Biomedical subjects
T M Dyke
Publications and source records attributed to T M Dyke.
Attenuation by phenylbutazone of the renal effects and excretion of frusemide in horses.
The objectives of this study were to determine the effect of phenylbutazone premedication on the pharmacokinetics and urinary excretion of frusemide in horses; and on frusemide-induced changes in urinary electrolyte excretion. Six Standardbred mares were used in a 3-way crossover design. The pharmacokinetics and renal effects of frusemide (1 mg/kg bwt i.v.) were studied with and without phenylbutazone premedication (8.8 mg/kg bwt per os 24 h before, followed by 4.4 mg/kg bwt i.v. 30 min before frusemide administration). A control (saline) treatment was also studied. Administration of frusemide without phenylbutazone led to diuresis, natriuresis, kaliuresis and chloruresis, and altered the ratio of sodium:chloride excretion from 0.4 to 1.0 in the first hour of diuresis. When frusemide and phenylbutazone were administered, sodium and chloride excretion in the first hour were significantly (P<0.05) reduced by 40 and 32%, respectively, when compared to frusemide administrationwithout phenylbutazone. The fractional clearance of sodium and chloride was also significantly reduced. Potassium excretion, potassium fractional clearance and the ratio of sodium to chloride excretion were not affected by administration of phenylbutazone. During peak diuresis, phenylbutazone did not affect the efficiency of frusemide with respect to electrolyte excretion. The plasma disposition of frusemide was not affected by phenylbutazone. However, the renal excretion of frusemide decreased by approximately 25%. We conclude that the decreased urinary excretion of frusemide by phenylbutazone led to an attenuation of frusemide-induced increases in urinary excretion of sodium and chloride. Since the efficiency of frusemide was not affected by phenylbutazone, we conclude that phenylbutazone attenuates the renal excretion of frusemide without inhibiting the intrarenal activity of frusemide in horses.
The pharmacokinetics of furosemide in anaesthetized horses after bilateral ureteral ligation.
The pharmacokinetics of furosemide were investigated in anaesthetized horses with bilateral ureteral ligation (BUL) with (n = 5) or without (n = 5) premedication with phenylbutazone. Horses were administered an intravenous (i.v.) bolus dose of furosemide (1 mg/kg) approximately 60-90 min after BUL. Plasma samples collected up to 3 h after drug administration were analysed by a validated high performance liquid chromatography method. Median plasma clearance (CLp) of furosemide in anaesthetized horses with BUL was 1.4 mL/min/kg. Apparent steady state volume of distribution (Vd(ss)) ranged from 169 to 880 mL/kg and the elimination half life (t1/2) ranged from 83 min to 209 h. No differences in plasma concentration or kinetic parameter estimates were observed when phenylbutazone was administered before furosemide administration. BUL markedly reduces the elimination of furosemide in horses and models the potential effects that severe changes in kidney function may have on drug kinetics in horses.
Exercise-training-induced alterations in hepatic function in mares.
The effects of exercise training on hepatic function in horses were determined by studying the plasma clearance of antipyrine (20 mg/kg iv) in adult mares that either underwent treadmill training for 5 wk (n = 7) or remained in box stalls for the same time period (n = 6). Training consisted of treadmill exercise at 60% (12 min/day) and 90% (3 min/day) of pretraining maximal oxygen consumption (V(O2)max) for 6 days/wk for 5 wk. V(O2)max and velocity to obtain a blood lactate concentration of 4 mmol/l were significantly increased (from 129 to 149 ml x min-1 x kg-1 and from 5.6 to 6.1 m/s, respectively) as a result of training. The plasma clearance and volume of distribution of antipyrine increased significantly in the trained group (from 5.5 to 6.4 ml x min-1 x kg-1 and from 813 to 881 ml/kg, respectively) and decreased significantly in the untrained group. Elimination half-lives did not change as a result of training or box rest. Increases in plasma antipyrine clearance were indicative of an increase in hepatic metabolism of antipyrine. Increases in the volume of distribution of antipyrine suggest that total body water increases as a result of exercise training.
Antipyrine pharmacokinetics and urinary excretion in female horses.
