Pharmacokinetics of extended-release ivermectin microspheres after oral administration to healthy pigs

We compared the pharmacokinetics of ivermectin premix and ivermectin microspheres in pigs after single and multiple administration regimes. In the single-dose experiments, 24 piglets were randomly divided into three groups and given ivermectin at 0.3 mg/kg using (a) 1.0% ivermectin administered subcutaneously, (b) 0.25% ivermectin premix orally, and (c) 0.25% ivermectin microspheres orally. In the multiple-dose experiment, 6 pigs in two equal groups received ivermectin premix and microspheres orally at 0.3 mg/kg for 7 consecutive days to monitor the valley plasma levels. The plasma samples were detected by fluorescence high-performance liquid chromatography, and concentration–time data were fitted to a noncompartmental model. After oral administration of ivermectin microspheres at a single dose, the elimination rate constant (Kel), the half-life (t_1/2), the peak time (T_max), the mean residence time (MRT), and the peak concentration (C_max) were 0.012 ± 0.0031/hr, 59.94 ± 20.18 hr, 9.50 ± 0.93 hr, 55.96 ± 11.40 hr, and 37.75 ± 3.45 ng/ml, respectively. The C_max of microspheres was not statistically different (p > .05) compared with that of premix groups (39.81 ± 5.83 ng/ml). Moreover, the AUC of the microcapsule groups was increased from 1,129.76 ± 245.62 to 1,607.33 ± 343.35 hr ng/ml compared with the premix groups, and the relative bioavailability increased by an average of 17.53% after oral administration with ivermectin microspheres. Multiple-dose administration also indicated pigs fed with ivermectin microspheres can get a higher minimum steady-state concentration and a longer maintenance time than ivermectin premix.     

高效液相色谱法测定赛鸽用复方吡喹酮胶囊中吡喹酮和伊维菌素的含量

用高效液相色谱法同时测定赛鸽用复方吡喹酮胶囊中吡喹酮和伊维菌素的含量.采用Nova-Pak C18柱(150 mm×3.9 mm,4 μm),以乙腈-甲醇-水(53:35:12)为流动相,流速为1.0 mL/min,检测波长254 nm,柱温25℃.在此色谱条件下,吡喹酮和伊维菌素的分离良好,吡喹酮和伊维菌素分别在511～1 534μg/mL和10.1～30.6μg/mL浓度范围内峰面积与浓度呈良好的线性关系(r＞0.999).按外标法以峰面积计算进行测定,吡喹酮和伊维菌素的平均回收率分别为99.9%和98.3%,RSD分别为0.3%和0.6%(n=9).本方法简便、快速、准确,适用于赛鸽用复方吡喹酮胶囊中吡喹酮和伊维菌素含量的测定.     

RP-HPLC检测复方注射剂中伊维菌素和吡喹酮的含量

为了用高效液相色谱法同时测定复方注射剂中伊维菌素和吡喹酮的含量。采用Hyper-C lone 5u C18柱（250 mm×4.60 mm,5μm）,以乙腈-甲醇-水（53∶35∶12）为流动相,流速为1.0mL/m in,检测波长254 nm,柱温30℃的液相检测方法。结果表明,在此色谱条件下,吡喹酮和伊维菌素的分离良好,吡喹酮和伊维菌素分别在30~500μg/mL和5~40μg/mL浓度范围内峰面积与浓度呈良好的线性关系（r2〉0.99）。按外标法以峰面积计算进行测定,吡喹酮和伊维菌素的平均回收率分别为98.93%和95.89%,RSD分别为0.33%和1.58%（n=9）。说明该方法简便、快速、准确,适用于复方吡喹酮注射液中吡喹酮和伊维菌素含量的测定。     

Efficacy of daily oral ivermectin in the treatment of 10 cases of generalized demodicosis in adult dogs

