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SUMMARY

Clorazepate dipotassium was administered orally to 8 healthy dogs at a dosage of 2 mg/kg of body weight, q 12 h, for 21 days. Serum disposition of nordiazepam, the principle metabolite of clorazepate, was determined after the first and last dose of clorazepate. Disposition variables were analyzed by use of model-independent pharmacokinetics by the predictive equations method and the trapezoidal rule method. Complete blood counts, serum chemical analyses, and urinalyses were performed before administration of clorazepate and at 10 and 21 days after administration of clorazepate.

Maximal nordiazepam concentrations ranged from 446 to 1,542 ng/ml (814 ± 334 ng/ml), at 59 to 180 minutes (97.9 ± 42.0 minutes) after a single oral dose of clorazepate. Maximal nordiazepam concentrations ranged from 927 to 1,460 ng/ml (1,308 ± 187.6 ng/ml), at 120 to 239 minutes (153 ± 57.9 minutes) after multiple oral doses of clorazepate. Serum disposition was significantly altered after multiple doses of clorazepate. Using data determined by the predictive equations method, the mean residence time after multiple doses (712 ± 214 minutes) was longer (P < 0.05) than after a single dose (527 ± 95.8 minutes). Oral volume of distribution after multiple doses of clorazepate (1.76 ± 0.647 L/kg) was smaller (P < 0.02) than after a single dose (3.18 ± 1.52 L/kg). Oral clearance after multiple doses of clorazepate (3.09 ± 0.726 ml/min/kg) was less (P < 0.001) than after a single dose (6.54 ± 2.15 ml/min/kg). Absorption half-life after multiple doses (72 minutes) was longer (P < 0.01) than after a single dose (33 minutes). The elimination half-life after a single dose (284 minutes) was not significantly different after multiple doses (355 minutes).

Significant changes (P < 0.05) in serum chemical values after multiple doses of clorazepate included decreased concentrations of albumin, total protein, and calcium and increased concentrations of urea nitrogen and glucose. Serum activities of alkaline phosphatase and alanine transaminase increased after multiple doses of clorazepate. Significant changes (P < 0.05) in the hemogram included increased total wbc count, segmented neutrophils, lymphocytes, and eosinophils. Urine pH after multiple doses (5.88 ± 0.641) was lower (P < 0.01) than after a single dose (7.44 ± 1.29). All changes in laboratory values remained within our reference ranges.

Mild sedation and ataxia developed in only 1 dog after the first dose of clorazepate. These effects were transient and did not redevelop with additional dosing.

An oral clorazepate dosage of 2 mg/kg, q 12 h, maintains serum nordiazepam concentrations considered to be therapeutic in human beings (500 to 1,900 ng/ml).

Free access
in American Journal of Veterinary Research

Summary

Dexamethasone pharmacokinetics was studied in 10 healthy dogs receiving high-dose administration of dexamethasone (dosage, 0.1 mg/kg of body weight, iv), alone or combined with acth (dosage, 0.5 U/kg, iv), or low-dose administration of dexamethasone (dosage, 0.01 mg/kg, iv) in an incomplete cross-over design. Serum samples were obtained at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 720, 1,080, 1,440, 1,920, 2,400, and 2,880 minutes after dexamethasone administration; dexamethasone was measured by radioimmunoassay validated for use in dogs. Dexamethasone pharmacokinetics was adequately described by a two-compartment first-order open model.

Comparison of pharmacokinetics for the low- and high-dose protocols revealed dose dependence; area under the curve, mean residence time, clearance, and volume of distribution increased significantly when dexamethasone dosage increased. The elimination rate constant was significantly (P < 0.05) less, and the elimination half-life significantly greater for the high-dose protocols; however, the distribution rate constant and distribution half-life were not significantly different when high-dose protocols were compared with the low-dose protocol. Dose-dependent increases in volume of distribution and clearance may be related to saturation of protein-binding sites. Concurrent administration of acth did not affect dexamethasone disposition.

