weight 578 kg) and the second dose was administered in the period 1-4 weeks after parturition (mean weight 518 kg). The dose administered at each time was approximately 6.6 mg/kg, intravenously (i.v.). Plasma gentamicin concentrations were determined using fluorescence polarization immunoassay and pharmacokinetic analysis was performed using a two-compartment open model. The plasma concentration vs. time profiles and total area-under-the-curve were almost identical for mares at late gestation vs. early lactation. Mean volume of distribution at steady-state was 0.15 (+/-0.02) and 0.16 (+/-0.03) L/kg, systemic clearance was 1.06 (+/-0.17) and 1.11 (+/-0.17) mL/kg/min, and mean (harmonic) elimination half-life was 2.2 and 2.1 h, for pregnant and nonpregnant mares, respectively. We concluded that there were no differences in drug distribution and clearance between pregnant and nonpregnant lactating mares. Gentamicin was also assayed in plasma of newborn foals after an injection of 6.6 mg/kg to three of the mares within 60 min of parturition. Gentamicin was undetectable in plasma samples from these foals and, therefore, apparently does not cross the placenta of mares at term.

Plasma pharmacokinetics of warfarin enantiomers in cats.

Abstract: The purpose of this study was to determine the dispositions of S-warfarin and R-warfarin in normal cats following intravenous and oral administrations of racemic warfarin. Citrated blood samples were collected from 10 cats prior to and at times 5, 15, and 30 min, 1, 2, 3, 4, 5, 6, 12, 24, 36, 48, 72, 96, and 120 h following a single intravenous bolus of 0.5 mg/kg of racemic warfarin. After a 21-day washout period, samples were then similarly collected in three groups of four cats for 120 h following oral administration of 0.1, 0.25, and 0.5 mg/kg racemic warfarin. S-warfarin and R-warfarin were detected using a high-performance liquid chromatography assay validated for cat plasma. Drug concentration-time curves were subjected to non-compartmental analysis. Median pharmacokinetic parameters associated with the intravenous administration of 0.5 mg/kg racemic warfarin were as follows: t1/2 (S:28.2, R:18.3 h), area under the plasma concentration-time curve (AUC; S:33.0, R:24.6 h*microg/mL), area under the moment curve (AUMC; S:1889, R:527.8 h*h*microg/mL), and mean residence time (MRT; S:38.7, R:20.9 h). For each parameter, S-warfarin was significantly different from R-warfarin (P 96.5%) protein-bound. Quantitation of the warfarin content in commercially available tablets indicated an unequal distribution of the drug throughout the tablet.

Single‐dose pharmacokinetics of flumequine in cod (Gadus morhua) and goldsinny wrasse (Ctenolabrus rupestris)

Abstract: Knowledge of the pharmacokinetic properties of drugs to combat bacterial infections in cod (Gadus morhua) and wrasse (Ctenolabrus rupestris) is limited. One antimicrobial agent likely to be effective is flumequine. The aim of this study was to investigate the pharmacokinetic properties of flumequine in these two species. Flumequine was administered intravenously to cod (G. morhua) at a dose of 5 mg/kg bodyweight and wrasse (C. rupestris) at a dose of 10 mg/kg. Flumequine was also administered orally to both species at a dose of 10 mg/kg body weight, and as a bath treatment at a dose of 10 mg/L water for 2 h. Identical experimental designs were used otherwise. The study was performed in seawater with a salinity of 3.2% and a temperature of 8.0 +/- 0.2 degrees C (cod) and 14.5 +/- 0.4 degrees C (wrasse). Pharmacokinetic modelling of the data showed that flumequine had quite different pharmacokinetic properties in cod and wrasse. Following intravenous administration, the volumes of distribution at steady-state (Vss) were 2.41 L/kg (cod) and 2.15 L/kg (wrasse). Total body clearances (Cl) were 0.024 L/hxkg (cod) and 0.14 L/hxkg (wrasse) and the elimination half-lives (t1/2lambda z) were calculated to be 75 h (cod) and 31 h (wrasse). Mean residence times (MRT) were 99 h (cod) and 16 h (wrasse). Following oral administration, the t1/2 lambda z were 74 h (cod) and 41 h (wrasse). Maximal plasma concentrations (tmax) were 3.5 mg/L (cod) and 1.7 mg/L (wrasse), and were observed 24 h post-administration in cod and 1 h post-administration in wrasse. The oral bioavailabilities (F) were calculated to be 65% (cod) and 41% (wrasse). Following bath administration, maximal plasma concentrations were 0.13 mg/L (cod) and 0.09 mg/L (wrasse), and were observed immediately after the end of the bath.

