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- Author or Editor: Cornelius E. Uboh x
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Abstract
Objective—To compare pharmacokinetics of triamcinolone acetonide (TA) following IV, intra-articular (IA), and IM administration and determine its effect on plasma concentrations of hydrocortisone and cortisone.
Animals—6 Thoroughbreds.
Procedures—TA (0.04 mg/kg) was administered IV, IM, or IA, and plasma TA, hydrocortisone, and cortisone concentrations were determined.
Results—IV administration of TA was fitted to a 2-compartment model. Median distribution half-life was 0.50 hours (range, 0.24 to 0.67 hours); elimination half-life was 6.1 hours (range, 5.0 to 6.4 hours). Transfer half-life of TA from joint to plasma was 5.2 hours (range, 0.49 to 73 hours); elimination half-life was 23.8 hours (range, 18.9 to 32.2 hours). Maximum plasma concentration following IA administration was 2.0 ng/mL (range, 0.94 to 2.5 ng/mL), and was attained at 10 hours (range, 8 to 12 hours). Maximum plasma concentration following IM administration was 0.34 ng/mL (range, 0.20 to 0.48 ng/mL) and was attained at 13.0 hours (range, 12 to 16 hours); concentration was still quantifiable at 360 hours. Hydrocortisone plasma concentrations were significantly different from baseline within 0.75, 2, and 1 hours after IV, IA, and IM administration, respectively, and remained significantly different from baseline at 96 and 264 hours for IV and IA administration. Following IM administration of TA, plasma concentrations of hydrocortisone did not recover to baseline concentrations by 360 hours.
Conclusions and Clinical Relevance—Pharmacokinetics of TA and related changes in hydrocortisone were described following IV, IA, and IM administration. A single administration of TA has profound effects on secretion of endogenous hydrocortisone.
SUMMARY
Naproxen (+6-methoxy- [α-methyl] -2-naphthalene acetic acid) is a nonsteroidal anti-inflammatory drug that is used for the treatment of inflammatory conditions in horses. We developed a model that describes the drug's disposition and renal excretion, including synovial fluid disposition and elimination after iv administration in horses. The plasma disposition, after iv administration of 5 mg/kg of body weight, was described by a two-compartment model; mean ± sd distribution and elimination half-lives were 1.42 ± 0.42 and 8.26 ± 2.56 hours, respectively. Plasma concentration of naproxen after iv administration of 5 mg/kg was 55.3 ± 13.5 and 0.61 ± 0.42 mg/L at 5 minutes and 48 hours after its administration, respectively. Steady-state volume of distribution was 0.163 ± 0.053 L/kg, and area under the plasma concentration time-curve was 372.1 ± 128.2 mg/h/L. The peak synovial fluid concentration of 12.68 ± 12.39 mg/L was measured at 6 hours, and decreased to 0.71 ± 0.38 mg/L at 36 hours after naproxen administration. The decrease of naproxen concentration in synovial fluid paralleled that in plasma. The appearance half-life of naproxen in synovial fluid was 4.64 hours, and the elimination half-life was 6.73 hours. Total body clearance was 0.015 ± 0.006 L/h/kg. The percentage of plasma protein binding was 97.0 ± 2.9% at plasma concentrations between 5 and 100 mg/L. This was significantly (P < 0.05) higher than the percentage of binding at plasma concentrations of 0.5, 1, and 500 mg/L, which was 75.2 ± 11.8%. Most of the drug was excreted as glucuronidated naproxen and unconjugated desmethylnaproxen. The recovery of naproxen and all metabolites in urine at 36 hours was 64.6 ± 7.2% of the total dose. Of this total, 39.6 ± 10.3% and 8.5 ± 7.9% were glucuronidated naproxen and desmethylnaproxen, respectively; 0.3 ± 0.1% and 16.6 ± 7.9% were free naproxen and desmethylnaproxen, respectively.
Abstract
Objective—To investigate the pharmacokinetics of fentanyl administered transdermally and IV in sheep.
Animals—21 adult female sheep.