Free access
in American Journal of Veterinary Research

SUMMARY

Four methods of evaluating renal function were performed in 6 cats anesthetized with halothane in oxygen. Glomerular filtration rate (gfr) was measured simultaneously in each cat by exogenous creatinine clearance (ecc), bolus inulin clearance, and 99mTc(Sn)-diethylenetriaminepentaacetic acid (dtpa) clearance determined by 2 different methods. In the first dtpa clearance method (dtpa-1), we measured radioactivity in serial blood specimens to construct plasma disappearance curves for calculation of gfr. In the second dtpa clearance method (dtpa-2), we used serial external head counts of radioactivity and a single blood specimen to construct plasma disappearance curves for calculation of gfr. Bolus inulin clearance was calculated from plasma disappearance curves using a 1-compartment open pharmacokinetic model (IN- 1) and a 2-compartment open pharmacokinetic model (IN- 2). Glomerular filtration rates were measured over 3 hours, for creatinine and dtpa methods, and over 4 hours for the inulin methods.

The gfr obtained with the reference method (ecc) was 2.56 ± 0.61 ml/min/kg of body weight (mean ± SD). Values for gfr determined by ecc and dtpa-1 were significantly correlated (r = 0.852; P ≤ 0.05). Correlation between ecc and dtpa 2 was not as good (r = 0.783; P ≤ 0.10), but the 2 dtpa methods significantly correlated with one another (r = 0.897; P ≤ 0.05). Regardless of the method of calculation, bolus inulin clearance was poorly correlated with ecc (IN-1: r = 0.538, P ≥ 0.10; in-2: r = 0.430, P ≥ 0.10) and dtpa-1 in-1: r = 0.601, P ≥ 0.10; in-2: r = 0.625, P ≥ 0.10). The 2 methods of calculating inulin clearance were highly correlated (r = 0.927; P ≤ 0.01). The dtpa clearance calculated from directly measured plasma disappearance curves (dtpa-1) compared favorably with ecc as an estimate of gfr and appears to be a safe, reliable, and less invasive method of determining gfr in cats.

Free access
in American Journal of Veterinary Research

SUMMARY

Norfloxacin was given to 6 healthy dogs at a dosage of 5 mg/kg of body weight iv and orally in a complete crossover study, and orally at dosages of 5, 10, and 20 mg/kg to 6 healthy dogs in a 3-way crossover study. For 24 hours, serum concentration was monitored serially after each administration. Another 6 dogs were given 5 mg of norfloxacin/kg orally every 12 hours for 14 days, and serum concentration was determined serially for 12 hours after the first and last administration of the drug. Complete blood count and serum biochemical analysis were performed before and after 14 days of oral norfloxacin administration, and clinical signs of drug toxicosis were monitored twice daily during norfloxacin administration. Urine concentration of norfloxacin was determined periodically during serum acquisition periods. Norfloxacin concentration was determined, using high-performance liquid chromatography with a limit of detection of 25 ng of norfloxacin/ml of serum or urine.

Serum norfloxacin pharmacokinetic values after single iv dosing in dogs were best modeled, using a 2-compartment open model, with distribution and elimination half-lives of 0.467 and 3.56 hours (harmonic means), respectively. Area-derived volume of distribution (Vd area) was 1.77 ± 0.69 L/kg (arithmetic mean ± sd), and serum clearance (ClS) was 0.332 ± 0.115 L/h/kg. Mean residence time was 4.32 ± 0.98 hour. Comparison of the area under the curve (AUC; derived, using model-independent calculations) after iv administration (5 mg/kg) with AUC after oral administration (5 mg/kg) in the same dogs indicated bioavailability of 35.0 ± 46.1%, with a mean residence time after oral administration of 5.71 ± 2.24 hours.