Pharmacodynamics of warfarin in cats.

Abstract: The overall purpose of this study was to evaluate the pharmacodynamic response to warfarin in cats. The specific aim was to determine if a log-linear indirect response model (Nagashima et al., 1969) used to describe the in vivo effect of warfarin in humans could be applied to cats. The pharmacokinetics of racemic warfarin were described using a non-compartmental approach. The relationship between prothrombin complex activity (PCA) and normalized prothrombin time (PTR) was defined for feline plasma under our experimental conditions, and determined to be: %PCA=12.38+648 e-PTR/0.492. These data were then integrated and used to predict the warfarin dose associated with therapeutic anti-coagulation defined as an International Normalized Ratio (INR) of 2.0-3.0. The maximum prothrombinopenic response to warfarin in cats after a single intravenous dose of 0.5 mg/kg occurred at 24-48 h. Pharmacodynamic modeling suggested that each cat had a narrow therapeutic range of the steady-state concentration of total warfarin required to appropriately block prothrombin complex synthesis (median: 265.2-358.7 ng/mL). The median daily dose range predicted to yield therapeutic concentrations of warfarin was 0.061-0.088 mg/kg per day. Wide inter-individual variations in both pharmacokinetics and pharmacodynamic response suggest that a more optimal dosing of warfarin may be possible with the development of individual pharmacokinetic/pharmacodynamic algorithms, analogous to those currently employed in human patients.

Iontophoresis of dexamethasone‐phosphate into the equine tibiotarsal joint

Abstract: In human rehabilitation medicine, dexamethasone-phosphate is theoretically iontophoresed to localized subcutaneous tissue where conversion to dexamethasone occurs. This delivery system has recently been introduced into veterinary medicine for the same purpose. However, the pharmacokinetic justification for parenteral delivery of this prodrug remains undocumented. Utilizing iontophoretic methods that are relevant to both human and veterinary clinical practice, the present investigation compared injection and iontophoresis of dexamethasone-phosphate into the equine tibiotarsal joint, also known as the tarsocrual joint. The tibiotarsal joints of seven horses were injected with 4 mL of 6 mg/mL dexamethasone-phosphate. With a similar drug concentration and over the same application site, six different horses underwent simultaneous cathodic iontophoresis (4 mA, 40 min) or passive application (0 mA, 40 min) on contralateral limbs. Following all applications, tibiotarsal joint synovium was collected. Local venous blood samples were also collected from the iontophoretic and passive application sites for analysis of plasma drug concentrations. Because of the potential for conversion of dexamethasone-phosphate to dexamethasone, an extraction and analysis protocol was developed for both chemicals. The technique demonstrated a linear range of detection (0.39-12 microg/mL) and a capability for measuring both chemicals in plasma and synovium. Conversion of dexamethasone-phosphate to dexamethasone occurred during synovial incubation (37 degrees C) and following freeze-thaw cycles. In contrast to the measurable synovial concentrations of dexamethasone-phosphate (2.3 +/- 0.96 mg/mL) and dexamethasone (0.27 +/- 0.07 mg/mL) following injection, neither drug was detected in the synovium or the local venous blood following iontophoretic or passive applications. In conclusion, these results do not confirm iontophoretic or passive delivery of measurable dexamethasone-phosphate into the tibiotarsal joint using current clinical methods.

Changes in serum thyroxine and thyroid-stimulating hormone concentrations in epileptic dogs receiving phenobarbital for one year.

Abstract: A multicentric prospective study was conducted to monitor the effect of phenobarbital on serum total thyroxine (T4) and thyroid-stimulating hormone (TSH) concentrations in epileptic dogs. Serum T4 concentrations were determined for 22 epileptic dogs prior to initiation of phenobarbital therapy (time 0), and 3 weeks, 6 months, and 12 months after the start of phenobarbital. Median T4 concentration was significantly lower at 3 weeks and 6 months compared to time 0. Thirty-two percent of dogs had T4 concentrations below the reference range at 6 and 12 months. Nineteen of the 22 dogs had serum TSH concentrations determined at all sampling times. A significant upward trend in median TSH concentration was found. No associations were found between T4 concentration, dose of phenobarbital, or serum phenobarbital concentration. No signs of overt hypothyroidism were evident in dogs with low T4, with one exception. TSH stimulation tests were performed on six of seven dogs with low T4 concentrations at 12 months, and all but one had normal responses. In conclusion, phenobarbital therapy decreased serum T4 concentration but did not appear to cause clinical signs of hypothyroidism. Serum TSH concentrations and TSH stimulation tests suggest that the hypothalamic-pituitary-thyroid axis is functioning appropriately.

