Pharmacokinetics and pharmacodynamics of intravenously and subcutaneously administered pantoprazole in sheep (Ovis aries).

Abomasal ulcers are recognized in sheep of all ages, but research regarding therapeutic interventions is limited. Proton Pump Inhibitors (PPIs) such as pantoprazole, are clinically used with a paucity of evidence regarding efficacy in mature sheep. Intravenous and subcutaneously administered pantoprazole dosed at 1.0 mg/kg in adult sheep will increase the pH of abomasal fluid compared to pre-administration baseline. The objectives were to assess the effect of pantoprazole, after single and multiple administration, on abomasal fluid pH in adult sheep. A third objective was to describe the pharmacokinetic parameters of IV and SC pantoprazole. Four clinically healthy adult Southdown ewes previously fitted with a gastrostomy tube in the abomasum were utilized in this randomized, 2-way cross-over trial. Ewes received pantoprazole (1.0 mg/kg) as a single and 3-dose regimen (every 24 hours). After a 10 day washout period the reverse treatment was applied. Blood for analysis of pantoprazole concentration was collected intermittently for 24 hours, and abomasal fluid pH was measured at intervals for a 96-hour period. The pH of the abomasal fluid was higher in pantoprazole treatments for up to 24 hours after dosing. Following intravenous administration of pantoprazole to study ewes, elimination half-life, volume of distribution, and clearance of pantoprazole was estimated as 3.29 hours, 0.35 L/kg, and 65.26 mL/hr/kg respectively. After subcutaneous dosing, maximum concentration, time to maximum concentration, half-life of elimination, and volume of distribution, were estimated as 2604 ng/mL, 0.55 hours, 2.48 hours, and 0.37 L/kg. Additionally, the bioavailability was estimated as 83.33%. Pantoprazole administered IV or SC may be useful for treatment or prevention of abomasal ulcers in adult sheep.

The pharmacokinetics and pharmacodynamics of esomeprazole in sheep after intravenous dosing.

Abomasal (gastric) ulceration is a morbidity in sheep, and currently, there is a paucity of pharmacokinetic and pharmacodynamic data for gastroprotectant drugs reported for this species. The proton pump inhibitor esomeprazole has been used in small animal and human patients for gastroprotection via increasing the gastric pH. The objective of this study was to report the pharmacokinetic parameters and pharmacodynamic effect of esomeprazole in sheep after single intravenous dosing. Four healthy adult Southdown cross ewes had blood collected over a 24 h time period after single intravenous dosing of esomeprazole at 1.0 mg/kg. Abomasal fluid was sampled over 24 h before and after esomeprazole administration. Plasma samples were analyzed for concentrations of esomeprazole and the esomeprazole metabolite, esomeprazole sulfone by high performance liquid chromatography. Pharmacokinetic and pharmacodynamic data were evaluated with specialized software. Esomeprazole was rapidly eliminated after IV administration. Elimination half-life, area under the curve, initial concentration (C0), and clearance were 0.2 h, 1,197 h*ng/mL, 4,321 ng/mL, and 0.83 mL/h/kg, respectively. For the sulfone metabolite elimination half-life, area under the curve and maximum concentration were 0.16 h, 22.5 h*ng/mL, and 65.0 ng/mL, respectively. Abomasal pH was significantly elevated from 1 to 6 h after administration and remained above 4.0 for at least 8 h after administration. No adverse effects were noted in these sheep. Esomeprazole was rapidly eliminated in sheep, similar to goats. Abomasal pH was increased, but future studies will be necessary to develop a clinical management approach to the use of esomeprazole in sheep.

Pharmacokinetics and Egg Residues of Oral Meloxicam in Bantam Cochin Chickens.

