Plasma chloramphenicol concentrations in cats after parenteral administration of chloramphenicol sodium succinate

Five cats were dosed on five occasions with 20 mg chloramphenicol/kg body weight. The drug was given three times as chloramphenicol sodium succinate (by intravenous, intramuscular and subcutaneous injections) and twice as crystalline chloramphenicol in capsules. Plasma chloramphenicol concentrations were determined at fixed intervals after administration. Parenteral injection of the ester usually produced highest plasma levels at the initial sampling, 0.5 h after dosing. When capsules were given, there was greater variation between cats: highest plasma levels were recorded usually at 0.5-2 h after dosage but delayed absorption was evident in some cases. There were no statistically significant differences between the different routes with regard to mean plasma antibiotic levels at each sampling or mean area under the curve of plasma level versus time, except that mean plasma levels at 0.5 h were higher with intravenous or intramuscular injection than with oral administration.     

Effect of ingesta on systemic availability of chloramphenicol from two oral preparations in cats

On five separate occasions, five adult cats were dosed orally with 100 mg chloramphenicol tablets or chloramphenicol palmitate suspension. Each preparation was given once when the cats were fasted and once when fed ad lib. In addition, fasted cats were given the tablet preparation on one occasion with 10 ml water orally immediately afterwards. Chloramphenicol concentrations were determined at intervals after dosing, and all urine passed in 24 h after dosing was collected for chloramphenicol assay. The initial plasma antibiotic concentrations were lower with chloramphenicol palmitate suspension than with chloramphenicol tablets, and the bioavailability of chloramphenicol from the palmitate ester was especially poor in starved cats. Chloramphenicol palmitate may thus be undesirable for antimicrobial therapy in inappetent cats. Food and fluid did not appear to influence the availability of chloramphenicol from the tablet preparation, although effects on plasma drug concentrations within 1.5 h of dosing would have been missed in this study. A relatively large proportion of an oral dose of chloramphenicol is excreted unchanged in feline urine. Because of the potential toxicity of the drug, chloramphenicol dose rates should be restricted in cats with renal insufficiency or another antibiotic used.     

Ronidazole pharmacokinetics after intravenous and oral immediate-release capsule administration in healthy cats

Ronidazole (RDZ) is an effective treatment for feline Tritrichomonas foetus infection, but has produced neurotoxicity in some cats. An understanding of the disposition of RDZ in cats is needed in order to make precise dosing recommendations. Single-dose pharmacokinetics of intravenous (IV) RDZ and immediate-release RDZ capsules were evaluated. A single dose of IV RDZ (mean 9.2mg/kg) and a 95mg immediate-release RDZ capsule (mean 28.2mg/kg) were administered to six healthy cats in a randomized crossover design. Plasma samples were collected for 48 h and assayed for RDZ using high pressure liquid chromatography (HPLC). Systemic absorption of oral RDZ was rapid and complete, with detection in the plasma of all cats by 10 min after dosing and a bioavailability of 99.64 (±16.54)%. The clearance of RDZ following IV administration was 0.82 (±0.07) ml/kg/min. The terminal half-life was 9.80 (±0.35) and 10.50 (±0.82) h after IV and oral administration, respectively, with drug detectable in all cats 48h after both administrations. The high oral bioavailability of RDZ and slow elimination may predispose cats to neurotoxicity with twice-daily administration. Less frequent administration should be considered for further study of effective treatment of T foetus-infected cats.     

