Toxicokinetics of the active doxorubicin metabolite, doxorubicinol, in sulphur-crested cockatoos (Cacatua galerita)

The pharmacokinetics of doxorubicinol, a cytotoxic metabolite of the anticancer drug, doxorubicin, were studied in four healthy sulphur-crested cockatoos (Cacatua galerita) after a 20 min intravenous infusion of 2 mg/kg. Plasma doxorubicinol concentrations were measured by HPLC. The pharmacokinetic parameters were estimated using a non-compartmental method. The mean (+/- SD) peak concentration was 8341 +/- 3132 microg/L at 17.5 +/- 5.0 min after the start of the infusion, and doxorubicinol concentrations declined biexponentially to 154.3 +/- 34.5 microg/L, 40 min after the end of the infusion. Systemic clearance was 0.940 +/- 0.473 L/h/kg, mean residence time was 0.165 +/- 0.133 h, and steady-state volume of distribution was 0.123 +/- 0.0526 L/kg. The terminal half-life was 0.660 +/- 0.611 h. Detectible but unquantifiable concentrations of doxorubicinol were present in the plasma ultrafiltrate of two birds during the infusion, indicating very extensive plasma protein binding. Physiological, haematological and biochemical monitoring over 3 weeks showed that doxorubicinol at a single infused dose of 2 mg/kg caused no toxicities of major concern.     

Phase I evaluation of low-dose suramin as chemosensitizer of doxorubicin in dogs with naturally occurring cancers

BACKGROUND: Low and nontoxic concentrations (10-50 microM) of suramin, which is a nonspecific inhibitor of multiple growth factors, including fibroblast growth factors, enhances the activities of cytotoxic chemotherapeutic agents, such as doxorubicin and paclitaxel, both in vitro and in vivo. Suramin has not been evaluated as a chemosensitizing agent in dogs with cancer. HYPOTHESIS: Nontoxic suramin can be used safely as a chemosensitizer in dogs. ANIMALS: Sixteen dogs of various breeds with measurable tumors were treated; 1 dog that had undergone amputation for osteosarcoma received adjuvant therapy. METHODS: The dogs received 53 courses of treatment with suramin in combination with doxorubicin. The suramin dosage was 6.75 mg/kg IV 3 h before standard doxorubicin administration every 2 weeks. The pharmacokinetics and clinical efficacy were determined. RESULTS: The pharmacokinetics of low-dose suramin followed a 2-compartment model with half-lives of 2 h and 6 days. The distribution volume was a 0.34 +/- 0.12 L/kg, and clearance was 1.86 +/- 0.76 mL/kg/h. During the time interval that doxorubicin was present at therapeutically active concentrations (ie, from the start of infusion to 24 hours), the plasma concentrations were maintained within 20% of the target range (8-60 microM) in 72% of the treatments. The toxicity of the suramin/doxorubicin combination was mild and comparable to the toxicity expected for doxorubicin monotherapy. Objective partial responses were observed in 2 out of 16 evaluable dogs (13%). All 5 dogs that previously received doxorubicin showed improved responses to the suramin/doxorubicin combination. CONCLUSIONS AND CLINICAL IMPORTANCE: A fixed, low-dose suramin regimen yields the desired target plasma concentrations in most dogs, and appears to enhance the activity of doxorubicin without enhancing toxicity.     

Liver function tests in dogs with portosystemic shunts: measurement of serum bile acid concentration

Sulfobromophthalein excretion and plasma ammonia and serum bile acid concentrations were measured in 11 dogs with portal vascular anomalies. The fasting serum bile acid concentration was increased in all 11 dogs (78.9 +/- 16.1 mumol/L; normal, 2.6 +/- 0.4 mumol/L). For values measured in 8 dogs, the 2-hour postprandial serum bile acid concentration was increased further (177.0 +/- 26.4 mumol/L; normal, 7.6 +/- 2.3 mumol/L). The fasting plasma ammonia concentration was markedly increased in all 11 dogs (246.9 +/- 40.3 micrograms/dl; normal, 27 to 15 micrograms/dl). Thirty minutes after the oral administration of ammonium chloride, the plasma ammonia concentration was increased further in the 7 dogs (510.7 +/- 45.5 micrograms/dl; normal, 57.5 to 20.5 micrograms/dl). Results of the sulfobromophthalein excretion test were abnormal in 10 of 11 dogs (12.3 +/- 1.4%; normal, less than 5% retention after 30 minutes).     