Abstract The purpose of this study was to evaluate the efficacy of oral ivermectin at the dosage of 0.35 mg kg^-1 day^-1 for the treatment of generalized demodicosis in 10 adult dogs. Five of these 10 dogs had failed to respond to previous topical amitraz therapy. The mean time to obtain negative skin scrapings was 2.7 months and the mean duration of treatment was 4 months (range 2.5–8.5 months). Three patients (30%) were cured and they remained free of mites within 1 year follow-up. Two dogs (20%) were in remission for less than 6 months and five dogs (50%) relapsed. These five cases that relapsed were retreated with the above dosage of ivermectin and topical amitraz solution (1 mL Taktic/30 mL mineral oil) applied to site(s) of recurrence. One of these five cases that relapsed was in remission for more than 6 months, two dogs were in remission for less than 6 months and two dogs are still receiving treatment. Résumé— Le propos de cette étude est d'évaluer l'efficacieté de l'ivermectine par voie orale à un dosage de 0,35 mg/kg/jour dans le traitement de la démodécie généralisée chez 10 chiens adultes. Cinq de ces chiens n'avaient pas répondu à une thérapeutique topique préalable à l'amitraz. Le délai moyen pour obtenir la négativation des raclages cutanés est de 2,7 mois, et la durée moyenne de traitement est de 4 mois (extrême 2,5–8,5 mois). Trois patients (30%) ont été guéris et n'ont pas rechuté dans l'année qui a suivi le traitement. Deux des chiens (20%) ont été en rémission pendant moins de 6 mois et 5 chiens (50%) ont rechuté. Ces 5 chiens qui ont rechuté ont été retraités avec l'ivermectine à la même posologie associée à une thérapeutique topique à l'amitraz (1 ml de Taktic dans 30 ml d'huile minérale), appliquée aux sites de rechute. Un de ces 5 chiens fut en rémission pendant plus de 6 mois, 2 chiens pendant moins de 6 mois, enfin, les deux derniers reçoivent encore le traitement. [Fondati, A. Efficacy of daily oral ivermectin in the treatment of 10 cases of generalized demodicosis in adult dogs (Efficacité de l'ivermectine administrée oralement tous les jours dans le traitement de 10 cas de démodécie généralisée du chien adulte). Veterinary Dermatology 1996; 7 : 99–104.] Resumen El objetivo de este estudio fue evaluar la eficacia de la ivermectina oral con una dosis de 0.35 mg/Kg-dia para el tratamiento de la demodicosis generalizada en 10 perros adultos. Cinco de los 10 perros no habian respondido previamente a la terapia tópica con amitraz. El tiempo medio de obtención de raspados cutáneos negativos fue de 2.7 meses y la duratión media del tratamiento, de 4 meses (de 2.5 a 8.5 meses). Tres pacientes (30%) se curaron y permanecieron sin ácaros en un año de seguimiento. Dos perros (20%) estuvieron en remisión durante menos de 6 meses y en cinco (50%) se produjeron recaidas. Los animales que recayeron fueron tratados con la dosis de Ivermectina especificada arriba y solutión tópica de amitraz (1 mL Taktic/30 mL aceite mineral) aplicado a la(s) zona(s) de recidiva. Uno de los casos que recayó había estado en remisión durante 6 meses, dos perros estuvieron en remisión durante menos de 6 meses y dos estan aún bajo tratamiento. [Fondati, A. Efficacy of daily oral ivermectin in the treatment of 10 cases of generalized demodicosis in adult dogs (Eficacia de la Ivermectina oral en dosis diarias en el tratamiento de 10 casos de demodicosis generalizada en perros adultos). Veterinary Dermatology 1996; 7 : 99–104.] Zusammenfassung— Zweck dieser Studie war, die Wirksamkeit von oralem Ivermectin mit einer Dosierung von 0,35 mg/kg und Tag bei der Behandlung von generalisierter Demodikose bei 10 erwachsenen Hunden auszuwerten. 5 dieser 10 Hunden hatten auf eine vorausgegangene topische Amitraz-Therapie nicht angesprochen. Die Durchschnittszeit, um negative Hautgeschabsel zu erhalten, lag bei 2,7 Monaten, die Durchschnittsdauer der Behandlung bei 4 Monaten (mit einer Spannweite von 2,5 bis 8,5 Monaten). 3 Patienten (30%) wurden geheilt und blieben innerhalb des überwachungszeitraumes von 1 Jahr milbenfrei. Zwei Hunde (20%) waren in Remission für weniger als 6 Monate und 5 Hunde (50%) hatten ein Rezidiv. Diese fünf Rezidivfälle wurden mit der oben genannten Dosis Ivermectin und topischer Amitraz-Lösung (1 ml Taktic/30 ml Mineralöl) an den Stellen erneuter Veränderungen behandelt. Einer dieser fünf Rezidivfälle war in Remission für mehr als 6 Monate, zwei Hunde waren in Remission für weniger als 6 Monate und zwei Hunde sind immer noch unter Therapie. [Fondati, A. Efficacy of daily oral ivermectin in the treatment of 10 cases of generalized demodicosis in adult dogs (Wirksamkeit einer täglichen oralen Ivermectingabe bei der Behandlung von 10 Fällen von generalisierter Demodikose bei erwachsenen Hunden). Veterinary Dermatology 1996; 7 : 99–104.]     