Procedures—Fentanyl was administered IV to 6 healthy sheep. Transdermal fentanyl patches (TFPs) were applied to 15 sheep 12 hours prior to general anesthesia and surgery. Seria blood samples were collected for 18 hours after IV injection and 84 hours after TFP application. Fentanyl concentrations were quantified via liquid chromatography-mass spectrometry, and pharmacokinetic values were estimated.
Results—All sheep completed the study without complications. Following a dose of 2.5g/kg administered IV, the half-life was 3.08 hours (range, 2.20 to 3.36 hours), volume of distribution at steady state was 8.86 L/kg (range, 5.55 to 15.04 L/kg), and systemic clearance was 3.62 L/kg/h (range, 2.51 to 5.39 L/kg/h). The TFPs were applied at a mean dose of 2.05 g/kg/h. Time to maximum plasma concentration and maximal concentration were 12 hours (range, 4 to 24 hours) and 1.30 ng/mL (range, 0.62 to 2.73 ng/mL), respectively. Fentanyl concentrations were maintained at > 0.5 ng/mL for 40 hours after TFP application.
Conclusions and Clinical Relevance—IV administration of fentanyl resulted in a short half-life. Application of a TFP resulted in stable blood fentanyl concentrations in sheep. (Am J Vet Res 2010;71:1127—1132)
Abstract
Objective—To evaluate whether urine supernatant contains amplifiable DNA and to determine factors that influence genotyping of samples from racehorses after storage and transportation.
Sample Population—580 urine, 279 whole blood, and 40 plasma samples obtained from 261 Thoroughbreds and Standardbreds.
Procedures—Genomic DNA was isolated from stored blood and urine samples collected from racehorses after competition. Quantified DNA was evaluated to determine whether 5 equine microsatellite loci (VHL20, HTG4, AHT4, HMS6, and HMS7) could be amplified by use of PCR techniques. Fragment size of each amplified locus was determined by use of capillary electrophoresis.
Results—High–molecular-weight and amplifiable DNA were recovered from refrigerated blood samples, but recovery from urine varied. Deoxyribonucleic acid was recovered from both urine supernatant and sediment. Freeze-thaw cycles of urine caused accumulation of amplifiable DNA in the supernatant and clearance of naked DNA. Repeated freeze-thaw cycles significantly decreased DNA yield and induced DNA degradation, which resulted in failure to detect microsatellite loci. Select drugs detected in test samples did not affect PCR amplification. Contaminants in DNA isolates inhibited PCR amplification and resulted in partial microsatellite profiles.
Conclusions and Clinical Relevance—Properly stored urine and blood samples were successfully genotyped, but subjecting urine to freeze-thaw cycles was most detrimental to the integrity of DNA. Increasing the volume of urine used improved recovery of DNA.
Abstract
Objective—To determine the pharmacokinetics of methylprednisolone (MP) and develop a pharmacokinetic-pharmacodynamic model of the related changes in plasma concentrations of endogenous hydrocortisone (HYD) and cortisone (COR) following intra-articular administration of methylprednisolone acetate (MPA) in horses.
Animals—6 Thoroughbreds.
Procedures—In each horse, 200 mg of MPA was injected intrasynovially into a carpal joint, and plasma MP, HYD, and COR concentrations were determined via liquid chromatography-mass spectrometry.
Results—A 5-compartment pharmacokinetic-pharmacodynamic model was used to describe the concatenated changes in the plasma concentrations of MP, HYD, and COR and to estimate the instantaneous rate of endogenous HYD production. The median transfer half-life (t1/2t) of methylprednisolone from the joint to plasma and elimination half-life (t1/2e) from plasma were 1.7 and 19.2 hours, respectively. Maximum plasma concentration of methylprednisolone was 7.26 ± 3.3 ng/mL at 8 hours, which decreased to 0.11 ± 0.08 ng/mL at 144 hours after injection. At 3 hours after MPA administration, plasma COR and HYD concentrations were significantly decreased from baseline values (from 2.9 ± 0.28 ng/mL to 2.10 ± 1.0 ng/mL and from 61.1 ± 18.9 ng/mL to 25.7 ± 12.1 ng/mL, respectively).