Pharmacokinetics of intramuscularly administered pethidine in dogs and the influence of anaesthesia and surgery

The plasma concentration of pethidine was measured after it had been administered intramuscularly to fully conscious dogs, and to dogs in the postoperative period and during general anaesthesia. The absorption of the drug was erratic except in the anaesthetised animals and the plasma concentrations of the drug were also higher in this group. Correlation of plasma concentrations of the drug with its analgesic activity revealed a 'critical' concentration of pethidine of 0.4 micrograms/ml for complete analgesia; useful though not complete analgesia was achieved with concentrations above 0.2 micrograms/ml. These concentrations were maintained for 90 minutes after the administration of the drug at a dose of 2.0 mg/kg and for 120 minutes after a dose of 3.5 mg/kg.     

Pharmacokinetics and plasma protein binding (in vitro) of oxytetracycline in buffalo (Bubalus bubalis)

The pharmacokinetics of oxytetracycline given in a single dose (22 mg/kg) either IV or IM was studied in 4 female buffalo calves. The half-life (t1/2) after IV administration varied between 169.02 and 216.56 minutes and that after IM administration, between 630 and 990 minutes. The drug was distributed well in the body after IM administration (Vdarea 1.18 to 2.15 L/kg). The total body clearances varied between 1.02 and 1.45 and between 1.17 and 1.49 ml/kg/min after the IV and the Im dosings, respectively. It has been proposed that oxytetracycline is excreted mainly by glomerular filtration in the buffalo species, but tubular reabsorption also may have a small part. About 42% of the drug was bound to plasma proteins at concentrations of 2 to 20 micrograms of oxytetracycline/ml. The drug dosage schedules to maintain serum levels of 0.5, 1, 2, and 5 micrograms/ml also are determined.     

Drug Residues in Serum of Dogs Receiving Anticancer Chemotherapy

Background: The presence of drug residues in blood samples can represent an occupational hazard. However, studies on cytotoxic drug residues in serum of dogs are lacking in veterinary oncology. Objective: To evaluate possible occupational hazards associated with handling of blood samples from dogs receiving oncolytic drugs 7 days after treatment. Animals: Twenty‐seven client‐owned dogs treated for lymphoma or mast cell tumors with vincristine, vinblastine, cyclophosphamide, or doxorubicin. Methods: Prospective, observational study. Serum samples were either taken 7 days after administration of vincristine, cyclophosphamide, doxorubicin (lymphoma), and vinblastine (mast cell tumor), or 1–2 days after the last concurrent oral administration of cyclophosphamide (mast cell tumor). Additionally, serum was collected within 5 minutes of treatment. Measurement of drug residues in serum was performed by liquid chromatography tandem mass spectrometry (LC/MS/MS). Results: In 33 samples collected within 5 minute of treatment, the median serum concentrations were vincristine: 37 μg/L (range: 11–87 μg/L), vinblastine: 13 μg/L (range: 13–35 μg/L), cyclophosphamide: 2,484 μg/L (range: 1,209–2,778 μg/L), doxorubicin: 404 μg/L (range: 234–528 μg/L). In 81 serum samples collected 7 days after treatment vinblastine (7 μg/L) was detected in 1 sample, and cyclophosphamide (7 and 9 μg/L) in 2 samples collected 1–2 days after oral administration of cyclophosphamide. Medications were not detected in any of the other samples. Conclusions and Clinical Importance: Handling of blood samples from dogs receiving oncolytic chemotherapy 7 days after treatment with vincristine, vinblastine, cyclophosphamide, and doxorubicin should not present a health hazard.     

