Pharmacokinetic studies of theophylline in horses

Ingvast-Larsson, C, Paalzow, G., Paalzow, L., Ottosson, T., Lindholm, A. & Appelgren, L.E. Pharmacokinetic studies of theophylline in horses. J. vet. Pharmacol. Therap. 8, 76–81.
The pharmacokinetics of theophylline were determined in Standardised trotters after single intravenous and oral administration. A bi-exponential equation was fitted to the intravenous data and a tri-exponential equation to the oral data. The biological half-life of theophylline was found to be 14.8 h, the volume of distribution 1.02 l/kg and the total plasma clearance 0.86 ml/kg/min. The oral absorption of the drug was complete (bioavailability 108%) and rapid (absorption half-life 0.4 h).
Professor L. E. Appelgren, Department of Pharmacology and Toxicology, Biomedicum. Box 573, S-75J 23 X'ppsala, Sweden.     

Pharmacokinetic studies of cimetidine hydrochloride in adult horses

Histamine type II (H2) antagonists inhibit gastric acid secretion and are useful in treating gastric and duodenal ulcer disease. To provide some information on the pharmacokinetics of the H2 antagonist cimetidine, adult horses were given 3.3 mg/kg cimetidine intravenously (iv) or 3.3 and 10 mg/kg orally. Plasma cimetidine concentrations after 3.3 mg/kg orally were too low to measure. Following 3.3 mg/kg iv, cimetidine displayed two-compartment characteristics with a t1/2 of 0.083 +/- 0.039 h and t1/2 of 2.23 +/- 0.64 h. The total body clearance was 0.443 +/- 0.160 litre/h/kg and the mean residence time was 2.74 +/- 1.11 h. This clearance and t1/2 are similar to that in man. The volume of distribution (Vss) and volume of the central compartment (Vc) were 1.138 +/- 0.230 and 0.276 +/- 0.102 litre/kg, respectively. After a single oral dose of 10 mg/kg as crushed tablets, peak plasma concentration of 1.81 +/- 0.82 micrograms/ml occurred at approximately 1.4 h. Oral absorption of cimetidine appeared variable and slow with an extent of absorption of 0.296 +/- 0.183 and a mean residence time for absorption of 1.99 +/- 0.79 h. This was less than in man. Based on a desired average steady state plasma concentration of 1.0 microgram/ml, 11.0 mg/kg/day iv and 48 mg/kg/day orally can be recommended in adult horses.     

Pharmacokinetic study of oral amitriptyline in horses

The purpose of this study was to evaluate the pharmacokinetics of oral amitriptyline in horses. Oral amitriptyline (1 mg/kg) was administered to six horses. Blood samples were collected from jugular and lateral thoracic vein at predetermined times from 0 to 24 hr after administration. Plasma concentrations were determined by high-performance liquid chromatography and analyzed using noncompartmental methods. Pharmacodynamic parameters including heart rate, respiration rate, and intestinal motility were evaluated, and electrocardiographic examinations were performed in all subjects. The mean maximum plasma concentration (C_max) of amitriptyline was 30.7 ng/ml, time to maximum plasma concentration (T_max) 1–2 hr, elimination half-life (t_1/2) 17.2 hr, area under plasma concentration–time curve (AUC) 487.4 ng ml⁻¹ hr⁻¹, apparent clearance (Cl/F) 2.6 L hr⁻¹ kg⁻¹, and apparent volume of distribution (Vd/F) 60.1 L/kg. Jugular vein sampling overestimated the amount of amitriptyline absorbed and should not be used to study uptake following oral administration. Heart rate and intestinal motility showed significant variation (p < .05). Electrocardiography did not provide conclusive results. Further studies are required to discern if multiple dose treatment would take the drug to steady state as expected, consequently increasing plasma concentrations.     

中药复方禽病康在鸡体内的药代动力学研究

以血清一氧化氮（NO）变化为药理效应指标,用药理效应法研究了中药复方制剂禽病康在免疫抑制雏鸡体内的药代动力学特征,并探讨了其扶正固本、增强机体免疫功能的作用机制。结果表明,免疫抑制雏鸡单剂量口服禽病康的效应动力学参数为：最低起效剂量Xmin=2.61 g/kg,效应呈现半衰期t1/2ka（E）=0.61 h,效应达峰时间tp（E）=1.82 h,效应消除半衰期t1/2b（E）=3.25 h;以时间-体存量进行数学模型拟合,符合一级吸收二室模型,其数学表达式为C=24.221e-0.931t＋3.485e-0.012t＋27.705e-1.166t。禽病康药代动力学结果表明其口服后吸收较快,分布也快,而消除较慢,体内存留时间长,药效维持时间长。     

