Objective—To characterize pharmacokinetics and pharmacodynamics of detomidine gel administered sublingually in accordance with label instructions to establish appropriate withdrawal guidelines for horses before competition.
Animals—12 adult racehorses.
Procedures—Horses received a single sublingual administration of 0.04 mg of detomidine/kg. Blood samples were collected before and up to 72 hours after drug administration. Urine samples were collected for 5 days after detomidine administration. Plasma and urine samples were analyzed via liquid chromatography–mass spectrometry, and resulting data were analyzed by use of noncompartmental analysis. Chin-to-ground distance, heart rate and rhythm, glucose concentration, PCV, and plasma protein concentration were also assessed following detomidine administration.
Results—Mean ± SD terminal elimination half-life of detomidine was 1.5 ± 1 hours. Metabolite concentrations were below the limit of detection (0.02, 0.1, and 0.5 ng/mL for detomidine, carboxydetomidine, and hydroxydetomidine, respectively) in plasma by 24 hours. Concentrations of detomidine and its metabolites were below the limit of detection (0.05 ng/mL for detomidine and 0.10 ng/mL for carboxydetomidine and hydroxydetomidine) in urine by 3 days. All horses had various degrees of sedation after detomidine administration. Time of onset was ≤ 40 minutes, and duration of sedation was approximately 2 hours. Significant decreases, relative to values at time 0, were detected for chin-to-ground distance and heart rate. There was an increased incidence and exacerbation of preexisting atrioventricular blocks after detomidine administration.
Conclusions and Clinical Relevance—A 48-hour and 3-day withdrawal period for detection in plasma and urine samples, respectively, should be adopted for sublingual administration of detomidine gel.
Procedure—Venous blood was collected from each
horse prior to and 0.25, 0.5, 0.75, 1, 2, 3, 4, 4.5, 5, and
6 hours after IV administration of 250 mg (first experiment)
or 500 mg (second experiment) of furosemide.
Urine was collected hourly between 1 and 6 hours after
administration of furosemide at both doses.
Concentrations of furosemide were determined by use
of an ELISA. Concentration of furosemide and urine
specific gravity was modeled as a function of time,
accounting for inter- and intrahorse variabilities. On the
basis of pharmacokinetic and specific gravity data, the
probability of exceeding a concentration of 100 ng of
furosemide/ml as a function of time was determined,
using a semiparametric smooth functional averaging
method. A bootstrap approach was used to assess the
inherent variation in this estimated probability.
Results—The estimated probability of exceeding the
threshold of 100 ng of furosemide/ml and urine specific
gravity < 1.012 was approximately 0% between
4.0 and 5.5 hours after IV administration of 250 mg of
furosemide/horse, and ranged from 0 to 1% between
4 and 5.5 hours after IV administration of 500 mg of
furosemide/horse. The probability of a horse being
falsely identified as in violation of regulatory concentrations
was inversely associated with time.
Conclusions and Clinical Relevance—Coupling plasma
furosemide concentration with urine specific gravity
testing will greatly reduce the chance that some horses
are misclassified as being in violation of regulatory concentrations.
(Am J Vet Res 2001;62:1349–1353)
Objective—To estimate the probability for exceeding
a threshold concentration of furosemide commonly
used for regulatory purposes after IV administration
of furosemide in horses.
Animals—12 mature healthy horses (6 Thoroughbreds
and 6 Quarter Horses).
Procedure—Venous blood was collected from each
horse prior to and 0.25, 0.5, 0.75, 1, 2, 3, 4, 4.5, 5, and
6 hours after administration of 250 or 500 mg of
furosemide. Concentrations of furosemide were
determined, using an ELISA. Concentration of
furosemide was modeled as a function of time,
accounting for inter- and intrahorse variabilities. On
the basis of pharmacokinetic data, the probability for
exceeding a concentration of 100 ng/ml as a function
of time was determined, using a semiparametric
smooth functional averaging method. A bootstrap
approach was used to assess inherent variation in
this estimated probability.