Cytotoxic Drug Residues in Urine of Dogs Receiving Anticancer Chemotherapy

The presence of cytotoxic drug residues in urine of dogs may represent an exposure risk for pet owners and other people as well as a potential environmental contaminant. However, studies on cytotoxic drug residues in excretions of clinical patients are lacking in veterinary oncology. Hypothesis: Variable concentrations of cytotoxic residues are present in urine samples, depending on sampling time and substance. Animals: Client‐owned dogs with lymphoma or mast cell tumors treated with standard chemotherapy protocols. Methods: Urine samples were collected before, directly after, and on days after administration of chemotherapy. Measurement of vincristine, vinblastine, cyclophosphamide, and doxorubicin residues in canine urine was performed by a quantitative liquid chromatography tandem mass spectrometry (LC/MS/MS) method. Results: Median cyclophosphamide residue concentration was 398.2 μg/L directly after treatment (d0) and was below the level of detection on days 1–3 (d1, d2, d3). Median vincristine residue concentration was 53.8 μg/L directly after treatment and was 20.2, 11.4, and 6.6 μg/L on days 1, 2, and 3. Median vinblastine residues were 144.9 (d0), 70.8 (d1), 35.6 (d2), and 18.7 μg/L (d3) with low concentrations detectable for 7 days after treatment. Median urine doxorubicin concentrations were 354.0 (d0), 165.6 (d1), 156.9 (d2), and 158.2 μg/L (d3). Low concentrations of doxorubicin were measurable up to 21 days after administration. Conclusions and Clinical Importance: Variable concentrations of chemotherapeutics were measured in urine samples, depending on sampling time point and drug. Findings may inform current chemoprotection guidelines and help minimize exposure risks.     

Evaluation of a low-dose synthetic adrenocorticotropic hormone stimulation test in clinically normal dogs and dogs with naturally developing hyperadrenocorticism.

OBJECTIVE: To determine whether low doses of synthetic ACTH could induce a maximal cortisol response in clinically normal dogs and to compare a low-dose ACTH stimulation protocol to a standard high-dose ACTH stimulation protocol in dogs with hyperadrenocorticism. DESIGN: Cohort study. ANIMALS: 6 clinically normal dogs and 7 dogs with hyperadrenocorticism. PROCEDURE: Each clinically normal dog was given 1 of 3 doses of cosyntropin (1, 5, or 10 micrograms/kg [0.45, 2.3, or 4.5 micrograms/lb] of body weight, i.v.) in random order at 2-week intervals. Samples for determination of plasma cortisol and ACTH concentrations were obtained before and 30, 60, 90, and 120 minutes after ACTH administration. Each dog with hyperadrenocorticism was given 2 doses of cosyntropin (5 micrograms/kg or 250 micrograms/dog) in random order at 2-week intervals. In these dogs, samples for determination of plasma cortisol concentrations were obtained before and 60 minutes after ACTH administration. RESULTS: In the clinically normal dogs, peak cortisol concentration and area under the plasma cortisol response curve did not differ significantly among the 3 doses. However, mean plasma cortisol concentration in dogs given 1 microgram/kg peaked at 60 minutes, whereas dogs given doses of 5 or 10 micrograms/kg had peak cortisol values at 90 minutes. In dogs with hyperadrenocorticism, significant differences were not detected between cortisol concentrations after administration of the low or high dose of cosyntropin. CLINICAL IMPLICATIONS: Administration of cosyntropin at a rate of 5 micrograms/kg resulted in maximal stimulation of the adrenal cortex in clinically normal dogs and dogs with hyperadrenocorticism.     

Comparison of the effects of asparaginase administered subcutaneously versus intramuscularly for treatment of multicentric lymphoma in dogs receiving doxorubicin

OBJECTIVE: To determine the effectiveness and safety of asparaginase administered s.c. versus i.m. for treatment of multicentric lymphoma in dogs receiving doxorubicin. DESIGN: Prospective study. ANIMALS: 49 dogs with multicentric lymphoma. PROCEDURE: Dogs were treated with doxorubicin every 3 weeks, for a total of 5 treatments, and were given 3 weekly treatments of asparaginase, s.c. or i.m. Using high-performance liquid chromatography, mean plasma asparagine, aspartic acid, glutamine, and glutamic acid concentrations were determined in dogs before and during treatment with asparaginase (10,000 U/m2 of body surface area, once a week for 3 weeks). Asparaginase was administered s.c. in 23 dogs and i.m. in 26 dogs. Variables evaluated included time to response to chemotherapy, remission and survival times, and clinical and serum biochemical indicators of toxicoses. RESULTS: Using the World Health Organization's staging system for lymphoma, 30 dogs were in clinical stage III and 19 were in clinical stage IV. One week after asparaginase treatment, plasma asparagine concentrations were low and plasma aspartic acid, glutamine, and glutamic acid concentrations were high. Differences in plasma amino acid concentrations were not found between s.c. and i.m. groups. For dogs in clinical stage IV, i.m. administration of asparaginase significantly decreased the number of days to complete remission, compared with s.c. administration (8 vs 17 days, respectively). For dogs in clinical stage III, i.m. administration favorably increased the duration of first remission (191 vs 103 days) and survival time (289 vs 209 days). Overall, dogs treated i.m. had a faster response to chemotherapy (9 vs 15 days), a longer remission (191 vs 109 days), and a longer survival time (286 vs 198 days), compared with all dogs treated s.c. Asparaginase toxicoses were not observed regardless of the route of administration. CLINICAL IMPLICATIONS: For dogs with multicentric lymphoma that are receiving doxorubicin, i.m. treatment with asparaginase is more effective than s.c. treatment.     