Pharmacokinetic disposition of intravenous and oral pentoxifylline in horses

The pharmacokinetics of pentoxifylline (P) and its alcohol metabolite I (MI) were determined after administration of intravenous pentoxifylline, sustained release pentoxifylline tablets (Trental®), and crushed pentoxifylline tablets in corn syrup, to five healthy adult horses. Pharmacokinetics were evaluated in a model-independent manner. After intravenous administration, pentoxifylline was rapidly eliminated (mean residence time 1.09 f 0.67 h), had a large steady-state volume of distribution (2.81 f 1.16 Vkg), and high clearance (3.06 51.05 I/kg/h). Oral absorption of pentoxifylline from both dose forms varied
considerably between individuals. Times to peak concentration ranged from 1–10 h for either dose form. There was no difference in relative bioavailability (Fâ'™)between whole (0.98 k 0.30) and crushed Trental® tablets. Ratios between areas under the curve (AUC) for pentoxifylline and MI were different following administration of oral versus intravenous doses. This finding suggests that route of administration may affect the metabolic profile of pentoxifylline. Given the extreme differences in absorption characteristics between indi-viduals in this study, recommendations are not made as to appropriate dose, dose interval, or dose form for administration of pentoxifylline to horses.     

Pharmacokinetic disposition of theophylline in horses after intravenous administration

The pharmacokinetics of theophylline were determined in 6 healthy horses after a single IV administration of 12 mg of aminophylline/kg of body weight (equivalent to 9.44 mg of theophylline/kg). Serum theophylline was measured after the IV dose at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 15 hours. Serum concentration plotted against time on semilogarithmic coordinates, indicated that theophylline in 5 horses was best described by a 2-compartment open model and in 1 horse by a 1-compartment open model. The following mean pharmacokinetic values were determined; elimination half-life = 11.9 hours, distribution half-life = 0.495 hours, apparent specific volume of distribution = 0.885 +/- 0.075 L/kg, apparent specific volume of central compartment = 0.080 L/kg, and clearance = 51.7 +/- 11.2 ml/kg/hr. Three horses with reversible chronic obstructive pulmonary disease were serially given 1, 3, 6, 9, 12, and 15 mg of aminophylline/kg in single IV doses (equivalent to 0.8, 2.4, 4.7, 7.1, 9.44, and 11.8 mg of theophylline/kg, respectively). The horses were exposed to a dusty barn until they developed clinical signs of respiratory distress and were then given the aminophylline. Effects of increasing doses on different days were correlated with clinical signs, blood pH, and blood gases. The 3 horses had a decrease in the severity of clinical signs after the 9, 12, or 15 mg doses of aminophylline/kg. The horses at 0.5 hour after dosing had a significant decrease in PaCO2 (43.6 +/- 5.5 to 39.4 +/- 6.7 mm of Hg, P less than 0.001) and a significant increase in blood pH (7.38 +/- 0.017 to 7.41 +/- 0.023, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic adjustment of gentamicin dosing in horses with sepsis

Serum gentamicin concentrations were measured and pharmacokinetic values were calculated for 12 equine patients receiving parenteral gentamicin therapy. Horses were selected for monitoring of gentamicin pharmacokinetics if they met several criteria of high risk for gentamicin-induced toxicosis. Two blood samples were obtained, one immediately before gentamicin dosing and one at 1 hour after dosing. Gentamicin serum concentrations were analyzed and dosage adjustments were made on the basis of calculated one-compartment pharmacokinetic values. Nine of the 12 horses required dosage adjustment to optimize therapeutic concentrations. Even for horses for which there was no evidence of decreased renal function, variation in the disposition of gentamicin was substantial. Because of the larger volume of distribution in foals, an initial dosage of 3 mg/kg every 12 hours was found to best approximate target concentrations. Therefore, published standard dosages were a poor means of achieving desired peak and trough concentrations in many animals. Seemingly, for optimal treatment of horses with sepsis, gentamicin dosage adjustments based on the patient's pharmacokinetic values is required.     

Pharmacokinetic interactions between flunixin and sulphadimidine in horses.