Backyard poultry are commonly treated in veterinary hospitals; however, there is limited information regarding appropriate dosing of medications and withdrawal times for eggs. Six healthy adult bantam Cochin hens were given a single oral dose of meloxicam (1 mg/kg). Meloxicam plasma concentrations and egg residues were analyzed by high-performance liquid chromatography. Noncompartmental analysis was used to calculate pharmacokinetic parameters. The apparent terminal half-life, maximum concentration, and time to maximum concentration were 5.94 ± 0.92 hours, 7.03 ± 2.68 µg/mL, and 2.83 ± 1.33 hours, respectively. Meloxicam was detected in egg whites for 4.8 ± 1.5 days and egg yolks for 9.8 ± 2.4 days. Results were compared with previous studies in white leghorn and Columbian Wyandotte hens. Bantam Cochin hens demonstrated a significantly longer mean apparent terminal half-life, greater area under the curve, smaller elimination rate constant, and longer egg residue times compared with white leghorn hens. However, the pharmacokinetic results from the bantam Cochin hens did not significantly differ from those reported for the Columbian Wyandotte hens. Until pharmacodynamic studies can be performed, dosing of oral meloxicam in bantam Cochins should follow recommendations for Columbian Wyandotte hens to reduce the likelihood of adverse effects. These results better inform appropriate dosing of meloxicam in domestic hens, as well as recommended withdrawal times for egg consumption.

Pharmacokinetics of esomeprazole in goats (Capra aegagrus hircus) after intravenous and subcutaneous administration.

Background: Stressed and hospitalized goats are at risk of developing abomasal (gastric) ulceration, but there is a paucity of pharmacokinetic studies for proton pump inhibiting drugs, such as, esomeprazole in goats. Objectives: The objectives for this study were to estimate plasma pharmacokinetic parameters for esomeprazole in adult goats after intravenous (IV) and subcutaneous (SQ) administration. A secondary objective was to describe the plasma kinetics of the metabolite esomeprazole sulfone after IV and SC administration in goats. Materials and methods: Esomeprazole was administered to 5 adult goats in a crossover study at doses of 1 mg/kg IV or 2 mg/kg SC. Plasma samples were collected over 36 h and analyzed via reverse phase HPLC to determine concentrations of esomeprazole and esomeprazole sulfone. Pharmacokinetic parameters were derived via non-compartmental analysis. Results: Following IV administration, mean values for plasma clearance (Cl), elimination half-life [T1/2 (λz)], C0, and volume of distribution (V z ) of esomeprazole were estimated at 24.9 mL/min/kg, 6 min, 2.324 µg/mL, and 0.23 L/kg, respectively. After SC administration elimination half-life, maximum concentration (Cmax) and time to maximum concentration (Tmax) of esomeprazole were estimated at 29 min, 1.038 µg/mL, and 22 minutes respectively. Maximum concentrations of the sulfone metabolite were 32 and 18 ng/mL after IV and SC administration. Conclusion: Esomeprazole was rapidly eliminated from plasma after both IV and SC injection in goats. The elimination half-life in goats appears to be shorter than reported in dogs, as well as less than that reported for pantoprazole in goats. The sulfone metabolite was detected and also rapidly eliminated from the plasma after both IV and SC administration. Additional pharmacodynamic investigations are needed to determine the efficacy of esomeprazole on abomasal (gastric) acid suppression in goats and could include larger doses or additional routes of administration.

Pharmacokinetic and pharmacodynamic properties of pantoprazole in calves.