Flunixin pharmacokinetics and serum thromboxane inhibition in the dog

Flunixin meglumine administered orally to beagle dogs at doses of 0.55, 1.10 or 1.65 mg/kg bodyweight was rapidly absorbed to produce maximum mean plasma concentrations of 2.40 +/- 0.70, 4.57 +/- 1.12 and 7.42 +/- 2.07 micrograms/ml, respectively. Thereafter, the plasma concentrations of flunixin fell rapidly to values less than 0.10 micrograms/ml from 24 hours after drug administration at all dosage levels. The maximum mean inhibition of serum thromboxane B2 was 91.5 per cent after the lowest dose of flunixin and 98.8 per cent for both the intermediate and high dose rates. At plasma concentrations of flunixin above 2 micrograms/ml there was more than 90 per cent inhibition of thromboxane.     

Evaluation of the effects of dietary n-3 fatty acid supplementation on the pharmacokinetics of doxorubicin in dogs with lymphoma

OBJECTIVE: To determine the effect of dietary n-3 fatty acids on the pharmacokinetics of doxorubicin in dogs with lymphoma. ANIMALS: 23 dogs with lymphoma in stages IIIa, IVa, and Va. PROCEDURE: Dogs receiving doxorubicin chemotherapy were randomly allocated to receive food with a high (test group) or low (control group) content of n-3 fatty acids. Serum doxorubicin and doxorubicinol concentrations were measured via high-performance liquid chromatography before and 6 to 9 weeks after initiation of the diets. Lymph node concentrations of doxorubicin were assessed 6 hours after the initial treatment. Dogs' body composition was assessed by means of dual-energy x-ray absorptiometry scans. RESULTS: No significant differences in doxorubicin pharmacokinetics were detected between treatment groups. Significant differences existed between the first and second sampling times among all dogs for area under the curve, maximum serum concentration, and clearance. Differences in body composition did not affect measured pharmacokinetic variables. The terminal elimination half-life was longer in dogs in which a long-term remission was achieved than in dogs that did not have remission. CONCLUSIONS AND CLINICAL RELEVANCE: Dietary supplementation of n-3 fatty acids is common in veterinary patients with neoplasia, but supplementation did not affect doxorubicin pharmacokinetics in this population of dogs. Explanations for the beneficial effects of n-3 fatty acids other than alterations in the pharmacokinetics of chemotherapy drugs should be investigated. Dogs may metabolize drugs differently prior to remission of lymphoma than when in remission. The pharmacokinetics of doxorubicin at the time of the first administration may predict response to treatment.     

Use of zinc acetate to treat copper toxicosis in dogs.

Zinc acetate was used for the treatment and prophylaxis of hepatic copper toxicosis in 3 Bedlington Terriers and 3 West Highland White Terriers. Two dogs of each breed were treated for 2 years, and 1 of each breed for 1 year. A dosage of 200 mg of elemental zinc per day was required to achieve therapeutic objectives related to copper, which included a doubling of plasma zinc concentration to 200 micrograms/dl and a suppression of oral 64 copper absorption. The dosage was later reduced to 50 to 100 mg/day to avoid an excessive increase in plasma zinc concentration. The preliminary clinical results were good. Three dogs had mild to moderate active liver disease and high liver copper concentrations at the time of initiation of zinc administration. Biopsy of the liver 2 years later revealed a reduction in hepatitis and copper concentrations. One other dog without active hepatitis also had a reduction in hepatic copper concentrations over a 2-year period. All 6 dogs have done well clinically. On the basis of these findings, we believe zinc acetate to be an effective and nontoxic treatment for copper toxicosis in dogs.     