The pharmacokinetic aspects of sulphadimidine were studied in clinically healthy (control) and Flunixin-medicated horses after a single intravenous and oral administration of 100 mg/kg body weight. Plasma sulphadimidine concentration were determined by high-performance liquid chromatography (HPLC). Following the intravenous injection, all plasma sulphadimidine data were best approximated by a two-compartment open model using sequential, weight non-linear regression. Flunixin induced a 67% increase in the rate of sulphadimidine return to the central compartment from peripheral tissues (K21) and there were a trend to a 30% increase in K12. The sulphadimidine elimination half-life was decreased 21%, the Vdss was reduced by 18% and MRT was decreased by 20%. Following the oral administration, sulphadimidine was rapidly absorbed in control and Flunixin-medicated horses with absorption half-lives (t1/2 ab) of 0.5 and 0.43 hours respectively. The peak plasma concentration (Cmax) were 93.7 and 109 micrograms/ml attained at (tmax) 2.36 and 1.9 hours respectively. The elimination half-life after oral administration (t1/2 ab) was shorter in flunixin pre-medicated horses than in control ones. The systemic bioavalability percentages (F%) of sulphadimidine after oral administration of 100 mg/kg body weight was 79.3 and 71.2% in control and flunixin medicated horses, respectively. Therefore care should be exercised in the use of sulphadimidine in equine patients concurrently treated with flunixin.     

Pharmacokinetic profiles of the active metamizole metabolites in healthy horses

Metamizole (MT) is an analgesic and antipyretic drug labelled for use in humans, horses, cattle, swine and dogs. MT is rapidly hydrolysed to the active primary metabolite 4‐methylaminoantipyrine (MAA). MAA is formed in much larger amounts compared with other minor metabolites. Among the other secondary metabolites, 4‐aminoantipyrine (AA) is also relatively active. The aim of this research was to evaluate the pharmacokinetic profiles of MAA and AA after dose of 25 mg/kg MT by intravenous (i.v.) and intramuscular (i.m.) routes in healthy horses. Six horses were randomly allocated to two equally sized treatment groups according to a 2 × 2 crossover study design. Blood was collected at predetermined times within 24 h, and plasma was analysed by a validated HPLC‐UV method. No behavioural changes or alterations in health parameters were observed in the i.v. or i.m. groups of animals during or after (up to 7 days) drug administration. Plasma concentrations of MAA after i.v. and i.m. administrations of MT were detectable from 5 min to 10 h in all the horses. Plasma concentrations of AA were detectable in the same range of time, but in smaller amounts. Maximum concentration (C_max), time to maximum concentration (T_max) and AUMC_0‐last of MAA were statistically different between the i.v. and i.m. groups. The AUC_IM/AUC_IV ratio of MAA was 1.06. In contrast, AUC_0‐last of AA was statistically different between the groups (P < 0.05) with an AUC_IM/AUC_IV ratio of 0.54. This study suggested that the differences in the MAA and AA plasma concentrations found after i.m. and i.v. administrations of MT might have minor consequences on the pharmacodynamics of the drug.     

Pharmacokinetic disposition of dimethyl sulfoxide administered intravenously to horses

Dimethyl sulfoxide (DMSO) was administered IV to 6 Thoroughbred horses at 2 dosages: 1.0 g/kg and 0.1 g/kg. The pharmacokinetics seemed linear, with biological half-lives of 8.6 +/- 0.3 hours and 9.8 +/- 2.2 hours for the 1.0 g/kg and 0.1 g/kg dosages, respectively. This was further substantiated by mean residence times of 9.8 +/- 0.44 hours and 13.8 +/- 4.25 hours, areas under the curve of 12.55 +/- 1.42 mg/ml/hr and 1.63 +/- 0.49 mg/ml/hr, and the clearances of 0.081 +/- 0.009 L/kg/hr and 0.066 +/- 0.022 L/kg/hr for the large and small dosages, respectively. At 12 hours after 1.0 g/kg was administered, 26.6% of the DMSO dose was excreted unchanged into the urine; at 12 hours after 0.1 g/kg was administered, 25.3% of the DMSO dose was excreted unchanged into the urine. It was predicted that 29.4% and 40.6% of the total DMSO dose would be excreted into the urine for the 1.0 g/kg and 0.1 g/kg dosages, respectively. A 10% DMSO concentration in normal saline solution was safe to give as rapid IV infusion. Slow administration is recommended for more concentrated solutions. Based on the half-life, DMSO should be administered 2 times a day IV for the treatment of increased intracranial pressure and/or cerebral edema in horses.     