Biovailability of ivermectin administered orally to dogs

The bioavailability of three formulations of ivermectin was determined following oral administration to dogs. The average peak plasma level (C _max) of ivermectin administered in the standard tablet formulation at 6 and 100 µg/kg of body weight was 2.97 and 44.31 ng/g, respectively. This suggest dose-dependent pharmacokinetics.C _max and total ivermectin bioavailability, as assessed from the area under the plasma curve (AUC), were similar between two tablet formulations of ivermectin administered at 100 µg/kg. Furthermore,C _max was similar following administration of radiolabelled ivermectin at 6 µg/kg in either a beef-based chewable formulation or in the standard tablet formulation.     

Pharmacokinetics of single-dose oral pregabalin administration in normal dogs

ObjectiveTo describe the pharmacokinetics of pregabalin in normal dogs after a single oral dose.Study designProspective experiment.AnimalsSix adult Labrador/Greyhound dogs (four females and two males) aged 2.6 (2.6–5.6) years old (median and range) weighing 33.4 (26.8–42.1) kg.MethodsAfter jugular vein catheterization, the dogs received a single oral dose of pregabalin (～4 mg kg^?1). Blood samples were collected at: 0 (before drug administration), 15 and 30 minutes and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 hours after drug administration. Plasma pregabalin concentration was measured by HPLC. Noncompartmental analysis was used to estimate pharmacokinetic variables.ResultsNo adverse effects were observed. The median (range) pharmacokinetic parameters were: Area under the curve from time 0 to 36 hours = 81.8 (56.5–92.1) μg hour mL^?1; absorption half-life = 0.38 (0.25–1.11) hours; elimination half-life = 6.90 (6.21–7.40) hours; time over 2.8 μg mL^?1 (the presumed minimal effective concentration) = 11.11 (6.97–14.47) hours; maximal plasma concentration (C_max) = 7.15 (4.6–7.9) μg mL^?1; time for C_max to occur = 1.5 (1.0–4.0) hours. Assuming an 8-hour dosing interval, predicted minimal, average, and maximal steady state plasma concentrations were 6.5 (4.8–8.1), 8.8 (7.3–10.9), and 13.0 (8.8–15.2) μg mL^?1. The corresponding values assuming a 12-hour interval were 3.8 (2.4–4.8), 6.8 (4.9–7.9), and 10.1 (6.6–11.6) μg mL^?1.Conclusions and clinical relevancePregabalin 4 mg kg^?1 PO produces plasma concentrations within the extrapolated therapeutic range from humans for sufficient time to suggest that a twice daily dosing regime would be adequate. Further study of the drug's safety and efficacy for the treatment of neuropathic pain and seizures in dogs is warranted.     