The pharmacokinetics and pharmacodynamics of furosemide in anesthetized dogs with normal and experimentally decreased renal function

The pharmacokinetics and the biliary and urinary excretions following intravenous administration of furosemide (5 mg/kg) were investigated in the anesthetized dogs with normal and experimentally reduced renal function. After the administration, furosemide caused diuretic and choleretic response, and was excreted into urine and bile at almost similar rate to plasma concentration decay in normal dogs. Half maximum diuretic response was obtained at 1.5 micrograms/ml of plasma concentration and 100 micrograms/min of urinary excretion rate of furosemide. Acute renal failure was produced in dogs by the intravenous administration of mercuric chloride (HgCl2, 2 mg/kg). In HgCl2-treated dogs, the prolongation of half life (T1/2 beta) and the decrease in plasma clearance were noted with the decreased diuretic response. These changes in parameters appeared to be associated with the decrease in excretion of furosemide into the urine, but not into the bile. Plasma level-diuretic response relationship was extensively shifted to the right in HgCl2-treated dogs, while urinary dose-response relationship did not change significantly between two groups. These results suggest that the decreased response to furosemide in HgCl2-treated dogs seems to be due to the decreased renal clearance rather than to the subsensitivity to furosemide on the site of action.     

Doxorubicin pharmacokinetics following a single-dose infusion to sulphur-crested cockatoos (Cacatua galerita)

OBJECTIVE: To determine the pharmacokinetics of doxorubicin in sulphur-crested cockatoos, so that its use in clinical studies in birds can be considered. DESIGN: A pharmacokinetic study of doxorubicin, following a single intravenous (i.v.) infusion over 20 min, was performed in four healthy sulphur-crested cockatoos (Cacatua galerita). PROCEDURE: Birds were anaesthetised and both jugular veins were cannulated, one for doxorubicin infusion and the other for blood collection. Doxorubicin hydrochloride (2 mg/kg) in normal saline was infused i.v. over 20 min at a constant rate. Serial blood samples were collected for 96 h after initiation of the infusion. Plasma doxorubicin concentrations were assayed using an HPLC method involving ethyl acetate extraction, reverse-phase chromatography and fluorescence detection. The limit of quantification was 20 ng/mL. Established non-parametric methods were used for the analysis of plasma doxorubicin data. RESULTS: During the infusion the mean +/- SD for the Cmax of doxorubicin was 4037 +/- 2577 ng/mL. Plasma concentrations declined biexponentially immediately after the infusion was ceased. There was considerable intersubject variability in all pharmacokinetic variables. The terminal (beta-phase) half-life was 41.4 +/- 18.5 min, the systemic clearance (CI) was 45.7 +/- 18.0 mL/min/kg, the mean residence time (MRT) was 4.8 +/- 1.4 min, and the volume of distribution at steady state (V(SS)) was 238 +/- 131 mL/kg. The extrapolated area under the curve (AUC(0-infinity)) was 950 +/- 677 ng/mL x h. The reduced metabolite, doxorubicinol, was detected in the plasma of all four parrots but could be quantified in only one bird with the profile suggesting formation rate-limited pharmacokinetics of doxorubicinol. CONCLUSIONS AND CLINICAL RELEVANCE: Doxorubicin infusion in sulphur-crested cockatoos produced mild, transient inappetence. The volume of distribution per kilogram and terminal half-life were considerably smaller, but the clearance per kilogram was similar to or larger than reported in the dog, rat and humans. Traces of doxorubicinol, a metabolite of doxorubicin, were detected in the plasma.     

Neurohormonal, hemodynamic, and electrocardiographic evaluations of healthy dogs receiving long-term administration of doxorubicin

OBJECTIVE: To evaluate diagnostic testing that could be used to establish an early diagnosis of cardiotoxicosis induced by long-term administration of doxorubicin. ANIMALS: 13 adult mixed-breed dogs. Procedures-7 dogs were administered doxorubicin chloride (30 mg/m(2), IV, q 21 d for 168 days [cumulative dose, 240 mg/m(2)]), and 6 dogs received saline (0.9% NaCl) solution (5 mL, IV, q 21 d for 168 days; control group). Echocardiography, ECG, arterial blood pressure, plasma renin activity (PRA), and plasma concentrations of norepinephrine and brain natriuretic peptide (BNP) were assessed before each subsequent administration of doxorubicin and saline solution. RESULTS: Dogs that received doxorubicin had a significant decrease in R-wave amplitude, compared with values for the control group, from 30 to 210 mg/m(2). Doxorubicin-treated dogs had decreases in fractional shortening and left ventricular ejection fraction evident as early as 30 mg/m(2), but significant differences between groups were not detected until 90 mg/m(2)was reached. There was also a significant increase in PRA (>or= 120 mg/m(2)) and left ventricular end-systolic and end-diastolic dimensions (>or= 60 and >or= 180 mg/m(2), respectively). Systemic arterial pressure, remaining echocardiographic variables, and concentrations of norepinephrine and BNP had significant variations, but of no clinical importance, during doxorubicin administration. CONCLUSIONS AND CLINICAL RELEVANCE: Doxorubicininduced cardiotoxicosis developed at 120 mg/m(2), but there were no clinical signs of dilated cardiomyopathy or congestive heart failure. Echocardiography and determination of PRA were able to detect early cardiac alterations during the development of dilated cardiomyopathy, despite apparently differing degrees of sensitivity to development of doxorubicin-induced cardiotoxicosis.     