Tissue distribution of benzylpenicillin after intramammary administration in the isolated perfused bovine udder.

Abstract: Udders from previously healthy lactating cows were perfused with warmed and gassed Tyrode solution in vitro. Benzylpenicillin was administered in three formulations: an oily suspension with micronized particles of <10 microm diameter, an oily suspension with average particle size of 40 microm and an aqueous solution (3 million IU benzylpenicillin-potassium, volume 15 mL). The antibiotics were administered intracisternally to six front and six rear quarters each. Moreover, a dry-off-ointment (100 000 IU benzylpenicillin-potassium and 100 000 IU benzylpenicillin-benzathine, volume 7.5 mL) was tested in four udder halves. Perfusate samples were collected over 3 h. Furthermore, glandular tissue at different vertical distances from the teat base and the regional lymph node were sampled after 3 h. The determination of benzylpenicillin was performed by high pressure liquid chromatography with UV detection. With increasing distance from the teat base, the concentration of benzylpenicillin in tissue exponentially decreased. Using the aqueous solution or oily suspension that contained micronized active principle, higher concentrations were reached compared to the formulation with particle sizes of 40 microm. In udder lymph nodes, the concentration was highest after treatment with the coarse suspension. The transfer from the dry-off-ointment with benzathine-salt into perfusate was very low. These results suggest that it is possible to study tissue distribution of antibiotics in the isolated perfused bovine udder.

The effect of raloxifene on coronary arteries in aged ovariectomized ewes.

Abstract: Background – Ovariectomized sheep are a useful model of postmenopausal osteoporosis and other postmenopausal conditions. Estrogen may have a protective effect on the coronary arteries in postmenopausal women. The effects of raloxifene, a selective estrogen receptor modulator, on coronary arteries in aged ovariectomized ewes was investigated. Methods and Results – Forty eight aged ewes were randomly assigned to undergo sham surgery (Sham, n=7), ovariectomy (OVX, n=10), ovariectomy with estradiol supplementation (OVXE, n=8), ovariectomy with raloxifene supplementation, 0.02 mg/kg per day (RAL1, n=10), or ovariectomy with raloxifene supplementation, 0.10 mg/kg per day (RAL2, n=13). Contrast coronary angiography was performed 6 months after intervention. Diameters of the right main and left anterior descending coronary arteries in the RAL1, RAL2 and Sham groups were not different from each other, but were significantly greater than the OVX and OVXE groups. Intracoronary nitroglycerin did not affect the relationships of the diameters in any group. There were no differences in vascular remodeling between the groups. Conclusions – The results indicate that raloxifene in this sheep model allows greater dilation of coronary arteries than estrogen. Raloxifene may provide a significant protective functional effect on coronary arteries in postmenopausal heart disease.

Enhanced plasma and target tissue availabilities of albendazole and albendazole sulphoxide in fasted calves: evaluation of different fasting intervals.

Abstract: The influence of different pre- and post-treatment fasting periods on the plasma availability and disposition kinetics of albendazole (ABZ) and its sulphoxide metabolite (ABZSO) in cattle was investigated. The effect of fasting on the distribution of ABZ and ABZSO to different target tissues/fluids was also characterised. In Experiment I, 35 parasite-free Holstein calves were divided into seven groups according to the following feeding conditions and treated intraruminally with ABZ (10 mg/kg): control group (fed ad libitum), 24 h fasting either prior to (24 h pre-) or post (24 h post-) treatment, 24 h fasting with either 6 (6 h pre + 18 h post) or 12 h (12 h pre + 12 h post-) of feed restriction prior to treatment, 12 h fasting either prior to (12 h pre-) or post (12 h post) treatment. In Experiment II, calves from the same pool of animals were subjected to a 24 h fasting period prior to the same ABZ treatment and killed (two animals) at either 24, 36 or 48 h post-administration to obtain samples of abomasal/intestinal mucosa and fluid contents, bile and lungs. Plasma (Experiment I) and tissues/fluids (Experiment II) samples were analysed by HPLC. All the fasting periods investigated induced marked changes to the plasma availability and disposition kinetics of the ABZSO metabolite. Enhanced plasma availability between 37 and 118%, delayed peak concentrations and extended mean residence times for ABZSO were observed in fasted compared to fed calves. The changes in plasma kinetics, reflecting an altered quantitative gastrointestinal absorption, were reflected in increased availability of ABZ and ABZSO in the target tissues/fluids of fasted calves. The availabilities of ABZ and ABZSO in the gastrointestinal mucosa and fluids in fasted calves were markedly greater than in those fed ad libitum.