Urine concentration was 33.8 ± 15.3 μg/ml at 4 hours after a single dose of 5 mg/kg given orally, whereas concentration after 20 mg/kg was given orally was 56.8 ± 18.0 μg/ml at 6 hours after dosing. Twelve hours after drug administration, urine concentration was 47.4 ± 20.6 μg/ml after the 5-mg/kg dose and 80.6 ± 37.7 μg/ml after the 20-mg/kg dose.

Absorption lag time after oral administration ranged from 0.186 ± 0.103 hour after multiple doses (5 mg/kg) to 0.385 ± 0.254 hour after a single dose of 10 mg/kg. The AUC increased (P < 0.01) as the dose increased. However, AUC per unit dose decreased linearly with dose (P < 0.05), most probably because of a dose-dependent decrease in absorption from the gastrointestinal tract.

Free access
in American Journal of Veterinary Research

Summary

Dispositions of caffeine and antipyrine were compared as indicators of decreasing hepatic function in dogs with experimentally induced progressive liver disease. Dimethylnitrosamine, a hepatospecific toxin, was administered orally to 16 dogs; 6 dogs served as controls (group 1). Three classes of liver disease were defined by histologic features: mild (group 2; n = 5), moderate (group 3; n = 6), and severe (group 4; n = 5). Disposition of antipyrine, and 24 hours later, caffeine was studied 3 weeks after the last dose of toxin in each dog. For both drugs, rapid IV administration of 20 mg/kg of body weight was administered and serum samples were obtained at intervals for determination of at least 5 terminal-phase drug half-lives. For both drugs, clearance and mean residence time differed among groups (P ≤ 0.01). Clearance of antipyrine and caffeine was decreased in groups 3 and 4, compared with groups 1 and 2. Antipyrine and caffeine mean residence times were longer in group-3 dogs, compared with dogs of groups 1 and 2. Correction of caffeine and antipyrine clearances for hepatic weight increased discrimination between groups 3 and 4. The clearance and mean residence time ratios of antipyrine to caffeine were calculated for each group and, when compared with values for group-1 dogs, were used to test for differences between the 2 drugs in response to disease. Ratios did not differ among groups. These results indicate that the disposition of antipyrine and caffeine may change similarly with progression of dimethylnitrosamine-induced liver disease.

Free access
in American Journal of Veterinary Research

Summary

Sixteen horses were allotted at random to 3 groups: vehicle only; low dosage (vehicle and 3 mg of U-74389G/kg of body weight); high dosage (vehicle and 10 mg of U-74389G/kg). These solutions were given prior to reperfusion. The ascending colon was subjected to 2 hours of ischemia followed by 2 hours of reperfusion. Before, during, and after ischemia, full-thickness colonic tissue biopsy specimens were obtained for measurement of malondealdehyde (mda) concentration and myeloperoxidase activity and for morphologic evaluation.

Although increases were not significant, mda concentration and myeloperoxidase activity increased during ischemia and reperfusion. Administration of U-74389G did not have significant effects on mda concentration and myeloperoxidase activity. However, the lower dosage tended (P = 0.08) to reduce myeloperoxidase activity at 30 and 60 minutes of reperfusion.

In horses of the vehicle-only group, ischemia induced a decrease in mucosal surface area that was continued into the reperfusion period (P ≤ 0.05). Administration of U-74389G at both dosages (3 and 10 mg/kg) prevented the reperfusion-induced reduction in mucosal surface area, which was significant at 60 minutes (high dosage; P = 0.05) and 90 minutes (low and high dosages; P = 0.02). After initial reduction in horses of all groups, mucosal volume increased for the initial 60 minutes of reperfusion.

Our results indicate that lipid peroxidation may be partially involved in continued cellular death after ischemia of the ascending colon of horses. The 21-aminosteroid, U-74389G, prevented further loss of mucosa and partially attenuated the induced increase in myeloperoxidase activity during reperfusion of the ascending colon.

Free access
in American Journal of Veterinary Research