Plasma free cortisol concentrations in dogs with hyperadrenocorticism.

Unbound or free cortisol constitutes a small fraction of total plasma cortisol, but is believed to represent the biologically active portion of this circulating glucocorticoid. We tested the hypothesis that the percentage free cortisol was altered in plasma from dogs with hyperadrenocorticism, which could account for a greater target tissue response to this circulating hormone. The percentage free cortisol in plasma samples from human beings, healthy dogs, and dogs with hyperadrenocorticism was estimated, using centrifugal ultrafiltration-dialysis. Total cortisol concentrations were determined by use of radioimmunoassay. Total cortisol concentrations appeared greater in plasma from human beings than in plasma from either group of dogs. However, the percentage free cortisol was lower in plasma from human beings, resulting in a calculated concentration of free cortisol that was quite similar between plasma from human beings and healthy dogs. Total plasma cortisol concentrations were greater (P less than 0.01) in samples from dogs with hyperadrenocorticism (190 +/- 113 nmol/L; mean +/- SD) than in healthy dogs (102 +/- 85 nmol/L), but the percentage free cortisol was not different between these 2 groups (dogs with hyperadrenocorticism, 16 +/- 9%; healthy dogs, 13 +/- 6%). However, plasma free cortisol concentrations (product of total and the percentage of free cortisol) were greater (P less than 0.01) in samples from dogs with hyperadrenocorticism (36 +/- 41 nmol/L) than in those from healthy dogs (16 +/- 9 nmol/L). Significant (P less than 0.001) positive linear relationships were found between total cortisol concentrations and percentage free cortisol in plasma samples from healthy dogs and dogs with hyperadrenocorticism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative pharmacokinetics of the photosensitizer tin-etiopurpurin in dogs and rats

Photodynamic therapy is a promising new treatment for local eradication of cancer. Little work has been done to define the pharmacokinetics of photodynamic drugs or the variability in drug disposition that may occur between different species and pathophysiological states of tissues. Pharmacokinetic studies of tin-etiopurpurin (SnET2), a lipophilic photosensitizer, were conducted on six Beagle dogs and six Sprague-Dawley rats. Blood was collected up to 24 h following drug administration for measurement of tin-etiopurpurin concentration. Dogs and rats were euthanatized 24 h post-administration and tissues were collected for drug analyses. The plasma drug concentrations were best described by a 2-compartment model (Ct = Ae-alpha t + Be-beta t). Median distribution and elimination half-lives were 0.24 and 0.34 h and 10.21 and 5.25 h for dogs and rats, respectively. The apparent volumes of distribution were 4.26 +/- 1.75 L/kg for dogs and 1.84 +/- 0.36 L/kg for rats. Systemic clearance was 7.56 +/- 2.45 ml/kg/min and 6.63 +/- 0.91 ml/kg/min for dogs and rats, respectively. Drug was detected in all tissues analyzed 24 h after drug administration. Drug was detected only sporadically in skin and muscle and was generally below the limit of detection of the assay. Where comparisons could be made, concentrations of SnET2 were significantly greater in all tissues except jejunum of rats compared to dogs 24 h after drug administration.     

