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Summary

Disposition kinetic variables of HI-6, a bispyridinium oxime, have been determined in mice, rats, rabbits, Rhesus monkeys, Beagles, sheep, and human beings. The drug has a short half-life, small apparent volume of distribution and high body clearance in these species, and is eliminated mainly by renal excretion. Using regression analysis and double logarithmic plots of the pharmacokinetic variables vs body weight of the various species, it was observed that body (systemic) clearance is the pharmacokinetic variable to use for interspecies comparison of elimination of the drug. The allometric exponent denoting the proportionality of body clearance of HI-6 to body weight of the 7 species studied was 0.76, which may be related to the renal excretion process for the drug. The apparent volume of distribution was similar (260 to 304 ml/kg of body weight) in the various species. The results indicate that volume of distribution, body clearance, and with less confidence, half-life might be used for interspecies scaling and for predicting these variables in other mammalian species. On the basis of the pharmacokinetic variables in selected species (rats and mice excluded), iv administration of HI-6 at a dosing rate of 20 to 25 mg/kg at 4-hour intervals should provide an average steady-state plasma concentration of 16 to 20 µg/ml in domestic animals. The short half-life of HI-6 precludes increasing the dosage interval.

Free access
in American Journal of Veterinary Research

SUMMARY

Disposition kinetics of cloxacillin were examined in calves after topical administration of benzathine cloxacillin and single iv administration of sodium cloxacillin, and the susceptibility of 17 field isolates of Moraxella bovis was measured. For the IV pharmacokinetic phase, sodium cloxacillin was administered at dosage of 10 mg/kg of body weight to male Holstein calves (n = 6, weighing 146 to 170 kg), and serum concentration of cloxacillin was measured thereafter for 10 hours.

For the ocular pharmacokinetic phase, 6 calves were given either of 4 benzathine cloxacillin topical formulations consisting of 50-, 125-, 250-, or 375-mg doses. Treatment was repeated every 10 days until all 4 benzathine cloxacillin dosages were tested in the same 6 calves. Blood and tears were collected for 72 hours after each benzathine cloxacillin formulation was administered, and the concentration of cloxacillin in each specimen was measured, using a bioassay.

The minimal inhibitory concentration of cloxacillin for 17 field isolates of M bovis was determined by use of an agar pour-plate dilution assay.

After single iv administration of sodium cloxacillin, its half-life, body clearance, and volume of distribution were 19.5 ± 12.8 minutes, 18.3 ± 2.2 ml/min·kg, and 496 ± 290 ml/kg, respectively. After topical administration of benzathine cloxacillin, cloxacillin concentration in lacrimal fluid peaked between 30 and 45 minutes and ranged between 963 μg/ml and 3,256 μg/ml for the 125- and 375-mg doses, respectively. There was no detectable cloxacillin activity in the lacrimal fluid of any calf by 36 hours after topical administration of benzathine cloxacillin, and cloxacillin was not detected in the serum at any time. The mean lacrimal fluid cloxacillin concentration for the 4 groups during the first 8 hours was not significantly different; however, by 12 hours, the cloxacillin concentration in tears from calves of the 250- and 375-mg groups was significantly (P < 0.05) greater than that in calves of the 50- and 125-mg groups.

Cloxacillin concentration ≥ 3.13 μg/ml was maintained for a significantly (P < 0.05) longer time after treatment, using the 375-mg dose, compared with the 50-mg dose of benzathine cloxacillin. The minimal inhibitory concentration of cloxacillin for 1 isolate was 6.25 μg/ml, but was ≤ 3.13 μg/ml for 16 other M bovis isolates.

Free access
in American Journal of Veterinary Research

Abstract

Objective—To quantitate dose- and time-related magnitudes of interactive effects of morphine (MOR) and isoflurane (ISO) in horses and to characterize pharmacokinetics of MOR in plasma and the ventilatory response to MOR during administration of ISO.

Animals—6 adult horses.

Procedure—Horses were anesthetized 3 times to determine the minimum alveolar concentration (MAC) of ISO in O2 and then to characterize the change in anesthetic requirement as defined by the alteration in ISO MAC following IV administration of saline (0.9% NaCl) solution and 2 doses of MOR (low dose, 0.25 mg/kg; high dose, 2.0 mg/kg). Arterial blood samples were obtained before and after MOR and analyzed.

Results—Mean ± SD baseline ISO MAC was 1.43 ± 0.06%. The ISO MAC did not change with time after administration of saline solution. Effects of MOR on ISO MAC varied. Maximal change in MAC ranged from –20.2 to +28.3% and –18.9 to +56.2% after low and high doses of MOR, respectively. Typical half-life of MOR in plasma was 40 to 60 minutes and related to dose. Mean PaCO2 increased from 70 mm Hg before MOR to 88 to 102 mm Hg for 30 to 240 minutes after the high dose of MOR. Recovery from anesthesia after administration of the high dose of MOR was considered undesirable and dangerous.

