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This study aimed to investigate pharmacokinetics of fluoxetine in horses and validate a method for liquid chromatography mass spectrometry analysis of serum levels. Fluoxetine pharmacokinetics were determined using 10 healthy, adult horses. Fluoxetine pharmacokinetics following a single oral dose (0.25 mg/kg) were determined using blood samples collected prior to and at several time points over 7 days following administration. Serum concentrations of fluoxetine and its bioactive metabolite norfluoxetine were measured using liquid chromatography coupled to an accurate mass/high-resolution mass spectrometer. Pharmacokinetic parameters were estimated using a noncompartmental model. Time to maximum serum concentration and serum half-life of fluoxetine was 1.5 and 15.6 h, respectively. Steady-state serum concentrations were evaluated using five horses each receiving fluoxetine (0.25 mg/kg, PO, q24hrs) for 8 weeks and were found to be 62.9 ± 25.5 ng/ml on average. Norfluoxetine was not detected in any sample.

Methocarbamol (MCBL) is commonly used in performance horses for the treatment of skeletal muscle disorders. Current regulatory recommendations for show horses and racehorses are based on a single oral dose of 5 g, although doses in excess of this are often administered. The goal of the current study was to characterize the disposition of MCBL following higher dose administration and administration in combination with another commonly used drug in performance horses, phenylbutazone (PBZ). Exercised Thoroughbred horses were administered various doses of MCBL as a sole agent and MCBL in combination with PBZ. Blood samples were collected at various times, concentrations of MCBL and PBZ measured using LC-MS/MS and pharmacokinetic parameters calculated using compartmental analysis. Following administration of 15 g of MCBL, either as part of a single- or multiple-dose regimen, a number of horses exceeded the Association of Racing Commissioners International and the United States Equestrian Federation's recommended regulatory threshold at the recommended withdrawal time. There was not a significant difference between horses that received only MCBL and those that received MCBL and PBZ. Results of the current study support an extended withdrawal guideline when doses in excess of 5 g are administered.

Pimobendan is an inodilator used in the treatment of canine congestive heart failure (CHF). The aim of this study was to investigate the pharmacokinetics and cardiovascular effects of a nonaqueous oral solution of pimobendan using a single-dose, operator-blinded, parallel-dose study design. Eight healthy dogs were divided into two treatment groups consisting of water (negative control) and pimobendan solution. Plasma samples and noninvasive measures of cardiovascular function were obtained over a 24-h period following dosing. Pimobendan and its active metabolite were quantified using an ultra-high-performance liquid chromatography–mass spectrometer (UHPLC-MS) assay. The oral pimobendan solution was rapidly absorbed [time taken to reach maximum concentration (Tmax) 1.1 h] and readily converted to the active metabolite (metabolite Tmax 1.3 h). The elimination half-life was short for both pimobendan and its active metabolite (0.9 and 1.6 h, respectively). Maximal cardiovascular effects occurred at 2–4 h after a single oral dose, with measurable effects occurring primarily in echocardiographic indices of systolic function. Significant effects persisted for

The objective of this study was to evaluate the pharmacokinetic properties and physiologic effects of a single oral dose of alprazolam in horses. Seven adult female horses received an oral administration of alprazolam at a dosage of 0.04 mg/kg body weight. Blood samples were collected at various time points and assayed for alprazolam and its metabolite, α-hydroxyalprazolam, using liquid chromatography/mass spectrometry. Pharmacokinetic disposition of alprazolam was analyzed by a one-compartmental approach. Mean plasma pharmacokinetic parameters (±SD) following single-dose administration of alprazolam were as follows: Cmax 14.76 ± 3.72 ng/mL and area under the curve (AUC0-∞ ) 358.77 ± 76.26 ng·h/mL. Median (range) Tmax was 3 h (1-12 h). Alpha-hydroxyalprazolam concentrations were detected in each horse, although concentrations were low (Cmax 1.36 ± 0.28 ng/mL). Repeat physical examinations and assessment of the degree of sedation and ataxia were performed every 12 h to evaluate for adverse effects. Oral alprazolam tablets were absorbed in adult horses and no clinically relevant adverse events were observed. Further evaluation of repeated dosing and safety of administration of alprazolam to horses is warranted.