The binding and distribution of albendazole and its principal metabolites in Giardia duodenalis

Abstract: Trophozoites of the protozoan parasite Giardia duodenalis were exposed to various albendazole concentrations for 4 h, washed, fixed and incubated with antibodies raised against albendazole and its two major metabolites albendazole sulphoxide and albendazole sulphone. Tubulin antibodies were also used. A peroxidase- or FITC-conjugated secondary antibody was used to detect the primary antibody with transmission electron microscopy or confocal laser scanning microscopy, respectively. Albendazole, a benzimidazole compound, was detected in the mid-dorsal region of trophozoites, albendazole sulphoxide in the posterior-dorsal region and albendazole sulphone in clusters above the median bodies. Tubulin was recognised in the ventral disk. This is the first indication that G. duodenalis may be capable of metabolising albendazole and the potential path of the metabolised drug traced within the trophozoite. Fluorescence measurements revealed that albendazole sulphoxide binding decreased and albendazole sulphone binding increased with exposure of the trophozoites to increasing albendazole concentration. This indicates that if albendazole was being metabolised by trophozoites, it occurred to a greater extent following exposure to higher albendazole concentrations.

Characterization of urinary metabolites of testosterone, methyltestosterone, mibolerone and boldenone in greyhound dogs

Abstract: Androgenic steroids are used in female greyhound dogs to prevent the onset of estrus; moreover, these steroids also have potent anabolic activity. As anabolic steroids increase muscle mass and aggression in animals, the excessive use of these agents in racing greyhounds gives an unfair performance advantage to treated dogs. The biotransformation of most anabolic steroids has not been determined in greyhound dogs. The objective of the present study was to identify the urinary metabolites of testosterone, methyltestosterone, mibolerone, and boldenone in greyhound dogs. These steroids were administered orally (1 mg/kg) to either male or female greyhound dogs and urine samples were collected pre-administration and at 2, 4, 8, 12, 24, 72, and 96 h post-administration. Urine extracts were analyzed by high-performance liquid chromatography/mass spectrometry (HPLC/MS) to identify major metabolites and to determine their urinary excretion profiles. Major urinary metabolites, primarily glucuronide, conjugated and free, were detected for the selected steroids. Sulfate conjugation did not appear to be a major pathway for steroid metabolism and excretion in the greyhound dog. Phase I biotransformation was also evaluated using greyhound dog liver microsomes from untreated dogs. The identification of several in vivo steroid metabolites generated in this study will be useful in detecting these steroids in urine samples submitted for drug screening.

Withdrawal time estimation of veterinary drugs: extending the range of statistical methods.

Abstract: In order to use a drug in a food producing animal, evidence has to be provided that after a certain withdrawal time, drug residues in tissues, such as muscle meat, fat, liver, kidney etc., are below a given maximum residue limit (MRL), for a majority of animals. Several statistical methods, both regression based and nonparametric based methods, have been proposed, each relying on different sets of assumptions, which may or may not hold for the specific data situation. The purpose of this paper is to enrich the range of methods, i.e. to provide approaches for situations where current methods are inappropriate. Bayesian methods, using Markov chain Monte Carlo, are proposed to derive inference on the parameters of interest.

Response to criticisms of the US FDA parametric approach for withdrawal time estimation: rebuttal and comparison to the nonparametric method proposed by Concordet and Toutain.

Abstract: The benefits and drawbacks of using nonparametric methods for estimating product withdrawal times have been debated for many years. This issue was recently revived by Concordet & Toutain (1997a, b) when they described a nonparametric method for withdrawal time estimation. The authors urged the international adoption of this approach, basing their recommendation on three fundamental concerns: (1) the lack of a consistent official procedure for determining a withdrawal time within the European Union (EU); (2) the need to identify a statistical method for improving the international harmonization of withdrawal times for new chemical entities; and (3) a lack of confidence in the robustness of the US Food and Drug Administration/Center for Veterinary Medicine (US FDA) procedure, particularly with respect to minor violations in the underlying parametric assumptions. Due to the critical nature of these issues, the US FDA considers it vital to respond to these concerns. This paper provides a description of the US FDA parametric procedure. We also examine the statistical concerns expressed by Concordet and Toutain, identifying the reasons for our confidence in the US FDA parametric approach. Finally, using their Monte Carlo simulation models, we generate additional datasets to explore the behaviour of their nonparametric procedure and evaluate its ability to support US FDA regulatory activities.