Conclusions and Clinical Relevance—The sensitivity of the analytic method used allowed complete description of the related kinetics of MP, HYD, and COR following intra-articular administration of MPA. A single intra-articular administration of MPA profoundly affected the secretion of HYD and COR in horses; secretion of endogenous corticosteroids remained suppressed for as long as 240 hours after injection.
Abstract
Objective—To investigate the pharmacokinetics and behavioral effects of aminorex administered IV and PO in horses.
Animals—7 Thoroughbreds.
Procedures—In a cross-over design, aminorex (0.03 mg/kg) was administered IV or PO. Plasma and urinary aminorex concentrations were determined via liquid chromatography– mass spectrometry.
Results—Decrease of aminorex from plasma following IV administration was described by a 3-compartment pharmacokinetic model. Median (range) values of α, β, and γ half-lives were 0.04 (0.01 to 0.28), 2.30 (1.23 to 3.09), and 18.82 (8.13 to 46.64) hours, respectively. Total body and renal clearance, the area under the plasma time curve, and initial volume of distribution were 37.26 (28.61 to 56.24) mL·min/kg, 1.25 (0.85 to 2.05) mL·min/kg, 13.39 (8.82 to 17.37) ng·h/mL, and 1.44 (0.10 to 3.64) L/kg, respectively. Oral administration was described by a 2-compartment model with first-order absorption, elimination from the central compartment, and distribution into peripheral compartments. The absorption half-life was 0.29 (0.12 to 1.07) hours, whereas the β and γ elimination phases were 1.93 (1.01 to 3.17) and 23.57 (15.16 to 47.45) hours, respectively. The area under the curve for PO administration was 10.38 (4.85 to 13.40) ng·h/mL and the fractional absorption was 81.8% (33.8% to 86.9%).
Conclusions and Clinical Relevance—Aminorex administered IV had a large volume of distribution, initial rapid decrease, and an extended terminal elimination. Following PO administration, there was rapid absorption, rapid initial decrease, and an extended terminal elimination. At a dose of 0.03 mg/kg, the only effects detected were transient and central in origin and were observed only following IV administration.
Abstract
OBJECTIVE To evaluate plasma interleukin 6 (IL-6) concentration in Standardbred racehorses by means of a novel ELISA following validation of the assay for use with equine plasma samples.
SAMPLE Plasma samples obtained from 25 Thoroughbreds for use in assay validation and from 319 Standardbred racehorses at rest 2 to 2.5 hours prior to warm-up and racing.
PROCEDURES A sandwich ELISA was developed with equine anti–IL-6 polyclonal antibody and the biotin-streptavidin chemical interaction to enhance sensitivity. The assay was validated for specificity, sensitivity, precision, and accuracy by use of both recombinant and endogenous proteins.
RESULTS For the assay, cross-reactivity with other human and equine cytokines was very low or absent. Serial dilution of plasma samples resulted in proportional decreases in reactivity, indicating high specificity of the method. Partial replacement of detection antibody with capture antibody or pretreatment of samples with capture antibody caused assay signals to significantly decrease by 55%. The inter- and intra-assay precisions were ≤ 13.6% and ≤ 9.3%, respectively; inter- and intra-assay accuracies were within ranges of ± 14.1% and ± 8.6%, respectively, at concentrations from 78 to 5,000 pg/mL, and the sensitivity was 18 pg/mL. Plasma IL-6 concentration varied widely among the 319 Standardbreds at rest (range, 0 to 193,630 pg/mL; mean, 6,153 pg/mL; median, 376 pg/mL).
CONCLUSIONS AND CLINICAL RELEVANCE This ELISA method proved suitable for quantification of IL-6 concentration in equine plasma samples. Plasma IL-6 concentration was high (> 10,000 pg/mL) in 9.1% of the Standardbred racehorses, which warrants further investigation.