Eastern box turtle (Terrapene carolina) populations have significantly declined throughout their range (Currylow et al., 2011). While a combination of factors are likely playing a role in the decline of the box turtle, disease outbreaks have been emerging across the Eastern United States in chelonians and may be important (De Voe et al., 2004; Johnson et al., 2008; Allender et al., 2011). Herpesviruses and iridoviruses are two common virus families that lead to clinical signs of upper respiratory tract disease in affected chelonians (Harper et al., 1982; Brown et al., 1999; Johnson et al., 2008; Allender et al., 2011). Acyclovir has been used anecdotally in the treatment of both viral agents in chelonians (Marschang et al., 1997; De Voe et al., 2004; Funk & Diethelm, 2006); however, to date, only a single pharmacokinetic study has been performed in a single species (Gaio et al., 2007). Acyclovir and its pro-drug valacyclovir are guanine analogue antiviral drugs (Elion, 1993). They are activated by phosphorylation of a virus-specific thymidine kinase (TK). Acyclovir uptake has been shown to be enhanced in herpesvirus-infected cells, with a 10to 30-fold greater affinity for infected cells than uninfected cells (Beutner, 1995). Once incorporated into the viral genome, relatively low levels of the drug are needed to achieve viral inhibition, and adequate intracellular concentrations can be maintained for several hours (Beutner, 1995). Thymidine kinase genes or functional TK enzymes have similarly been identified in iridoviruses (Scholz et al., 1988; Jakob et al., 2001; Coupar et al., 2005; Tsai et al., 2005). This study evaluated the pharmacokinetics of acyclovir and valacyclovir after a single oral dose in twelve North American box turtles. Animals were housed individually in Vision cages (Model #332; Vision Products Plus Inc., Canoga Park, CA, USA) that maintained a thermal gradient of 72 F to 87 F. A varied diet of fruits and vegetables was provided every other day. All activities were approved by the University of Illinois IACUC (protocol 11003). A pilot study using oral acyclovir was initially performed at doses of 40 and 80 mg ⁄kg in one animal each. After the results demonstrated low maximum observed plasma concentration (Cmax) at the doses used, a decision was made to evaluate the pharmacokinetics of oral valacyclovir at 20 and 40 mg ⁄kg in one animal each. Based on these results, eight animals were administered a single oral dose of 40 mg ⁄kg valacyclovir. Venipuncture was performed via the subcarapacial sinus for all phases of the study. For the final study, blood (up to 0.3 mL) was collected in a 3-mL syringe with a 22-ga needle at 0, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, and 120 h following oral valacyclovir. Samples were placed in a lithium heparin microtainer (Becton Dickinson, Franklin Lakes, NJ, USA), centrifuged immediately, the plasma placed in a separate cryovial, and stored at )20 C. Samples were transported on dry ice to the Pharmacology Laboratory at the University of Tennessee for analysis. Plasma samples were analyzed using a reverse-phase highperformance liquid chromatography method (HPLC). The system consisted of a 2695 separations module, a 2475 fluorescence detector, and a computer equipped with Empower software (Waters, Milford, MA, USA). Valacyclovir and acyclovir were extracted from plasma samples using 1 cc HLB solid-phase extraction (SPE) cartridges. The compounds were separated on an Atlantis T3 (4.6 · 100 mm, 5 lm) column with a guard column. The mobile phase was a mixture of (A) 10 mM ammonium phosphate pH 2.9 and (B) acetonitrile (97:3). The flow rate was 1.2 mL ⁄min, and the column temperature was ambient. Fluorescence was measured at an excitation of 260 nm and an emission of 375 nm with a gain of ·100. Standard curves for plasma analysis were prepared by fortifying untreated, pooled turtle plasma with valacyclovir and acyclovir to produce a linear concentration range of 10–1500 ng ⁄mL. Average recovery for both drugs was 87%, while intraand inter-assay variabilities were

KuKanich, B., Hubin, M. The pharmacokinetics of ketoconazole and its effects on the pharmacokinetics of midazolam and fentanyl in dogs. J. vet. Pharmacol. Therap. 33, 42–49. Ketoconazole inhibits the Cytochrome P450 3A12 (CYP3A12) metabolizing enzyme as well as the p-glycoprotein efflux pump. The extent and clinical consequence of these effects are poorly understood in dogs. The objective was to assess the pharmacokinetics of ketoconazole after single and multiple doses and the effect of multiple doses of ketoconazole on midazolam (a known CYP3A12 substrate) and the opioid fentanyl. Six greyhound dogs were studied. The study consisted of three phases. Phase 1 consisted of i.v. midazolam (0.23 mg/kg base) and fentanyl (15.71 μg/kg base). Phase 2 consisted of a single oral dose of ketoconazole (mean dose 12.34 mg/kg). Phase 3 consisted of i.v. midazolam (0.23 mg/kg) and fentanyl (10 μg/kg) after 5 days of oral ketoconazole (12.25 mg/kg/day). Ketoconazole significantly inhibited its own elimination with the mean residence time (MRT) increasing from 6.24 h in Phase 1 to 12.54 h in Phase 3. Ketoconazole significantly decreased the elimination of midazolam, as expected, with the MRT increasing from 0.81 to 1.49 h. The elimination of fentanyl was not significantly altered by co-administration of ketoconazole with the MRT being 3.90 and 6.35 h. The MRT was the most robust estimate of decreased drug elimination.