Pharmacokinetics of an extended-release theophylline product in cats

OBJECTIVE: To evaluate the pharmacokinetics of a brand of extended-release theophylline tablets and capsules in healthy cats. DESIGN: Randomized 3-way crossover study. ANIMALS: 6 healthy cats. PROCEDURES: A single dose of aminophylline (10 mg/kg [4.5 mg/lb], IV), a 100-mg extended-release theophylline tablet, or a 125-mg extended-release theophylline capsule was administered to all cats. Plasma samples were collected via preplaced central catheters throughout a 36-hour period. Plasma samples were frozen until analyzed by use of a fluorescence polarization monoclonal immunoassay. RESULTS: All cats tolerated drug administration and plasma collection with no adverse effects. Peak concentrations were reached for both orally administered products between 8 and 12 hours after administration. Bioavailability was excellent. Plasma concentrations were within the human therapeutic concentration of 5 to 20 microg/mL. CONCLUSIONS AND CLINICAL RELEVANCE: Daily administration of the brand of theophylline tablets and capsules used in this study at 15 mg/kg (6.8 mg/lb) and 19 mg/kg (8.6 mg/lb), respectively, maintained plasma concentrations within the desired therapeutic range in healthy cats.     

Plasma chloramphenicol concentrations in cats following intramuscular administration of three different chloramphenicol preparations

Five adult cats were given 30 mg chloramphenicol/kg by intramuscular injection on three separate occasions, using a different preparation on each occasion. The preparations were an aqueous suspension of chloramphenicol, a solution of chloramphenicol in methylpyrrolidone, and an aqueous solution of chloramphenicol sodium succinate. Plasma chloramphenicol concentrations were determined chemically at fixed intervals after dosing. Chloramphenicol sodium succinate solution gave higher and more rapidly attained plasma chloramphenicol concentrations than the other two preparations. The extent of chloramphenicol absorption up to 8 h after administration was greater with the succincate ester than with chloramphenicol dissolved in methylpyrrolidone. There was no difference in bioavailability between the aqueous suspension and the solution in methylpyrrolidone.     

Insulin glargine has a long duration of effect following administration either once daily or twice daily in divided doses in healthy cats

The pharmacological effects of glargine administered once or twice daily were compared in six healthy cats. A two-way crossover study was performed with insulin and glucose concentrations measured following subcutaneous administration of glargine once daily (0.5U/kg) or twice daily (0.25U/kg, repeated after 12h). Nadir glucose concentration and mean daily glucose concentration did not differ significantly following insulin administration once daily or twice daily in divided doses. Time to reach last glucose nadir differed, with longer intervals occurring following twice daily dosing. Blood glucose failed to return to baseline concentration by 24h in three of six cats in each treatment group. Insulin variables were not significantly different following once or twice daily dosing. This study in healthy cats demonstrates that glargine has a long duration of action with carry-over effects to the next day likely, regardless of dosing regimen. A study in diabetic cats is required to determine the best dosing regimen.     

Maintenance of physiologic concentrations of plasma testosterone in the castrated male dog, using testosterone-filled polydimethylsiloxane capsules.

Effects of various numbers of polydimethylsiloxane (PDS) capsules filled with testosterone (PDS-T) on plasma testosterone (PT) in castrated male dogs were studied. Dogs were implanted with 1 empty PDS capsule or 1, 3, or 5 PDS-T capsules. Blood samples were collected prior to and after implantation, after castration with capsules in situ, and after capsule removal. The PT was determined in these samples by radioimmunoassay. One empty capsule had no effect on PT concentration; after castration, PT values fell to nondetectable amounts. One PDS-T capsule maintained PT at concentrations above nondetectable amounts after castration, but these concentrations were significantly (P less than 0.05) lower than were preimplantation values. Three or five PDS-T capsules were capable of maintaining PT concentrations in the castrated male dog similar to those concentrations seen in the intact dog.     