Results—The estimated probability of exceeding the
threshold of 100 ng of furosemide/ml ranged from
11.6% at 4 hours to 2.2% at 5.5 hours after IV administration
of 250 mg of furosemide/horse and 34.2% at
4 hours to 12.3% at 5.5 hours after IV administration
of 500 mg of furosemide/horse. The probability of a
horse being falsely identified in violation of regulatory
concentrations was inversely associated with time
and positively associated with dose.
Conclusions and Clinical Relevance—Interhorse
variability with respect to pharmacokinetics of
furosemide will result in misclassification of some
horses as being in violation of regulatory concentrations.
(Am J Vet Res 2001;62:320–325)
Objective—To investigate penciclovir pharmacokinetics following single and multiple oral administrations of famciclovir to cats.
Animals—8 adult cats.
Procedures—A balanced crossover design was used. Phase I consisted of a single administration (62.5 mg, PO) of famciclovir. Phase II consisted of multiple doses of famciclovir (62.5 mg, PO) given every 8 or 12 hours for 3 days. Plasma penciclovir concentrations were assayed via liquid chromatography—mass spectrometry at fixed time points after famciclovir administration.
Results—Following a single dose of famciclovir, the dose-normalized (15 mg/kg) maximum concentration (Cmax) of penciclovir (350 ± 180 ng/mL) occurred at 4.6 ± 1.8 hours and mean ± SD apparent elimination half-life was 3.1 ± 0.9 hours. However, the dose-normalized area under the plasma penciclovir concentration-time curve extrapolated to infinity (AUC0→∞) during phase I decreased with increasing dose, suggesting either nonlinear pharmacokinetics or interindividual variability among cats. Accumulation occurred following multiple doses of famciclovir administered every 8 hours as indicated by a significantly increased dose-normalized AUC, compared with AUC0→∞ from phase 1. Dose-normalized penciclovir Cmaxfollowing administration of famciclovir every 12 or 8 hours (290 ± 150 ng/mL or 780 ± 250 ng/mL, respectively) was notably less than the in vitro concentration (3,500 ng/mL) required for activity against feline herpesvirus-1.
Conclusions and Clinical Relevance—Penciclovir pharmacokinetics following oral famciclovir administration in cats appeared complex within the dosage range studied. Famciclovir dosages of 15 mg/kg administered every 8 hours to cats are unlikely to result in plasma penciclovir concentrations with activity against feline herpesvirus-1.
Objective—To evaluate effects of various doses of remifentanil on measures of analgesia in anesthetized cats.
Animals—6 healthy adult cats.
Procedures—Minimum alveolar concentration (MAC) for isoflurane and thermal threshold responses were evaluated in anesthetized cats. Remifentanil infusions of 0 (baseline), 0.0625, 0.125, 0.25, 0.5, 1, 2, 4, 8, and 16 μg/kg/min were administered; after a 45-minute equilibration period, isoflurane MAC and responses were determined. Isoflurane MAC was determined in anesthetized cats once for each remifentanil infusion rate by use of a standard tail clamp technique. Thermal threshold was measured in awake cats by use of a commercially available analgesiometric probe placed on the lateral portion of the thorax; remifentanil infusions were administered in randomized order to anesthetized cats, and thermal threshold determinations were made by an investigator who was unaware of the infusion rate.
Results—Mean ± SEM median effective concentration (EC50) for remifentanil and its active metabolite, GR90291, for the thermal threshold test was 1.00 ± 0.35 ng/mL and 307 ± 28 ng/mL of blood, respectively. Dysphoria was detected in all awake cats at the 2 highest remifentanil infusion rates. However, isoflurane MAC during remifentanil infusions was unchanged from baseline values, even at blood opioid concentrations approximately 75 times the analgesic EC50.
Conclusions and Clinical Relevance—Immobility and analgesia as reflected by thermal threshold testing were independent anesthetic end points in the cats. Results of MAC-sparing evaluations should not be used to infer analgesic potency without prior validation of an MAC-analgesia relationship for specific drugs and species.