The objective of this study was to describe the population pharmacokinetics (PK) of mosapride under fasting and fed conditions. A single 5-mg oral dose of mosapride was administered to fasted (n = 15) and fed (n = 12) beagle dogs. Plasma concentrations of mosapride were subsequently measured by liquid chromatography-tandem mass spectrometry. Data were analyzed using modeling approaches with the NONMEM 7.2 software. A one-compartment open PK model utilizing model event time (MTIME) with first-order absorption and first-order elimination was found to be more appropriate than all other PK models tested. The absorption rate constants of mosapride were significantly decreased under fed conditions, compared to fasting conditions. The observed bootstrap medians of PK parameters were generally consistent with the corresponding population mean estimates. Furthermore, with the exception of some mosapride concentrations, most of observed data fell into the range of the 5th and 95th percentiles of the simulated values. Overall, the final model was able to describe the observed mosapride concentrations reasonably well. These findings suggest that food intake affects both the rate and extent of absorption of mosapride and that the pharmacological effect of mosapride can differ significantly depending on food intake.

Clomipramine is a tricyclic antidepressant that has been recommended for the treatment of canine compulsive disorder. The pharmacokinetics of clomipramine in dogs have not been reported. This study describes the pharmacokinetics of clomipramine and its active metabolite, desmethylclomipramine, in six male dogs. Serial blood samples were collected following both a single oral dose of clomipramine (3 mg/kg) and 28 consecutive daily oral doses (3 mg/kg q 24 h). In addition, 'peak' and 'trough' samples were taken throughout the 28-day dosing period. Plasma was assayed for total (free and protein-bound) clomipramine and desmethylclomipramine, using gas-chromatography with mass spectrometric detection. Various pharmacokinetic parameters were then determined. Following a single dose of clomipramine, time of maximum plasma concentration (tmax) of clomipramine was 0.75-3.1 h, maximum plasma concentration (Cmax) was 16-310 ng/mL and elimination half-life (t1/2el) was 1.2-16 h; tmax of desmethylclomipramine was 1.4-8.8 h, Cmax was 21-134 ng/ mL and t1/2el was 1.2-2.3 h. Following multiple dosing, there was a numeric increase in these parameters; tmax of clomipramine was 3-8 h, Cmax was 43-222 ng/mL and t1/2el was 1.2-16 h; tmax of desmethylclomipramine was 1.4-8.8 h, Cmax was 21-134 ng/mL and t1/2el was 1.2-2.3 h. Clinically significant differences between dogs and humans in the pharmacokinetics of oral clomipramine are discussed.

Using scintillation counting and autoradiographical techniques, the whole-body distribution in week-old uninfected chickens of the anticoccidial agent sulphaquinoxaline (SQ) labelled with 35S was established at various time intervals after a single oral dose either alone or following continuous in-feed medication with unlabelled SQ, and after a single intravenous dose. The distribution was also established in chickens infected with the coccidia Eimeria acervulina or E. tenella, after a single oral dose of radiolabelled SQ administered either alone or following continuous in-feed medication with unlabelled SQ, as for uninfected chicks. In all uninfected chicks, SQ was rapidly absorbed from the gut and was distributed to all tissues. It appeared at high concentrations in the bile and kidneys 0.5 h after dosing. In chickens that had previously received unlabelled SQ in the diet, a radiolabelled dose maintained steadier tissue concentrations than the sharp rise and fall detected after a single oral dose. Intravenous dosing of uninfected chicks showed that SQ was secreted by the crop, gizzard and caecal epithelia into their lumina. Infection with E. acervulina or E. tenella coincided with an overall 3.5-fold sustained increase of SQ concentration in chick tissues. An updated hypothesis including these new observations for the anticoccidial mode of action of SQ in chickens is expounded.

Aspirin disposition in immature and adult dogs, assessed by plasma salicylate concentrations following single doses of aspirin given orally (p.o.) and intravenously (i.v.), was compared. Using a cross-over design, four immature (12-16-weeks-old) and eight adult (1-2-years-old) dogs were given a single dose of aspirin at 17.5 mg/kg body weight i.v. and a single dose of buffered aspirin at 35 mg/kg body weight p.o. Blood was collected from the jugular vein for 24 h following each dose. A fluorescence polarization immunoassay was used for determination of salicylate in plasma. Significant differences in aspirin disposition were identified between the two groups. Immature dogs had significantly shorter salicylate half-life, lower mean residence time, and more rapid salicylate clearance than adult dogs. The difference in volume of distribution between the two groups was not significantly different. Immature dogs had lower mean (+/- SD) peak plasma salicylate concentrations (64.5 +/- 2.38 mg/L) than adult dogs (95.9 +/- 12.2 mg/L) following a single oral dose of buffered aspirin at 35 mg/kg body weight. Predicted plasma salicylate concentration-time curves were constructed for various aspirin dosage regimens. This analysis showed that the previously recommended buffered aspirin dose for adult dogs of 25 mg/kg body weight p.o. every 8 h would be ineffective in maintaining plasma salicylate concentrations > 50 mg/L in immature dogs.