Summary
Concentration of sulfamethazine was measured in plasma and tissues (fat, liver, kidney, spleen, lungs, and skeletal muscle) of pigs given the drug iv and po. The plasma concentration vs time curve was best described by a 2-compartment model, with a distribution half-life of 0.46 hour and an elimination halflife of 16.9 hours. Bioavailability after oral administration was 85.8 ± 5.3%.
The tissue and plasma sulfamethazine concentration vs time data were used to develop a multicompartment pharmacokinetic model of sulfamethazine disposition in pigs. Plasma and tissue concentrations of sulfamethazine in pigs were measured at various intervals after multiple oral doses of sulfamethazine, and were compared to concentrations predicted by the model. Model predictions for tissue concentrations of sulfamethazine after addition of the drug to feed (110 μg/g of feed for 98 days; 550 μg/g for 30 days) were compared to results from other studies. The model accurately predicted the number of days for sulfamethazine concentration to fall below 0.1 μg of tissue/g (0.1 ppm, the tolerated concentration) in various tissues.
Abstract
Objective—To compare the pharmacokinetics of penicillin G and procaine in racehorses following IM administration of penicillin G procaine (PGP) with pharmacokinetics following IM administration of penicillin G potassium and procaine hydrochloride (PH).
Animals—6 healthy adult mares.
Procedure—Horses were treated with PGP (22,000 units of penicillin G/kg of body weight, IM) and with penicillin G potassium (22,000 U/kg, IM) and PH (1.55 mg/kg, IM). A minimum of 3 weeks was allowed to elapse between drug treatments. Plasma and urine penicillin G and procaine concentrations were measured by use of high-pressure liquid chromatography.
Results—Median elimination phase half-lives of penicillin G were 24.7 and 12.9 hours, respectively, after administration of PGP and penicillin G potassium. Plasma penicillin G concentration 24 hours after administration of penicillin G potassium and PH was not significantly different from concentration 24 hours after administration of PGP. Median elimination phase halflife of procaine following administration of PGP (15.6 hours) was significantly longer than value obtained after administration of penicillin G potassium and PH (1 hour).
Conclusions and Clinical Relevance—Results suggest that IM administration of penicillin G potassium will result in plasma penicillin G concentrations for 24 hours after drug administration comparable to those obtained with administration of PGP. Clearance of procaine from plasma following administration of penicillin G potassium and PH was rapid, compared with clearance following administration of PGP. (Am J Vet Res 2000;61:811–815)
Abstract
Objective—To determine pharmacokinetics and excretion of phenytoin in horses.
Animals—6 adult horses.
Procedure—Using a crossover design, phenytoin was administered (8.8 mg/kg of body weight, IV and PO) to 6 horses to determine bioavailability (F). Phenytoin also was administered orally twice daily for 5 days to those same 6 horses to determine steadystate concentrations and excretion patterns. Blood and urine samples were collected for analysis.
Results—Mean (± SD) elimination half-life following a single IV or PO administration was 12.6 ± 2.8 and 13.9 ± 6.3 hours, respectively, and was 11.2 ± 4.0 hours following twice-daily administration for 5 days. Values for F ranged from 14.5 to 84.7%. Mean peak plasma concentration (Cmax) following single oral administration was 1.8 ± 0.68 µg/ml. Steady-state plasma concentrations following twice-daily administration for 5 days was 4.0 ± 1.8 µg/ml. Of the 12.0 ± 5.4% of the drug excreted during the 36-hour collection period, 0.78 ± 0.39% was the parent drug phenytoin, and 11.2 ± 5.3% was 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH). Following twice-daily administration for 5 days, phenytoin was quantified in plasma and urine for up to 72 and 96 hours, respectively, and p-HPPH was quantified in urine for up to 144 hours after administration. This excretion pattern was not consistent in all horses.
Conclusion and Clinical Relevance—Variability in F, terminal elimination-phase half-life, and Cmax following single or multiple oral administration of phenytoin was considerable. This variability makes it difficult to predict plasma concentrations in horses after phenytoin administration. (Am J Vet Res 2001;62:483–489)