Objective—To characterize the pharmacokinetics of remifentanil in conscious cats and cats anesthetized with isoflurane.
Procedures—Remifentanil (1 μg/kg/min for 5 minutes) was administered IV in conscious cats or cats anesthetized with 1.63% isoflurane in oxygen in a randomized crossover design. Blood samples were obtained immediately prior to remifentanil administration and every minute for 10 minutes, every 2 minutes for 10 minutes, and every 5 minutes for 10 minutes after the beginning of the infusion. Blood was immediately transferred to tubes containing citric acid, flash frozen in liquid nitrogen, and stored at −80°C until analysis. Blood remifentanil concentration was determined by use of liquid chromatography–mass spectrometry. Remifentanil concentration-time data were fitted to compartment models.
Results—A 2-compartment model (with zero-order input because of study design) best described the disposition of remifentanil in awake and isoflurane-anesthetized cats. The apparent volume of distribution of the central compartment, the apparent volume of distribution at steady state, the clearance, and the terminal half-life (median [range]) were 1,596 (1,164 to 2,111) and 567 (278 to 641) mL/kg, 7,632 (2,284 to 76,039) and 1,651 (446 to 29,229) mL/kg, 766 (408 to 1,473) and 371 (197 to 472) mL/min/kg, and 17.4 (5.5 to 920.3) and 15.7 (3.8 to 410.3) minutes in conscious and anesthetized cats, respectively.
Conclusions and Clinical Relevance—The disposition of remifentanil in cats was characterized by a high clearance. Isoflurane anesthesia significantly decreased the volume of the central compartment, likely by decreasing blood flow to vessel-rich organs.
Objective—To verify the isoflurane anesthetic minimum alveolar concentration (MAC)-sparing effect of a previously administered target plasma fentanyl concentration of 16 ng/mL and characterize an anticipated further sparing in isoflurane MAC associated with higher target plasma fentanyl concentrations.
Procedures—Horses were assigned 2 of 3 target plasma fentanyl concentrations (16, 24, and 32 ng/mL), administered in ascending order. Following determination of baseline MAC, horses received a loading dose of fentanyl followed by a constant rate infusion; MAC determination was performed in triplicate at baseline and at each fentanyl concentration. Venous blood samples were collected throughout the study for determination of actual plasma fentanyl concentrations. Recovery from anesthesia was monitored, and behaviors were rated as excellent, good, fair, or poor.
Results—Mean ± SD fentanyl plasma concentrations were 13.9 ± 2.6 ng/mL, 20.1 ± 3.6 ng/mL, and 24.1 ± 2.4 ng/mL for target concentrations of 16, 24, and 32 ng/mL, respectively. The corresponding changes in the MAC of isoflurane were −3.28%, −6.23%, and +1.14%. None of the changes were significant. Recovery behavior was variable and included highly undesirable, potentially injurious excitatory behavior.
Conclusions and Clinical Relevance—Results of the study did not verify an isoflurane-sparing effect of fentanyl at a plasma target concentration of 16 ng/mL. Furthermore, a reduction in MAC was not detected at higher fentanyl concentrations. Overall, results did not support the routine use of fentanyl as an anesthetic adjuvant in adult horses.
Objective—To determine the effect of ranitidine on gastric emptying in horses.
Animals—11 adult horses.
Procedures—In vitro, isolated muscle strips from the pyloric antrum and duodenum of 5 horses were suspended in baths and attached to isometric force transducers. Once stable spontaneous contractions were observed, ranitidine or diluent was added at cumulative increasing concentrations. Isometric stress responses were compared. In vivo, 6 horses were assigned to a group in a prospective randomized crossover study design with a wash-out period of 2 weeks between trials. Ranitidine (2.2 mg/kg) or saline (0.9% NaCl) solution was administered IV, and 15 minutes later, acetaminophen (20 mg/kg), diluted in 400 mL of water, was administered via nasogastric tube to evaluate the liquid phase of gastric emptying. Serum acetaminophen concentration was measured at several time points for 3 hours by use of liquid chromatography tandem mass spectrometry. Frequency of defecation was recorded during the 3 hours of the study.