The distribution and some pharmacokinetic parameters of ivermectin in pigs

Ivermectin was injected subcutaneously into five pigs at the usual dose rate of 300 µg/kg and found to distribute well to all tissues and body fluids which were sampled 24 h post-injection. Ivermectin was detected in the contents and mucus at all levels of the gastrointestinal tract. The drug was excreted in bile, with high concentrations of the drug in the intestines and faeces. High concentrations of ivermectin were measured in skin, ears and ear wax, suggesting that the drug should be effective in the treatment of ectoparasitic infestations, particularly ear mites. The high lipid solubility of the drug may explain the high concentrations found in ear wax and skin. Ivermectin was also detected in the body fluids and tissues of an untreated pig penned with the treated animals. Direct contact appeared to be necessary for transfer of ivermectin from the treated to the untreated pig but coprophagia or urine drinking is a possible explanation.The pharmacokinetics of ivermectin administered subcutaneously at a dose rate of 300 µg/kg to six pigs were studied. There was marked individual variation in the pharmacokinetics of ivermectin. In one pig the area under the plasma concentration-time curve was particularly high. This may reflect individual variation in uptake and excretion of the drug. The mean elimination half-life of the drug was 35.2 h, suggesting that the drug is cleared slowly from pigs with drug detectable in plasma for 6–10 days. This persistence should allow a short period of protection before re-infection with parasites.     

Clinical pharmacology of clemastine in healthy dogs

The pharmacokinetic properties of clemastine were investigated in six healthy dogs and compared with the effect of the drug recorded as inhibition of wheal formation induced by intradermal injections of histamine. Clemastine clearance was high (median: 2.1 L h(-1) kg(-1)) and the volume of distribution large (13.4 L kg(-1)). The half-life after intravenous administration was 3.8 h and the plasma protein binding level in vitro was 98%. After oral administration, the bioavailability was only 3%. Given intravenously, clemastine (0.1 mg kg(-1)) inhibited wheal formation completely for 7 h, whereas the effect after oral administration (0.5 mg kg(-1)) was minor. The data show that most dosage regimens suggested in the literature for the oral administration of clemastine to dogs are likely to give too low a systemic exposure of the drug to allow effective therapy.     

Pharmacokinetics of levofloxacin after single intravenous,oral and subcutaneous administration to dogs

The pharmacokinetic properties of the fluoroquinolone levofloxacin (LFX) were investigated in six dogs after single intravenous, oral and subcutaneous administration at a dose of 2.5, 5 and 5 mg/kg, respectively. After intravenous administration, distribution was rapid (T_½dist 0.127 ± 0.055 hr) and wide as reflected by the volume of distribution of 1.20 ± 0.13 L/kg. Drug elimination was relatively slow with a total body clearance of 0.11 ± 0.03 L kg^?1 hr^?1 and a T_½ for this process of 7.85 ± 2.30 hr. After oral and subcutaneous administration, absorption half‐life and T_max were 0.35 and 0.80 hr and 1.82 and 2.82 hr, respectively. The bioavailability was significantly higher (p ? 0.05) after subcutaneous than oral administration (79.90 vs. 60.94%). No statistically significant differences were observed between other pharmacokinetic parameters. Considering the AUC_24 hr/MIC and C_max/MIC ratios obtained, it can be concluded that LFX administered intravenously (2.5 mg/kg), subcutaneously (5 mg/kg) or orally (5 mg/kg) is efficacious against Gram‐negative bacteria with MIC values of 0.1 μg/ml. For Gram‐positive bacteria with MIC values of 0.5 μg/kg, only SC and PO administration at a dosage of 5 mg/kg showed to be efficacious. MIC‐based PK/PD analysis by Monte Carlo simulation indicates that the proposed dose regimens of LFX, 5 and 7.5 mg/kg/24 hr by SC route and 10 mg/kg/24 hr by oral route, in dogs may be adequate to recommend as an empirical therapy against S. aureus strains with MIC ≤ 0.5 μg/ml and E. coli strains with MIC values ≤0.125 μg/ml.     