Evaluation of esophageal transit of tablets and capsules in 30 cats

We have reported tablet-induced focal esophagitis and esophageal stricture formation in cats. The proposed mechanism is thought to be abnormal esophageal tablet retention resulting in focal esophagitis with subsequent stricture formation. The objective of this study was to evaluate the passage of tablets and capsules when given alone (dry swallow) and when followed by a water bolus (wet swallow) to determine if this could, in part, explain the esophageal stricture formation we have observed in cats. Fluoroscopy was used to evaluate tablet or capsule passage after administration. The percentage of dry tablet swallows that successfully passed into the stomach was 0.0% at 30 and 60 seconds, 6.7% at 90 seconds, 13.3% at 120 seconds, 26.7% at 180 and 240 seconds, and 36.7% at 300 seconds. Wet tablet swallows successfully passed 90.0% of the time at 30 seconds, 93.3% of the time at 60 seconds, and 100.0% of the time thereafter. The percentage of dry capsule swallows that successfully passed was 16.7% at each time interval. Wet capsule swallows successfully passed 96.7% of the time at 30 seconds and 100% of the time thereafter. For each time interval, wet swallows achieved significantly greater percentage passage into the stomach when compared to dry swallows (P < .05). This study shows that tablets or capsules given by dry swallow have prolonged retention in the esophagus compared to those given by wet swallow. On the basis of this study, we recommend the routine administration of a water bolus to cats receiving tablets or capsules PO to facilitate esophageal clearance. This practice may help prevent medication-associated esophagitis or stricture formation.     

Comparison of pharmacodynamic variables following oral versus transdermal administration of atenolol to healthy cats

OBJECTIVE: To describe the disposition of and pharmacodynamic response to atenolol when administered as a novel transdermal gel formulation to healthy cats. ANIMALS: 7 healthy neutered male client-owned cats. PROCEDURES: Atenolol was administered either orally as a quarter of a 25-mg tablet or as an equal dose by transdermal gel. Following 1 week of treatment, an ECG and blood pressure measurements were performed and blood samples were collected for determination of plasma atenolol concentration at 2 and 12 hours after administration. RESULTS: 2 hours after oral administration, 6 of 7 cats reached therapeutic plasma atenolol concentrations with a mean peak concentration of 579 +/- 212 ng/mL. Two hours following transdermal administration, only 2 of 7 cats reached therapeutic plasma atenolol concentrations with a mean peak concentration of 177 +/- 123 ng/mL. The difference in concentration between treatments was significant. Trough plasma atenolol concentrations of 258 +/- 142 ng/mL and 62.4 +/- 17 ng/mL were achieved 12 hours after oral and transdermal administration, respectively. A negative correlation was found between heart rate and plasma atenolol concentration. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of atenolol at a median dose of 1.1 mg/kg every 12 hours (range, 0.8 to 1.5 mg/kg) in cats induced effective plasma concentrations at 2 hours after treatment in most cats. Transdermal administration provided lower and inconsistent plasma atenolol concentrations. Further studies are needed to find an effective formulation and dosing scheme for transdermal administration of atenolol.     

Influence of formulation on the pharmacokinetics and bioavailability of racemic ketoprofen in horses

The bioavailability of S(+) and R(-) ketoprofen (KTP) in six horses was investigated after oral administration of the racemic (rac) mixture. Two oral formulations were studied, an oil-based paste containing micronised rac-KTP and powder from the same source in hard gelatin capsules, each at a dose rate of 2.2 mg/kg. For the oil-based paste two feeding schedules were used; horses were either allowed free access to food or access to food was restricted for 4 h before and 5 h after dosing. The drug in hard gelatin capsules was administered to horses with restricted access to food. After intravenous administration of rac-KTP, S(+) enantiomer concentrations exceeded those of the R(-) enantiomer. For S(+) and R(-)KTP. respectively, pharmacokinetic parameters were, t_1/2β 0.99 ± 0.14 h, 0.70 ±0.13 h;C/_B 0.56±0.09,0.92±0.20 L/h/kg; V_d(ss), 0.53 ±0.11.0, 61±0.10L/kg. Following oral administration of rac-KTP as the oil-based paste to horses with free access to food, there were no detectable concentrations in plasma in three animals at any sampling time, while a fourth animal showed very low concentrations at two sampling times only. In the two remaining horses very low but detectable concentrations were present for 5 h. In the horses with restricted access to food, rac-KTP paste administration produced higher concentrations in plasma. However, bioavailability was very low, 2.67 ± 0.43 and 5.75 ± 1.48% for R(-) and S(+)KTP, respectively. When administered as pure drug substance in hard gelatin capsules, absorption of KTP was fairly rapid, but incomplete. Bioavailability was 50.55 ± 10.95 and 54.17 ±9.9% for R(-) and S(+)KTP, respectively. This study demonstrates that rac-KTP had a modest bioavailability when administered as a micronised powder in hard gelatin capsules to horses with restricted access to food. When powder from the same source was administered as an oil-based paste, it was for practical purposes not bioavailable, regardless of the feeding schedule.     