Results—Ranitidine increased the contractile activity of the pyloric antrum smooth muscle at a concentration of 10−4 M. No significant effect of ranitidine on plasma kinetics of acetaminophen was identified. Frequency of defecation did not differ between groups.
Conclusions and Clinical Relevance—Ranitidine did increase gastric motility in vitro, but no effect on liquid phase gastric emptying was identified in healthy horses by use of the acetaminophen absorption model. Results do not support the use of ranitidine to promote gastric emptying.
Objective—To determine the effects of domperidone on in vivo and in vitro measures of gastrointestinal tract motility and contractility in healthy horses.
Sample—18 adult horses and tissue samples from an additional 26 adult horses.
Procedures—Domperidone or placebo paste was administered to healthy horses in a 2-period crossover study. Gastric emptying was evaluated after oral administration of domperidone paste (1.1 or 5.0 mg/kg) or placebo paste by means of the acetaminophen absorption test in 12 horses. Frequency of defecation, weight of feces produced, fecal moisture, and stomach-to-anus transit time of microspheres were evaluated after administration of domperidone paste (1.1 mg/kg) or placebo paste in 6 horses. The effect of domperidone on smooth muscle contractile activity in samples of duodenum, jejunum, ileum, or colon obtained from 26 horses immediately after euthanasia (for nonsystemic medical problems) was investigated.
Results—Oral administration of 5.0 mg of domperidone/kg increased peak plasma acetaminophen concentration and area under the curve, indicating increased gastric emptying. Administration of 1.1 mg of domperidone/kg had no effect on gastric emptying, transit time, defecation frequency, or amount and moisture of excreted feces. Contractile activities of circular and longitudinal muscle strips from the duodenum, jejunum, ileum, or colon were not altered by domperidone. Dopamine increased contractile activity of longitudinal muscle strips but not that of circular muscle strips from the midjejunum. Domperidone decreased the dopamine-induced contractile activity of midjejunal longitudinal muscle strips.
Conclusions and Clinical Relevance—The potential beneficial effects of domperidone in horses with ileus need to be evaluated in horses with decreased gastric emptying or adynamic ileus.
Objective—To investigate the pharmacokinetics of penciclovir in healthy cats following oral administration of famciclovir or IV infusion of penciclovir.
Procedures—Cats received famciclovir (40 [n = 3] or 90  mg/kg, PO, once) in a balanced crossover-design study; the alternate dose was administered after a ≥ 2-week washout period. After another washout period (≥ 4 weeks), cats received an IV infusion of penciclovir (10 mg/kg delivered over 1 hour). Plasma penciclovir concentrations were analyzed via liquid chromatography-mass spectrometry at fixed time points after drug administration.
Results—Mean ± SD maximum plasma concentration (Cmax) of penciclovir following oral administration of 40 and 90 mg of famciclovir/kg was 1.34 ± 0.33 μg/mL and 1.28 ± 0.42 μg/mL and occurred at 2.8 ± 1.8 hours and 3.0 ± 1.1 hours, respectively; penciclovir elimination half-life was 4.2 ± 0.6 hours and 4.8 ± 1.4 hours, respectively; and penciclovir bioavailability was 12.5 ± 3.0% and 7.0 ± 1.8%, respectively. Following IV infusion of penciclovir (10 mg/kg), mean ± SD penciclovir clearance, volume of distribution, and elimination half-life were 4.3 ± 0.8 mL/min/kg, 0.6 ± 0.1 L/kg, and 1.9 ± 0.4 hours, respectively.
Conclusions and Clinical Relevance—Penciclovir pharmacokinetics following oral administration of famciclovir were nonlinear within the dosage range studied, likely because of saturation of famciclovir metabolism. Oral administration of famciclovir at 40 or 90 mg/kg produced similar Cmax and time to Cmax values. Therefore, the lower dose may have similar antiviral efficacy to that proven for the higher dose.