Daily ivermectin for treatment of generalized demodicosis in dogs

Abstract Twelve dogs with generalized demodicosis were treated with oral administration of ivermectin, 0.4 mg kg^-1 of body weight given once every 24 h. Results of skin scrapings were used to determine whether administration of ivermectin should be continued or stopped. Dogs that were free of clinical signs of demodicosis 12 months after administration of ivermectin was discontinued were considered cured. Five dogs were cured. The medían duration of treatment was 15 weeks (range 5–21 weeks). Seven dogs were failures, with five relapsing 3–11. 5 months after treatment was stopped, and two having persistent demodicosis in spite of treatment. Mild ivermectin toxicosis developed in one dog after 5 weeks of treatment; side-effects resolved shortly after the treatment was stopped. Resumen Se trataron doce perros con demodicosis generalizada con ivermectina oral, 0.4 mg/Kg de peso corporal una vez cada 24 h. Se realizaron raspados cutáneos para déterminar si debia retirarse o continuar con la administración de ivermectina. Se consideraron curados aquellos perros sin sintomatologia de demodicosis 12 meses después de retirar la terapia con ivermectina. La duración medía del tratamiento con ivermectina fue de 15 semanas (rango de 5–21). Se fracasó en siete perros, con cinco recidivas a los 3–11, 5 meses después de parar la terapia y dos con demodicosis persistente a pesar del tratamiento. Un perro desarrolló una toxicosis leve a la ivermectina a las 5 semanas del tratamiento; los efectos secundarios desaparecieron al poco de retirar el tratamiento. [Medleau, L., Ristic, Z., McElveen, D.R. Daily ivermectin for treatment of generalized demodicosis in dogs (Administración díaria de ivermectina para el tratamiento de le demodicosis generalizada en el perro). Veterinary Dermatology 1996; 7 : 209–212.] Résumé Douze chiens présentant une démodécie généralisée fürent traités par administration orale d'ivermectine à la dose de 0.4 mg/kg de poids une fois par jour. Les résultats des raclages cutanés servirent à déterminar la nécessité de continuer ou d'arrêter l'administration d'ivermectine. Les chiens ne présentant aucun symptôme de démodécie 12 mois après l'arrêt de l'ivermectine fürent considérés guéris. Cinq chiens fürent guéris. La durée moyenne du traitement fut de 15 semaines (intervalles de 5 à 21 semaines. Sept cas fürent des échecs, avec 5 chiens récidivant 3 à 11, 5 mois après l'arrêt du traitement, et 2 présentant une démodécie persistante malgré le traitement. Un chien a développé une intoxication modéree après 5 semaines de traitement; les effets secondaires disparaissant rapidement après l'arrêt du traitement. [Medleau, L., Ristic, Z., McElveen, D.R. Daily ivermectin for treatment of generalized demodicosis in dogs (Administration quotidienne d'ivermectine dans le traitement de la démodécie généralisée chez le chien). Veterinary Dermatology 1996; 7 : 209–212.] Zusammenfassung Zwölf Hunde mit generalisierter Demodikose wurden mit einer oralen Verabreichung von Ivermectin in der Dosierung von 0, 4 mg/kg Körpergewicht einmal alle 24 Stunden behandelt. Die Ergebnisse der Hautgeschabsel dienten zur Bestimmung, ob die Verabreichung weiterhin erfolgen sollte oder abzubrechen sei. Hunde, die 12 Monate nach Ende der Ivermectin-Verabreichung frei von klinischen Symptomen der Demodikose waren, wurden als geheilt betrachtet. Fünf Hunde waren geheilt. Die mittlere Therapiedauer betrug 15 Wochen (Spannweite 5 bis 21 Wochen). Bei sieben Hunden versagte die Therapie, wobei fünf nach 3 bis 11, 5 Monaten nach Behandlungsende ein Rezidiv bekamen und zwei Tiere trotz der Therapie einer persistierende Demodikose zeigten. Bel einem Hund entwickelte sich 5 Wochen nach der Behandlung eine milde Ivermectin-Intoxikation; die Nebenwirkungen verschwanden kurz nach Abbruch der Therapie. [Medleau, L., Ristic, Z., McElveen, D.R. Daily ivermectin for treatment of generalized demodicosis in dogs (Tägliche Ivermectinverabreichung als Behandlung für Hunde mit generalisierter Demodikose). Veterinary Dermatology 1996; 7 : 209–212.]     