Oxytetracycline pharmacokinetics, tissue depletion, and toxicity after administration of a long-acting preparation at double the label dosage

Oxytetracycline (OTC) concentration in plasma and tissues, plasma pharmacokinetics, depletion from tissue, and toxicity were studied in 30 healthy calves after IM administration of a long-acting OTC preparation (40 mg/kg of body weight) at double the label dosage (20 mg/kg). Plasma OTC concentration increased rapidly after drug administration, and by 2 hours, mean (+/- SD) values were 7.4 +/- 2.6 micrograms/ml, Peak plasma OTC concentration was 9.6 +/- 2.6 micrograms/ml, and the time to peak plasma concentration was 7.6 +/- 4.0 hours. Plasma OTC concentration decreased slowly for 168 hours (elimination phase) after drug administration, and the elimination half-life was 23.9 hours. Plasma OTC concentration exceeded 3.8 micrograms/ml at 48 hours after drug administration. From 168 to 240 hours after drug administration, plasma OTC concentration decreased at a slower rate than that seen during the elimination phase. This slower phase was termed the depletion phase, and the depletion half-life was 280.7 hours. Tissue OTC concentration was highest in kidneys and liver. Lung OTC concentration exceeded 4.4 micrograms/g of tissue and 2.0 micrograms/g of tissue at 12 and 48 hours after drug administration, respectively. The drug persisted the longest in kidneys and liver. At 42 days after drug administration, 0.1 micrograms of OTC/g of kidney was detected. At 49 days after drug administration, all OTC tissue concentrations were below the detectable limit. Reactions and toxicosis after drug administration were limited to an anaphylaxis-like reaction (n = 1) and injection site swellings (n = 2).     

Platinum pharmacokinetics in sulphur-crested cockatoos (Cacatua galerita) following single-dose cisplatin infusion

OBJECTIVE: To determine the pharmacokinetics of platinum (Pt) in cockatoos. DESIGN: A pharmacokinetic study of Pt, following a single i.v. infusion of cisplatin, was done in six healthy sulphur-crested cockatoos (Cacatua galerita). PROCEDURE: Birds were hydrated for 1 h before and 2 h after a 1-h cisplatin infusion (1 mg/kg, i.v.). Serial blood samples were collected for 96 h after initiation of the infusion and urine was collected for 2 h during the hydration period after cisplatin administration. Tissue samples from 10 organs were obtained at necropsy, 96 h after cisplatin infusion. Total Pt and filterable Pt in plasma, urinary Pt and tissue Pt concentrations were assayed by inductively coupled plasma-mass spectrometry. A noncompartmental pharmacokinetic analysis was performed on the plasma and urine data. RESULTS: For total Pt and filterable Pt, the respective mean systemic clearances were 0.373 and 0.699 L/kg hourly, the steady state volumes of distribution were 4.19 and 0.356 L/kg, and the mean residence times were 111 and 0.512 h. Total plasma Pt displayed a bi-exponential decay profile with average half-lives of 0.398 and 79.0 h, while filterable Pt had a monoexponential decay with mean half-life of 0.413 h. The renal clearance during the 2-h postinfusion period was 0.167 L/kg hourly. The kidneys had the highest Pt accumulation (4.54 micrograms/g DM). CONCLUSIONS AND CLINICAL RELEVANCE: Cisplatin infusion in cockatoos was well tolerated and Pt plasma concentrations were similar to those measured during treatment of solid tumours in human patients. Despite anatomical, physiological and biochemical differences among animal species, the pharmacokinetic disposition of Pt in the cockatoo shares some features with the kinetics reported previously in rodents, dogs and human beings.     

Effect of Desmopressin Acetate on Bleeding Times and Plasma von Willebrand Factor in Doberman Pinscher Dogs with von Willebrand''s Disease

Effects of desmopressin acetate (1-desamino-8-D-arginine vasopressin [DDAVP]) on plasma von Willebrand factor (vWf) were studied in 12 purebred Doberman pinschers confirmed to have von Willebrand's disease (vWd) (plasma vWf antigen [vWf:Ag] concentrations, less than 30 U/dl). Twelve dogs had subnormal plasma botrocetin cofactor (BCf) activity and 11 dogs had prolonged buccal mucosa bleeding times. Tranquilization of three dogs with lenperone and three dogs with xylazine did not induce significant changes in mean plasma vWf:Ag concentrations or mean BCf activities. Thirty and 120 minutes after administration of DDAVP (1 micrograms/kg subcutaneously), there was significant shortening of the mean buccal mucosa bleeding time. Ten dogs responded to DDAVP with increases in BCf activity which exceeded 10 U/dl at 30 or 120 minutes, or both, after the drug was administered. At the same time, increases in plasma vWf:Ag concentrations were smaller than the increases in BCf activity. It was shown by multimeric analysis that primarily the higher molecular weight forms of vWf increased in plasma in response to DDAVP.