Clinical and therapeutic studies on mange in horses

At Kafr El-Sheikh province, Egypt, out of 117 examined drafting horses, mites were detected in 20 (17.09%) horses. The recovered mites were 14 Chorioptes, four Psoroptes and two Sarcoptes whereas mites were not detected in four cases clinically showed typical mange lesions. Interestingly, neither the age nor the sex of the examined horses had a clear influence on the prevalence of the infection. Clinical signs observed in mange infested horses were in the form of irregular skin lesions, severe itching and sometimes biting of affected skin areas and decrease feed consumption. The skin lesions mainly start as erythematous area followed by developing of papules and crust formation. Skin scratches as a result of traumatized lesions usually occurred. Hair was lost on the affected parts developing irregular alopecic areas. Distribution of the lesions was varied according to the type of mite. Chorioptic mite was detected in para-anal fold, distal portion of legs and tail lesions, Psoroptic mite was detected in withers, mane, shoulder and flank lesions whereas Sarcoptic mite was isolated mainly from lesions on the head and neck. Complete clinical and parasitological cure for mite infestation were obtained within 2 weeks in both moxidectin and ivermectin treated groups with 100% recovery rate. Our results indicated that moxidectin oral gel is effective and good alternative for the treatment of chorioptic mange in horse to avoid drug resistance that may develop as a result of the intensive use of ivermectin alone for long periods.     

Pharmacokinetic studies of theophylline in dogs

The pharmacokinetics of theophylline were investigated in dogs following intravenous, single oral, and multiple oral doses of aminophylline. Mean half-life ( t _1/2) of theophylline following single intravenous administration was 5.7 h and the apparent specific volume of distribution ( V'd area) was 0.82 litre/kg. The bioavailability of theophylline was high (91%) following oral administration of aminophylline tablets and the absorption half-life ( t _{1/2 ab}) was 0.4 h.
Theophylline plasma concentrations observed following repeated oral administration of aminophylline tablets were somewhat greater than predicted. This suggests that theophylline plasma concentrations should be monitored and the dosage regimen individually adjusted in critically ill animals.     

Pharmacokinetic studies of phenylbutazone in cattle

The disposition kinetics and systemic availability of phenylbutazone were studied in healthy dairy cows. The same dose (6mg/kg) of phenylbutazone was administered by the i.v., i.m. and oral routes. The elimination half time after intravenous administration ranged from 32.4 to 60.8h. The result suggested that the distribution of phenylbutazone in cows can be described by a two-compartment open model. Total body clearance of the drug had a mean value of 0.0016 ml/kg-h. The overall tissue to plasma level ratio (k₁₂/k₂₁-β), after distribution equilibrium had been attained was 0.64. Phenylbutazone was shown, by an equilibrium dialysis method, to be highly bound to plasma proteins (93%) at serum levels of 100 μ/ml. The systemic availability of phenylbutazone was 69% and 89% when administered orally and intramuscularly respectively. Animals receiving half the dose of phenylbutazone (3 mg/kg) intravenously did not differ from cows receiving 6 mg/kg in elimination half-life and other distribution and elimination kinetic parameters. Based on the experimental data obtained, a dosage regimen is proposed, consisting of a priming oral dose of 9 mg/kg and maintenance doses of 4.5 mg/kg of phenylbutazone orally administered at 48 h intervals. The relatively long half-life in cattle, however, complicates the use of phenylbutazone because of the drug residue problem.     

奥比沙星在兔体内的药物动力学研究

应用反相高效液相色谱法（RP—HPLC）研究奥比沙星在健康家兔体内的药物动力学规律。家兔以10mg/kg的单剂量肌肉注射奥比沙星,取给药后不同时间的血浆,用高效液相色谱仪测定血浆中奥比沙星的质量浓度,MCPKP药物动力学软件程序处理血浆药物浓度与时间数据。房室模型分析表明,免肌注给药的药时数据适合吸收二室开放模型：吸收和消除半衰期（T1／2Ka,T1/2β）分别为0．2669h和7．1546h;达峰时间（Tmax）为0．563h;峰浓度（Cmax）为4．8717μg／mL;药时曲线下面积（AUC）为18．4535mg／L·h。奥比沙星在家免体内的主要药动学特征为：吸收迅速,分布快,消除较缓慢,达峰时间短,峰浓度高,药时曲线下面积大。     

Pharmacokinetic studies of theophylline in cats

The pharmacokinetics of theophylline were determined in adult cats and the data were fitted to a two-compartment model. Single intravenous and multiple oral doses of aminophylline were used. The mean plasma theophylline half-life ( t _1/2) following the single intravenous dose was 7.8 h and the mean apparent specific volume of distribution ( V '_d(area)) was 0.46 l/kg. The absorption half-life ( t _{1/2 ab} ) was 0.5 h and the bioavailability was 96% following oral administration. There was excellent agreement between the predicted and observed plasma theophylline concentrations following multiple oral doses.