Oral chloramphenicol dosage regimens in cats

Five adult domestic cats were each given three separate 3-day courses of chloramphenicol, using a different oral-dosage regimen each time. The regimens were: 120 mg/kg/day divided 8-hourly, 60 mg/kg/day divided 8-hourly, and 50 mg per cat every 12 h (25–40 mg/kg/day). The interval between successive courses was 3 weeks. On the third day of each course plasma samples were obtained at fixed intervals after dosing and were assayed chemically for chloramphenicol. The ranges from peak to trough chloramphenicol concentrations with each regimen were (values are means ± SEM): 63.8 ± 4.60 to 43.0 ± 3.32 μg/ml (120 mg/kg/day), 42.0 ± 3.63 to 24.7 ± 1.83 μg/ml (60 mg/kg/day), and 24.3 ± 1.72 to 7.5 ± 0.85 μg/ml (50 mg per cat 12-hourly). Because of these findings, previous toxicity studies, and the proposed therapeutic (effective and safe) concentration for chloramphenicol of 5–15 μg/ml, it is suggested that a regimen of 50 mg per animal every 12 h could be adequate for chloramphenicol therapy in cats of average size (2.5-3.9 kg) and should be evaluated clinically.     

Pharmacokinetics of ceftiofur in red deer (Cervus elaphus)

Twelve adult female red deer (Cervus elaphus) were given 250 mg of ceftiofur sodium by intramuscular injection (i.m.) and ballistic implant in a crossover design. Blood samples were taken from an in-dwelling jugular catheter prior to drug administration and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, and 72 h postadministration of the drug. Samples were centrifuged and plasma kept frozen at -70 degrees C until analysis for ceftiofur and active metabolites using an HPLC method. The pharmacokinetics of ceftiofur and metabolites after i.m. dosing and following ballistic implant were quite different. Absorption after i.m. injection was rapid; whereas following ballistic implant there was a lag-time until concentrations were detectable in plasma. The maximum concentration reached in plasma was higher following injection compared with ballistic implant, however the AUC calculated after ballistic implant was almost identical to the mean AUC found after i.m. dosing. The results indicate that i.m. administration of ceftiofur maintains adequate plasma levels for most susceptible bacterial pathogens for at least 12 h; therefore twice daily administration is needed in red deer. Ballistic implants produced plasma concentrations above the MIC for most bacterial pathogens from 4 to 24 h in most animals after administration; however, absorption of the drug was variable and some did not maintain effective concentrations for more than a few hours. Ceftiofur is a useful drug in red deer and twice daily i.m. administration dosing should allow treatment for susceptible bacterial pathogens.     

Pharmacodynamics and pharmacokinetics of flunixin in the cat

The non-steroidal anti-inflammatory agent (NSAID) flunixin was administered as single doses both orally and intravenously to six cats at a dose rate of 1.0 mg/kg in a two-part cross-over study. After oral dosing rapid absorption to a mean peak concentration of 2.586 micrograms/ml occurred at a mean time of 1.33 h. Similar mean plasma concentration-time AUC values for oral and intravenous dosing indicated that absorption by the former route was virtually complete. The decline in plasma concentration occurred fairly rapidly with both routes, and elimination half-life was approximately 1.0-1.5 h. The time course of inhibition of serum TXB2 concentration was similar for the two routes of administration, suggesting that similar dosing schedules are likely to be appropriate for evaluation of flunixin in clinical trials.     