Pharmacokinetics of carvedilol after intravenous and oral administration in conscious healthy dogs

OBJECTIVE: To determine the pharmacokinetics of carvedilol administered IV and orally and determine the dose of carvedilol required to maintain plasma concentrations associated with anticipated therapeutic efficacy when administered orally to dogs. ANIMALS: 8 healthy dogs. PROCEDURES: Blood samples were collected for 24 hours after single doses of carvedilol were administered IV (175 microg/kg) or PO (1.5 mg/kg) by use of a crossover nonrandomized design. Carvedilol concentrations were detected in plasma by use of high-performance liquid chromatography. Plasma drug concentration versus time curves were subjected to noncompartmental pharmacokinetic analysis. RESULTS: The median peak concentration (extrapolated) of carvedilol after IV administration was 476 ng/mL (range, 203 to 1,920 ng/mL), elimination half-life (t(1/2)) was 282 minutes (range, 19 to 1,021 minutes), and mean residence time (MRT) was 360 minutes (range, 19 to 819 minutes). Volume of distribution at steady state was 2.0 L/kg (range, 0.7 to 4.3 L/kg). After oral administration of carvedilol, the median peak concentration was 24 microg/mL (range, 9 to 173 microg/mL), time to maximum concentration was 90 minutes (range, 60 to 180 minutes), t(1/2) was 82 minutes (range, 64 to 138 minutes), and MRT was 182 minutes (range, 112 to 254 minutes). Median bioavailability after oral administration of carvedilol was 2.1% (range, 0.4% to 54%). CONCLUSIONS AND CLINICAL RELEVANCE: Although results suggested a 3-hour dosing interval on the basis of MRT, pharmacodynamic studies investigating the duration of beta-adrenoreceptor blockade provide a more accurate basis for determining the dosing interval of carvedilol.     

Pharmacokinetics of acetaminophen after intravenous and oral administration in fasted and fed Labrador Retriever dogs

Acetaminophen (paracetamol) is used in dogs to manage fever and mild pain. The aim of this study was to assess the pharmacokinetics of acetaminophen in both fed and fasted Labrador Retrievers after a single intravenous and oral administration (20 mg/kg). Six healthy dogs underwent three treatments in a randomized block study (a, n = 2; b, n = 2; c, n = 2). In phase one, group a received acetaminophen intravenously, group b and c orally after being fasted and fed, respectively. In phase two and three, groups were swapped, and the experiment was repeated. At the end of the trial, each dog received the same treatment. Acetaminophen plasma concentrations were detected using a validated HPLC‐UV method. The pharmacokinetic analysis was performed using a noncompartmental model. Clearance, volume at steady state and half‐life of acetaminophen in Labrador Retrievers were 0.42 L/kg hr, 0.87 L/kg and 1.35 hr, respectively. No significant statistical differences were found between fasted and fed dogs regarding maximum plasma concentration, time at maximum concentration and bioavailability as measured by the AUC. Feeding does not significantly affect the acetaminophen oral pharmacokinetics.     

Binding characteristics of ivermectin in plasma from collie dogs

Two types of experiments were performed in an effort to demonstrate a role for plasma proteins in determining the amount of ivermectin available for transport across the blood-brain barrier of collie dogs sensitive to the effects of the compound. The solubility of ivermectin in plasma from non-sensitive and sensitive collies was measured and found to be identical at 100 g/ml. An assay for measuring the low affinity binding interaction of ivermectin with plasma components was developed. The amount of ivermectin bound per unit of plasma was the same for samples from sensitive and non-sensitive dogs. Dog serum albumin and the high density lipoprotein portion of the plasma were both capable of binding ivermectin. No differences in the binding characteristics of ivermectin in plasma from ivermectin sensitive and non-sensitive collies were found.     