Pharmacokinetics of tinidazole in dogs and cats after single intravenous (15 mg/kg) and oral doses (15 mg/kg or 30 mg/kg) were studied in a randomized crossover study. Tinidazole was completely absorbed at both oral dose levels in cats and dogs. Peak tinidazole concentration in plasma was 17.8 micrograms/ml in dogs and 22.5 micrograms/ml in cats after 15 mg/kg p.o. The oral dose of 30 mg/kg resulted in peak levels of 37.9 micrograms/ml in dogs and 33.6 micrograms/ml in cats. The apparent total plasma clearance of the drug was about twofold higher in dogs than in cats, resulting in an elimination half-life that was twice as long in cats (8.4 h) as in dogs (4.4 h). The apparent volume of distribution was 663 ml/kg in dogs and 536 ml/kg in cats. Therapeutic plasma drug concentrations higher than the MIC values of most tinidazole-sensitive bacteria were achieved for 24 h in cats and for 12 h in dogs after a single oral dose of 15 mg/kg. From the pharmacokinetic standpoint tinidazole seems to be well-suited to clinical use in small animal practice.

The pharmacokinetics of propranolol were investigated in dogs following intravenous, single oral, and multiple oral doses. Mean half-life of the compound following single intravenous administration was 1.09 h, following single oral dose 1.58 h, and 2.14 h after chronic oral dosing. Half-life values previously reported in dogs for the levo and dextro isomers were 0.77 and 1.08h, respectively. The bioavailability of oral propranolol was low (2–17% available) following a single oral dose, but increased substantially after chronic oral dosing, suggesting saturation of the disposition processes for propranolol with multiple dosing regimens.

Adult Fasciola hepatica recovered from sheep 12 and 24 h after a single oral dose of albendazole (20 mg/kg) contained significant amounts of two oxidized metabolites of albendazole (ABZ), a sulphoxide (SX) and a sulphone (SO), but not ABZ. Flukes incubated in vitro with 10 microM SX or SO contained these metabolites at a level two to three times the level observed in flukes recovered from sheep 24 h after a curative oral dose of ABZ. The concentration of ABZ in flukes was 10-fold greater than either SX or SO after a 24 h in vitro incubation in 10 microM of the respective drug. Flukes exposed to ABZ in vitro contained two-fold higher SX levels than SX-treated flukes due to a combination of spontaneous oxidation in media and fluke-mediated oxidation of ABZ. Measurement of end-products of glucose metabolism following 24 h incubation in 10 microM of either ABZ, SX or SO did not show a significant difference between treated and untreated flukes.

Two possible causes of violative sulfonamide residues in swine were studied. To determine if sulfamethazine accumulated in the tissues of swine when the drug was administered in feed, the rates of plasma drug disappearance following a single oral dose and continuous feeding of the drug were compared. The rate of plasma drug disappearance was not significantly different (alpha = 0.05) when the two methods of drug dosing were compared. When feed containing 2 micrograms sulfamethazine/gm was fed to swine during a 7-day period preceding slaughter, the animal's liver contained violative residues. Violative concentrations of sulfamethazine were detected in the livers, kidneys, and skeletal muscle of swine which consumed feed containing 8 micrograms sulfamethazine/gm.

Ravis, W.R., Duran, S.H., Pedersoli, W.M. & Schumacher, J. A pharmacokinetic study of phenobarbital in mature horses after oral dosing. J. vet. Pharmacol. Therap.10, 283–289. The pharmacokinetics of phenobarbital were determined in six mature horses after a single oral dose. Horses were administered a 5.5 mg/kg of body weight oral dose of phenobarbital tablets. Based on the combined evaluation of i.v. and oral results, phenobarbital displayed two-compartment pharmacokinetics in the horse with a terminal half-life of 19.0 ± 4.4 (mean ± SD) h. This half-life is considerably shorter than those reported for dogs and humans. The steady-state volume of distribution (Vdss/F) and the total body clearance (Cl1/F) of phenobarbital were 0.753 ± 0.115 1/kg and 27.9 ± 9.2 ml/h/kg, respectively. The average extent of oral absorption was 101% with a range of 76 to 124% among the six horses. Examination of the absorption kinetics demonstrated a biphasic absorption process in four horses with a rapid absorption followed by a slower absorption phase. The mean residence time (MRT) was 36.9 ± 4.1 h and the mean residence time for oral absorption (MRTabs) was 11.3 h. Based on the results of the present study, an oral dosing regimen of 11 mg/kg of body weight every 24 h can be recommended.