Cats discriminate between cholecalciferol and ergocalciferol

A comparison was made of the ability of ergocalciferol and cholecalciferol to elevate plasma concentrations of vitamin D and 25-hydroxyvitamin D in cats. Cholecalciferol, given as an oral bolus in oil, resulted in a rapid elevation of plasma concentration of cholecalciferol followed by a rapid decline. In contrast, 25-hydroxyvitamin D concentration in plasma increased until day 3 after administration and remained elevated for a further 5 days. When 337 microg of both cholecalciferol and ergocalciferol in oil were given as an oral bolus to 10 cats, the peak plasma concentrations of cholecalciferol and ergocalciferol occurred at 8 or 12 h after administration. Peak concentrations of cholecalciferol were over twice those of ergocalciferol (570 +/- 80 vs. 264 +/- 42 nmol/l). The area under the curve 0-169 h for cholecalciferol was also more than twice that for ergocalciferol. When ergocalciferol and cholecalciferol were administered in a parenteral oil-based emulsion, higher concentrations of 25-hydroxyvitamin D3 than 25-hydroxyvitamin D2 were maintained in plasma. When both vitamins were included in the diet in the nutritional range, plasma concentrations of 25-hydroxyvitamin D2 were 0.68 of those of 25-hydroxyvitamin D3. Discrimination against ergocalciferol by cats appears to result from differences in affinity of the binding protein for the metabolites of the two forms of vitamin D. These results indicate that cats discriminate against ergocalciferol, and use it with an efficiency of 0.7 of that of cholecalciferol to maintain plasma 25-hydroxyvitamin D concentration.     

Digestion of bentiromide and absorption of xylose in healthy cats and absorption of xylose in cats with infiltrative intestinal disease

The digestion of bentiromide and the absorption of D-xylose was measured in 17 clinically healthy cats. The plasma xylose concentrations of the healthy cats were compared with values from 9 cats with diffuse infiltrative intestinal disease. The cats were administered 16.7 mg of bentiromide/kg and 0.5 g of xylose/kg via a stomach tube. Plasma samples were obtained before administration and 30, 60, 90, and 120 minutes after administration. The maximum mean plasma p-aminobenzoic acid concentration occurred at 60 minutes, with a value of 386 +/- 134 micrograms/dl (mean +/- SD). The maximum mean plasma xylose concentration also occurred at 60 minutes, with a value of 26.0 +/- 9.2 mg/dl. Plasma concentrations of p-aminobenzoic acid and xylose were lower in healthy cats than those reported for healthy dogs. There was no significant difference between xylose concentrations in healthy cats and cats with infiltrative intestinal disease.     

Serum chloramphenicol concentrations in preruminant calves: a comparison of two formulations dosed orally

Serum concentrations of chloramphenicol were determined after oral doses (55 mg/kg body weight) were administered to 7–9 day old Holstein-Friesian calves. Chloramphenicol in an oral solution produced greater serum concentrations than did an equivalent dose of chloramphenicol in capsules ( P <0.005). A second dose of each formulation administered 12 h after the first dose elevated serum chloramphenicol concentrations significantly ( P <0.001). The average serum chloramphenicol concentration exceeded 5 μg/ml of serum 1 h after administration of the solution compared with 4 h for the capsules. Average serum chloramphenicol concentration was greater than 5 μg/ml for at least 12 h after the dose was administered for both formulations. Of the eight calves receiving repeat doses of chloramphenicol, seven (87.5%) developed diarrhea in 76 ± 8.6 h. Six of the eight calves (75%) died during or shortly after the period of chloramphenicol administration.     

Comparative pharmacokinetics and pharmacodynamics of tablet, suspension and paste formulations of atenolol in cats