Conclusions and Clinical Relevance—Our results do not support routine clinical use of MOR administered IV at dosages of 0.25 or 2.0 mg/kg as an adjuvant to anesthesia in horses administered ISO. (Am J Vet Res 2003;64:166–175)

Full access
in American Journal of Veterinary Research

SUMMARY

The effect of age on the pharmacokinetics of chloramphenicol was determined after iv administration of chloramphenicol sodium succinate (25 mg/kg of body weight) to 6 foals at 1 day and 3, 7, 14, and 42 days of age. The disposition of chloramphenicol was best described, using a two-compartment open model in all foals at all ages evaluated. Significant age-related changes were observed in values for the major kinetic terms describing the disposition of chloramphenicol in foals; the greatest changes were observed between 1 day and 3 days of age.

The mean ± sd value for elimination rate constant (β) for chloramphenicol in 1-day-old foals (0.131 ± 0.06 h-1) was significantly (P < 0.005) lower than the value in 3-day-old foals (0.514 ± 0.156 h-1), and both values were significantly (P < 0.05) lower than values for β in 7-, 14-, and 42-day-old foals. With increasing age, the increase in the mean value for β resulted in decrease in the harmonic mean elimination half-time (t1/2β) for chloramphenicol, from 5.29 hours in 1-day-old foals to: 1.35 hours in 3-day-old foals; 0.61 hour in 7-day-old foals; 0.51 hour in 14-day-old foals; and 0.34 hour in 42-day-old foals. At 1, 3, and 7 days of age, values for t1/2β of chloramphenicol in a premature foal born after parturition was induced with oxytocin, were considerably longer than comparable t1/2β values for term foals born naturally.

The mean body clearance (ClB) of chloramphenicol in 1-day-old foals (2.25 ± 0.67 ml/min·kg of body weight) was significantly lower than values in: 3-day-old (6.23 ± 2.22 ml/min·kg; P < 0.05); 7-day-old (8.86 ± 1.90 ml/min·kg; P < 0.0005); 14-day-old (9.63 · 1.63 ml/min·kg; P < 0.0005); and 42-day-old (9.68 · 2.76 ml/min·kg; P < 0.0001) foals. In foals of all ages, ClB of chloramphenicol in the parturition-induced premature foal was lower than the mean value for term foals born naturally.

The volume of distribution (V′d[area]) of chloramphenicol decreased progressively with increasing age between day 1 and day 42, so that the mean value for 42-day-old foals (362 ± 163 ml/kg) was less than a third the mean value for 1-day-old foals (1,101 ± 284 ml/kg). The mean value for V′d(area) in 1-day-old foals was significantly greater than values for: 7-day-old (491 ± 158 ml/kg; P < 0.01); 14-day-old (426 ± 65 ml/kg; P < 0.005); and 42-day-old (362 ± 162; P < 0.0005) foals, and the mean value for V′d(area)on day 3 was significantly (P < 0.05) greater than the mean value for V′d(area) on days 7, 14, and 42.

Using dosage calculations based on mean values for the pharmacokinetic terms derived for each age group, it was predicted that to maintain plasma chloramphenicol concentration > 8 μg/ml, chloramphenicol sodium succinate (25 mg/kg) would have to be administered at dose intervals of 10, 3, 1.5, 1.5, and 1 hours in clinically normal foals 1 day and 3, 7, 14, and 42 days, of age, respectively. It was concluded that the marked changes in the disposition of chloramphenicol detectable during the first few days of life, the variation between individuals, the potentially major effect of prematurity, and the potential for compromised liver function in septicemic foals indicate that use of drugs, such as chloramphenicol, which rely heavily on hepatic metabolic processes for elimination, should be avoided whenever possible during the early neonatal period, unless plasma concentration is monitored.

Free access
in American Journal of Veterinary Research

Abstract

Objective—To determine pharmacokinetics and selected cardiopulmonary effects of fentanyl in isoflurane-anesthetized rhesus monkeys.

Animals—6 adult male rhesus monkeys.

Procedure—Fentanyl (8 mg/kg of body weight, IV) was administered to 6 monkeys anesthetized with isoflurane. End-tidal isoflurane concentration and esophageal temperature were kept constant, and ventilation was mechanically assisted. Heart rate, rhythm, aortic blood pressure, and blood pH, gas, and fentanyl concentrations were determined before and for 8 hours after administration of fentanyl. Pharmacokinetics of fentanyl were derived by use of noncompartmental methods based on statistical moment theory.

Results—Heart rate and mean arterial pressure decreased transiently following fentanyl administration. Maximal decreases were observed 5 to 15 minutes after administration. Arterial pH, PaCO2, and PaO2 ranged from 7.46 ± 0.04 to 7.51 ± 0.05 units, 29.2 ± 3 to 34.6 ± 4.4 mm Hg, and 412.6 ± 105.3 to 482.9 ± 71.2 mm Hg, respectively. The clearance, volume of distribution area, volume of distribution steady state, mean residence time, area under the curve, elimination rate constant, and half-life were 32.5 ± 2.48 ml/kg/min, 9.04 ± 1.91 L/kg, 7.0 ± 1.2 L/kg, 218.5 ± 35.5 min, 0.247 ± 0.019 mg/ml/min, 0.004 ± 0.001/min, and 192.0 ± 33.5 min, respectively.

Conclusions and Clinical Relevance—Transient but potentially clinically important decreases in heart rate and mean arterial pressure were observed following fentanyl administration. Distribution and clearance data were similar to those reported for dogs and humans. (Am J Vet Res 2000;61:931–934)

Full access
in American Journal of Veterinary Research