OBJECTIVE: To measure renal clearance of antipyrine and urinary excretion of antipyrine (AP) metabolites in horses by use of validated high-performance liquid chromatography (HPLC) methods. ANIMALS: 8 Standardbred mares. PROCEDURE: HPLC methods for measurement of AP in equine plasma and AP and its metabolites in equine urine were validated. Antipyrine (20 mg/kg of body weight) was administered i.v., and blood samples and urine specimens were collected over 24 hours. RESULTS: Median plasma clearance of AP in horses was 6.2 ml/min/kg, of which < 2% could be attributed to renal clearance. Urinary excretion of AP and its metabolites over 24 hours accounted for < 22% of the AP dose administered. The major metabolite of AP in urine was 4-hydroxyantipyrine. CONCLUSIONS AND CLINICAL RELEVANCE: Use of the proven validated methods for measuring AP and its metabolites indicated that AP has minimal renal clearance in horses, suggesting that plasma clearance of AP reflects hepatic clearance. Combined with AP metabolite data, the pharmacokinetics of AP may be useful for assessment of hepatic cytochrome P450 activity in horses.
Pharmacokinetics of multiple-dose administration of eltenac in horses.
OBJECTIVE: To compare pharmacokinetics of eltenac after first and last IV administrations (0.5 mg/kg), using a multiple dosing schedule. ANIMALS: 6 adult mares. PROCEDURE: Eltenac (50 mg/ml) was administered IV at a dosage of 0.5 mg/kg of body weight every 24 hours for days 0 through 4. On days 0 and 4, blood samples were collected before, then periodically for 8 hours after eltanac administration. Concentration of eltenac in plasma samples was determined by use of high-performance liquid chromatography. RESULTS: On day 0, median area under the plasma eltenac concentration versus time curve (AUC) was 6.77 microg.h/ml (range, 5.61 to 8.08 microg.h/ml), median plasma clearance was 1.23 ml/min/kg (range, 1.03 to 1.40 ml/min/kg), and median steady-state volume of distribution was 191 ml/kg (range, 178 to 218 ml/kg). Median terminal half-life of eltenac was 2.36 hours (range, 2.30 to 2.98 hours). On day 4, median eltenac AUC was 6.70 microg.h/ml (range, 5.21 to 7.44 microg.h/ml), median plasma clearance was 1.23 ml/min/kg (range, 1.12 to 1.53 ml/min/kg), and median steady-state volume of distribution was 193 ml/kg (range, 172 to 205 ml/kg). Median terminal half-life of eltenac was 2.40 hours (range, 2.11 to 3.25 hours). Protein binding of eltenac, determined by ultrafiltration, was > 99% at a total plasma concentration of 36 microg/ml. CONCLUSION: Pharmacokinetic variables determined for each horse were not different between days 0 and 4. CLINICAL RELEVANCE: Under conditions of this study, there was no clinically relevant accumulation of eltenac in equine plasma or alteration of pharmacokinetic variables after multiple IV dosing of 0.5 mg/kg of eltenac.
Hepatic blood flow in horses during the recuperative period from maximal exercise.
OBJECTIVE: To determine effects of walking or standing on hepatic blood flow of horses after brief, intense exercise. ANIMALS: 6 adult Thoroughbreds (4 mares, 2 geldings). PROCEDURE: Horses were preconditioned on a treadmill to establish uniform level of fitness. Once fit, treadmill speed causing each horse to exercise at 120% of maximal oxygen consumption was determined and used in simulated races at 14-day intervals. In a three-way crossover study, horses were exercised at a speed inducing 120% of maximal oxygen consumption until fatigued or for a maximum of 2 minutes. Three interventions were studied: resting on the treadmill (REST), exercised then standing on the treadmill for 30 minutes (MS), and exercised then walking at 2 m/s for 30 minutes (MW). At 60 seconds after completion of exercise, bromsulphalein (BSP) was infused IV, and blood samples were collected every 2 minutes for 30 minutes for analysis of BSP concentration. Hematocrit and plasma total solids concentration were measured. Pharmacokinetic parameters were derived, using nonlinear regression, and were compared, using Friedman's repeated measures analysis on ranks. RESULTS: Plasma BSP concentration was higher after exercise. Median hepatic blood flow (BSP clearance) decreased significantly from 23.8 (REST) to 20.7 (MS) and 18.7 (MW) ml/min/kg. Median steady-state volume of distribution of BSP decreased from 47.6 (REST) to 42.7 (MW) and 40.2 (MS) ml/kg. Differences among trials were not significant when horses walked or stood after exercise. CONCLUSIONS: Hepatic blood flow and pharmacokinetics of BSP are markedly altered immediately after exercise. Limiting movement of horses during this period did not affect hepatic blood flow.
Intensity-dependent effects of acute submaximal exercise on the pharmacokinetics of bromsulphalein in horses.