Introduction: Development of abomasal ulceration is a large concern, especially within calves; however, there is a paucity of research into the use of gastro protectants in ruminant species. Proton pump inhibitors, such as pantoprazole, are widely used in humans and companion animals. Their efficacy in ruminant species is undetermined. The objectives of this study were to 1) estimate the plasma pharmacokinetic parameters for pantoprazole in neonatal calves after three days of intravenous (IV) or subcutaneous (SC) administration, and 2) measure the effect pantoprazole had on abomasal pH over the treatment period. Methods: Pantoprazole was administered to 6 Holstein-Angus cross bull calves at a dose of 1 mg/kg (IV) or 2 mg/kg (SC), once a day (every 24 h) for three days. Plasma samples were collected over a 72 h period and analyzed via HPLC-UV for determining pantoprazole concentrations. Pharmacokinetic parameters were derived via non-compartmental analysis. Abomasal (n= 8) samples were collected via abomasal cannulas over a 12 h period, per calf per day. Abomasal pH was determined via a bench top pH analyzer. Results: Following Day 1 of IV administration, plasma clearance, elimination half-life, and volume of distribution of pantoprazole were estimated at 199.9 mL/kg/h, 1.44 h, and 0.51 L/kg, respectively. On Day 3 of IV administration, the reported values were 192.9 mL/kg/h, 2.52 h, and 1.80 L/kg mL, respectively. Elimination half-life and volume of distribution (V/F) of pantoprazole following SC administration were estimated at 1.81 h and 0.55 L/kg, respectively, on Day 1; and 2.99 h and 2.82 L/kg, respectively, on Day 3. Discussion: The reported values for IV administration were similar to those previously reported in calves. SC administration appears to be well absorbed and tolerated. The sulfone metabolite was detectable for 36 h after the last administration for both routes. Abomasal pH was significantly higher than the pre-pantoprazole pH 4, 6, and 8 h after administration in both the IV and SC groups. Further studies of pantoprazole as a treatment/preventative for abomasal ulcers are warranted.

The influence of storage time on ponazuril concentrations in feline plasma.

BACKGROUND: The pharmacokinetics of ponazuril have been determined in several species; however, there is very little information on the stability of the drug after storage for long periods of time. This study was undertaken to determine the stability of ponazuril in plasma samples stored at -80 °C, which is the temperature most commonly used in the author's laboratory. METHOD: Spiked plasma samples (0.3, 7.5, and 15 µg/mL) were stored at -80 °C for three months. Analysis occurred on the first day and then once a week for the following twelve weeks. The drug was extracted using a chloroform extraction and separated by high performance liquid chromatography using ultraviolet detection. RESULTS: There was no loss of drug for any concentration for the first four weeks of storage. There was an average loss of less than 5% from day 35 through day 70 and an average loss of 6% on day 77 and 84. The data suggest that ponazuril is stable for 4 weeks when stored at -80 °C and undergoes minimal loss in the remaining 8 weeks.

Pharmacokinetics of Pantoprazole and Pantoprazole Sulfone in Goats After Intravenous Administration: A Preliminary Report.

Background: Ruminant species are at risk of developing abomasal ulceration, but there is a lack of pharmacokinetic data for anti-ulcer therapies, such as the proton pump inhibitor pantoprazole, in goats. Objective: The primary study objective was to estimate the plasma pharmacokinetic parameters for pantoprazole in adult goats after intravenous administration. A secondary objective was to describe the pharmacokinetic parameters for the metabolite, pantoprazole sulfone, in goats. Methods: Pantoprazole was administered intravenously to six adult goats at a dose of 1 mg/kg. Plasma samples were collected over 36h and analyzed via reverse phase high performance liquid chromatography for determination of pantoprazole and pantoprazole sulfone concentrations. Pharmacokinetic parameters were determined by non-compartmental analysis. Results: Plasma clearance, elimination half-life, and volume of distribution of pantoprazole were estimated at 0.345 mL/kg/min, 0.7 h, and 0.9 L/kg, respectively following IV administration. The maximum concentration, elimination half-life and area under the curve of pantoprazole sulfone were estimated at 0.1 µg/mL, 0.8 h, and 0.2 hr*µg/mL, respectively. The global extraction ratio was estimated 0.00795 ± 0.00138. All animals had normal physical examinations after conclusion of the study. Conclusion: The reported plasma clearance for pantoprazole is lower than reported for foals, calves, and alpacas. The elimination half-life appears to be < that reported for foals and calves. Future pharmacodynamic studies are necessary for determination of the efficacy of pantoprazole on acid suppression in goats.