This study compared the pharmacokinetic and pharmacodynamic profiles of an extemporaneously prepared (compounded) atenolol paste and suspension for oral administration, against the commercially available divided tablet in healthy cats. Eleven healthy cats (mean: age 4 ± 0.4 year, weight 5.0 ± 0.7 kg) were dosed twice-daily with 12.5 mg atenolol (tablet, paste or suspension) for 7 days in a randomized cross-over design with a 7-day wash-out period. On day 7, an electrocardiogram was performed before and immediately after stress provocation (jugular venipuncture) at prestudy screening, and at 2, 6 and 12 h after morning dosing. Systolic arterial blood pressure (BP) was assessed following the second electrocardiogram. Plasma was collected at prestudy screening, and at 1, 2, 6 and 12 h to measure atenolol plasma concentrations. Mean atenolol dose was 2.5 mg/kg (range: 2.1-3.3 mg/kg). Stress-induced rise in heart rate was attenuated (P < 0.05) at every time point compared to baseline for all formulations. Although the paste significantly attenuated stress-induced elevation in heart rate at all time points, the effect was not consistently equivalent to the tablet. The BP was not altered (P > 0.05) at any time point by any formulation. In conclusion, there were no significant differences (P > 0.05) in any of the pharmacokinetic parameters or pharmacodynamic profiles of the paste and suspension compared to the commercially available tablet.     

Optimal Testing for Thyroid Hormone Concentration after Treatment with Methimazole in Healthy and Hyperthyroid Cats

Background: Methimazole suppresses thyroid hormone synthesis and is commonly used to treat feline hyperthyroidism. The degree of variation in thyroid hormone concentrations 24 hours after administration of methimazole and optimal time for blood sampling to monitor therapeutic efficacy have not been determined.
Objective: To assess thyroid hormone concentration variation in serum of normal and hyperthyroid cats after administration of methimazole.
Animals: Four healthy cats and 889 retrospectively acquired feline thyroid hormone profiles.
Methods: Crossover and retrospective studies . In the crossover study, healthy cats were treated with increasing doses of oral methimazole until steady state of thyroid suppression was achieved. Thyroid hormones and thyroid stimulating hormone (TSH) were serially and randomly monitored after methimazole. Paired t -tests and a 3-factor analysis of variance were used to determine differences between thyroid hormone concentrations in treated and untreated cats in the crossover study. Thyroid profiles from methimazole-treated hyperthyroid cats were retrieved from the Diagnostic Center for Population and Animal Health database and reviewed. Linear regression analysis evaluated relationships of dosage (mg/kg), dosing interval (q24h versus q12h), and time after methimazole to all thyroid hormone concentrations.
Results: All serum concentrations of thyroid hormones were significantly suppressed and TSH was significantly increased for 24 hours after administration of oral methimazole in healthy cats ( P < .005). In hyperthyroid cats, there were no significant relationships between thyroid hormone concentrations and time postpill or dosing interval.
Conclusions: Timing of blood sampling after oral methimazole administration does not appear to be a significant factor when assessing response to methimazole treatment.     

Transdermal absorption of a liposome-encapsulated formulation of lidocaine following topical administration in cats

OBJECTIVE: To determine plasma disposition after dermal application of a liposome-encapsulated formulation of lidocaine in cats. ANIMALS: 6 healthy adult cats with a mean (+/- SD) body weight of 4.1 +/- 0.44 kg. PROCEDURE: CBC determination and biochemical analysis of blood samples were performed for all cats. Cats were anesthetized by use of isoflurane, and catheters were placed IV in a central vein. The next day, blood samples were obtained from the catheters before and 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after applying a 4% liposome-encapsulated lidocaine cream (15 mg/kg) to a clipped area over the cephalic vein. Plasma concentrations of lidocaine were analyzed with a high-performance liquid chromatography assay. Results-Two cats had minimal transdermal absorption of lidocaine, with lidocaine concentrations below the sensitivity of the assay at all but 1 or 2 time points. In the other 4 cats, the median maximum plasma concentration was 149.5 ng/ml, the median time to maximum plasma concentration was 2 hours, and the median area under the concentration versus time curve from zero to infinity was 1014.5 ng.h/ml. CONCLUSIONS AND CLINICAL RELEVANCE: Maximum plasma concentrations of lidocaine remained substantially below toxic plasma concentrations for cats. On the basis of these data, topical administration of a liposome-encapsulated lidocaine formulation at a dose of 15 mg/kg appears to be safe for use in healthy adult cats.