OBJECTIVE: To determine the effects of acute exercise on hepatic blood flow by studying hepatic clearance of bromsulphalein for several submaximal exercise intensities. ANIMALS: 8 adult Standardbred mares. PROCEDURE: Horses were subjected to 4 submaximal exercise intensities (resting and 40, 60, and 80% maximal oxygen consumption). After horses had been running at the required treadmill speed for 1 minute, bromsulphalein (BSP; 5 mg/kg of body weight, IV) was administered during a 45- to 60-second period, and horses continued at the desired speed for an additional 15 minutes. Blood samples were collected at 2-minute intervals for 30 minutes, and plasma concentration of BSP was determined by spectrophotometry. Estimates of pharmacokinetic variables were compared among the 4 exercise intensities, using a Friedman repeated-measures analysis on ranks and linear regression. RESULTS: Median values for clearance of BSP from blood and plasma decreased significantly with exercise and was linearly related to exercise intensity. Exercise-induced differences were not detected in the volume of distribution of BSP. Elimination half-life of BSP increased significantly with increasing exercise intensity and was linearly related to exercise intensity. CONCLUSIONS: Acute submaximal exercise has a dramatic effect on clearance of BSP in horses. Presumably, exercise-induced decreases in splanchnic blood flow limit blood flow to the liver, decreasing hepatic clearance of BSP and leading to persistence of plasma concentrations of BSP. CLINICAL IMPLICATIONS: Drugs that are efficiently extracted by the liver may have decreased hepatic clearance when horses exercise at submaximal intensities.
Disposition of flunixin after intramuscular administration of flunixin meglumine to horses.
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Pharmacokinetics of intravenous and intragastric cimetidine in horses. I. Effects of intravenous cimetidine on pharmacokinetics of intravenous phenylbutazone.
Cimetidine was administered intravenously and by the intragastric route to six mares at a dose of 4.0 mg/kg of body weight (bw). Specific and sensitive high performance liquid chromatographic methods for the determination of cimetidine in horse plasma and urine and cimetidine sulfoxide in urine are described. Plasma cimetidine concentration vs. time data were analysed by non-linear least squares regression analysis to determine pharmacokinetic parameter estimates. The median (range) plasma clearance (Cl) was 8.20 (4.96-10.2) mL/min.kg of body weight, that of the steady-state volume of distribution (Vdss) was 0.771 (0.521-1.15) L/kg bw, and that of the terminal elimination half-life (t1/2 beta) was 92.4 (70.6-125) minutes. The median (range) renal clearance of cimetidine was 4.08 (2.19-6.23) mL/min.kg bw or 55.4 (36.3-81.8)% of the corresponding plasma clearance. Cimetidine sulfoxide was excreted in urine and its urinary excretion through 8 h accounted for 12.0 (9.8-16.6)% of the plasma clearance of cimetidine. The median (range) extent of intragastric bioavailability was 14.4 (6.82-21.8)% and the maximum plasma concentration after intragastric administration was 0.31 (0.24-0.50) microgram/mL. Intravenous cimetidine had no effect on the disposition of intravenous phenylbutazone or its metabolites except that the maximum plasma concentration of gamma-hydroxyphenylbutazone was less after cimetidine treatment.
The effects of submaximal exercise on the pharmacokinetics of furosemide in horses.
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Pharmacokinetic values of drugs frequently used in performance horses.
Tables of values of pharmacokinetic variables (volume of distribution, total body clearance, and plasma elimination half-life) of drugs frequently administered to performance horses are accompanied by explanatory notes. Drugs described include the nonsteroidal anti-inflammatory drugs, corticosteroids, anabolic steroids, central nervous system-modifying drugs, respiratory system drugs, diuretics, local anesthetics, and antibacterial drugs.
Sedatives, tranquilizers, and stimulants.
Drugs of relevance to equine practice that modify the central nervous system (CNS) can be broadly classified as depressants or stimulants. The pharmacologic mechanisms of action, uses, and side effects of selected CNS depressant and stimulant drugs in horses are reviewed. Knowledge of the way these CNS-modifying drugs may affect performance is limited.
Treatment of respiratory infections in horses with ceftiofur sodium.
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Megacolon in two related Clydesdale foals.
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Systemic therapy with aminoglycoside antibiotics in the horse.
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Ruptured splenic haematoma in a mare.
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Urethral obstruction in a stallion with possible synchronous diaphragmatic flutter.
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