Bioanalytical RP-HPLC method for the determination of ponazuril in plasma.

The goal of this investigation was to establish a reliable technique for the quantitation of ponazuril in limited sample volumes. Samples were extracted with chloroform and separation was achieved with a Symmetry RP18 column. Ultraviolet absorption was measured at 254 nm. A combination of 0.1% formic acid and acetonitrile (50:50) was used as the mobile phase. The calibration curve was linear from 0.1-25 µg/mL, with a lower limit of quantification of 0.1 µg/mL with a 100 µL sample. The precision and accuracy were well within the range set by the Food and Drug Administration and the recovery was over 95%. This technique was used to analyze ponazuril samples and found to be appropriate for pharmacokinetic studies.

Breed differences in the pharmacokinetics of orally administered meloxicam in domestic chickens (Gallus domesticus).

OBJECTIVE: To determine the pharmacokinetics of meloxicam in Wyandotte hens and duration and quantity of drug residues in their eggs following PO administration of a single dose (1 mg of meloxicam/kg [0.45 mg of meloxicam/lb]) and compare results with those previously published for White Leghorn hens. ANIMALS: 8 healthy adult Wyandotte hens. PROCEDURES: Hens were administered 1 mg of meloxicam/kg, PO, once. A blood sample was collected immediately before and at intervals up to 48 hours after drug administration. The hens' eggs were collected for 3 weeks after drug administration. Samples of the hens' plasma and egg whites (albumen) and yolks were analyzed with high-performance liquid chromatography. RESULTS: Mean ± SD terminal half-life, maximum concentration, and time to maximum concentration were 5.53 ± 1.37 hours, 6.25 ± 1.53 µg/mL, and 3.25 ± 2.12 hours, respectively. Mean ± SD number of days meloxicam was detected in egg whites and yolks after drug administration was 4.25 ± 2 days and 9.0 ± 1.5 days, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with White Leghorn hens, meloxicam in Wyandotte hens had a longer terminal half-life, greater area under the plasma concentration-versus-time curve from time 0 to infinity, a smaller elimination rate constant, and a longer mean residence time-versus-time curve from time 0 to infinity, and drug persisted longer in their egg yolks. Therefore, the oral dosing interval of meloxicam may be greater for Wyandotte hens. Results may aid veterinarians on appropriate dosing of meloxicam to Wyandotte hens and inform regulatory agencies on appropriate withdrawal times.

Determination of ceftazidime in plasma by RP-HPLC and ultraviolet detection.

A simple high-performance liquid chromatography method for the determination of ceftazidime in plasma has been developed. Using an ultrafiltration technique samples were separated by reverse-phase high-performance liquid chromatography on a Symmetry C18 4.6 × 250 mm column (5.0 µm) and ultraviolet absorbance was measured at 260 nm. The mobile phase was a mixture of 10 mm potassium phosphate monobasic pH 2.5 with phosphoric acid and acetonitrile (90:10). The standard curve ranged from 0.1 to 100 µg/ml. Intra- and inter-assay variability for ceftazidime was <12%, and the average recovery was 89%. The lower limit of quantification was 0.1 µg/ml. This method has been used successfully to analyze frog plasma samples at this institution and it could be applied to other small volume samples in a clinical or research setting.

Determination of grapiprant plasma and urine concentrations in horses.

OBJECTIVE: Non-steroidal anti-inflammatory drugs are inhibitors of cyclooxygenase (COX) in tissues and used as therapeutic agents in different species. Grapiprant, a member of the piprant class of compounds, antagonizes prostaglandin receptors. It is a highly selective EP4 prostaglandin E2 receptor inhibitor, thereby limiting the potential for adverse effects caused by wider COX inhibition. The objectives of this study were to determine if the approved canine dose would result in measurable concentrations in horses, and to validate a chromatographic method of analysis for grapiprant in urine and plasma. STUDY DESIGN: Experimental study. ANIMALS: A total of six healthy, adult mixed-breed mares weighing 502 ± 66 (397-600) kg and aged 14.8 ± 5.3 (6-21) years. METHODS: Mares were administered one dose of 2 mg kg-1 grapiprant via nasogastric tube. Blood and urine samples were collected prior to and up to 48 hours after drug administration. Drug concentrations were measured using high-performance liquid chromatography. RESULTS: Grapiprant plasma concentrations ranged from 71 to 149 ng mL-1 with the mean peak concentration (106 ng mL-1) occurring at 30 minutes. Concentrations were below the lower limit of quantification (50 ng mL-1) in four of six horses at 1 hour and in all six horses by 2 hours after drug administration. Grapiprant urine concentrations ranged from 40 to 4077 ng mL-1 and were still detectable at 48 hours after administration. CONCLUSIONS AND CLINICAL RELEVANCE: Currently, there are no published studies looking at the pharmacodynamics of grapiprant in horses. The effective concentration needed to control pain in dogs ranges 114-164 ng mL-1. Oral administration of grapiprant (2 mg kg-1) in horses did not achieve those concentrations. The dose was well tolerated; therefore, studies with larger doses could be conducted.

Determination of Thiafentanil in Plasma Using LC-MS.

A new method of analysis has been developed and validated for the determination of thiafentanil in plasma. After protein precipitation, samples were separated on an XBridge BEH C18 column and quantified using mass spectrometry. The mobile phase was a mixture of water with 0.1% formic acid and acetonitrile with 0.1% formic acid (90:10). The standard curve ranged from 0.1 to 25 ng/mL. Intra- and Inter-assay variability for thiafentanil was less than 10%, and the average recovery was greater than 95%. The lower limit of quantification was 0.1 ng/mL. This is the first validated method for thiafentanil analysis in plasma.

Development of a method for the determination of hydromorphone in plasma by LC-MS.

A simple high-performance liquid chromatography method for the determination of hydromorphone in small volume plasma has been developed. Following solid-phase extraction using Oasis HLB cartridges, samples were separated by reverse-phase high-performance liquid chromatography on an Atlantis T3 4.6 × 150 mm column (3.0 µm) and quantified using mass spectrometry. The mobile phase was a mixture of water with 0.1% formic acid and acetonitrile with 0.1% formic acid (91:9). The standard curve ranged from 1 to 500 ng/mL. Intra- and Inter-assay variability for hydromorphone was <10%, and the average recovery was >90%. The LLOQ was 1 ng/mL. This method was successfully applied to the analysis of hydromorphone samples at this institution. This method could be useful to those investigators dealing with small sample volumes, particularly when conducting pharmacokinetic studies that require multiple sampling from the same animal.

Pharmacokinetics and egg residues after oral administration of a single dose of meloxicam in domestic chickens (Gallus domesticus).

OBJECTIVE To determine the pharmacokinetics of meloxicam in domestic hens and duration and quantity of drug residues in their eggs following PO administration of a single dose (1 mg of meloxicam/kg). ANIMALS 8 healthy adult White Leghorn hens. PROCEDURES Hens were administered 1 mg of meloxicam/kg PO once. A blood sample was collected immediately before and at intervals up to 48 hours after drug administration. The hens' eggs were collected for 3 weeks after drug administration. Samples of the hens' plasma, egg whites (albumen), and egg yolks were analyzed by high-performance liquid chromatography. RESULTS The half-life, maximum concentration, and time to maximum concentration of meloxicam in plasma samples were 2.8 hours, 7.21 µg/mL, and 2 hours, respectively. Following meloxicam administration, the drug was not detected after 4 days in egg whites and after 8 days in egg yolks. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that meloxicam administered at a dose of 1 mg/kg PO in chickens appears to maintain plasma concentrations equivalent to those reported to be therapeutic for humans for 12 hours. The egg residue data may be used to aid establishment of appropriate drug withdrawal time recommendations.