Pharmacokinetic profiles of the active metamizole metabolites after four different routes of administration in healthy dogs

Metamizole (MT), an analgesic and antipyretic drug, is rapidly hydrolyzed to the active primary metabolite 4‐methylaminoantipyrine (MAA) and relatively active secondary metabolite 4‐aminoantipyrine (AA). The aim of this study was to assess the pharmacokinetic profiles of MAA and AA after dose of 25 mg/kg MT by intravenous (i.v.), intramuscular (i.m.), oral (p.o.), and rectal (RC) routes in dogs. Six dogs were randomly allocated to an open, single‐dose, four‐treatment, four‐phase, unpaired, crossover study design. Blood was collected at predetermined times within 24 hr, and plasma was analyzed by a validated HPLC‐UV method. Plasma concentrations of MAA and AA after i.v., i.m., p.o., and RC administrations of MT were detectable from 5 (i.v. and i.m.) or 30 (p.o. and RC) min to 24 hr in all dogs. The highest concentrations of MAA were found in the i.v., then i.m., p.o., and RC groups. Plasma concentrations of AA were similar for i.v., i.m., and RC, and the concentrations were approximately double those in the PO groups. The AUC_EV/IV ratio for MAA was 0.75 ± 0.11, 0.59 ± 0.08, and 0.32 ± 0.05, for i.m., p.o., and RC, respectively. The AUC_EV/IV ratio for AA was 1.21 ± 0.33, 2.17 ± 0.62, and 1.08 ± 0.19, for i.m., p.o., and RC, respectively. Although further studies are needed, rectal administration seems to be the least suitable route of administration for MT in the dog.     

Investigation of pharmacokinetic parameters of tiamulin after intramuscular and subcutaneous administration in normal dogs

Laber, G. Investigation of pharmacokinetic parameters of tiamulin after intramuscular and subcutaneous administration in normal dogs. J. vet. Pharmacol. Therap. 11 , 45–49.
Kinetic variables for tiamulin in the normal dog have been determined. Serum concentrations of tiamulin were compared after intramuscular (i.m.) and subcutaneous (s.c.) administration of a single dose of tiamulin. Following a single i.m. dose of 10 mg/kg body weight, the compound was calculated to have a C_max= 0.61 ± 0.15 μg/ml, a T _max= 6 h and a t _½= 4.7 ± 1.4 h. Tiamulin showed dose-dependent pharmacokinetics when given as a single s.c. dose of either 10 mg or 25 mg/kg body weight. For the lower dose, the values C_max= 1.55 ± 0.11 μg/ml, T _max= 8 h and 1 _max= 4.28 ± 0.18 h were obtained. For the higher dose C _max= 3.14 ± 0.04 μg/ml, T _max= 8 h and t _½= 12.4 ± 3.4 h were calculated. When tiamulin was administered subcutaneously at a dose rate of 10 mg/kg body weight, higher and better maintained serum levels were achieved than those following i.m. administration. After repeated s.c. doses no significant accumulation of tiamulin occurred. Assuming that a continuous effective serum concentration is necessary throughout the course of therapy, these data would indicate that tiamulin should be given every 24 h.     

Pharmacokinetics of doramectin and ivermectin after oral administration in horses

A study was undertaken in order to compare plasma disposition kinetic parameters of doramectin (DRM) and ivermectin (IVM) in horses after oral administration. Ten crossbreed adult horses, clinically healthy, weighing 380-470 kg body weight (bw) were selected for study. Faecal examinations were performed to determine faecal parasite egg counts. Horses were allocated to two groups of five animals to provide an even distribution considering the variables sex, body weight and faecal egg count. Group I, were treated with an oral paste formulation of IVM at 0.2 mg/kg b/w and Group II, were treated with an oral dose of 0.2 mg/kg bw of DRM prepared as paste from the injectable formulation for oral administration. Blood samples were collected by jugular puncture between 0 h and 75 days post-treatment. Plasma was separated and later solid phase extraction and derivatization samples were analysed by high performance liquid chromatography (HPLC); a computerised kinetic analysis was carried out. Data were compared using the Mann-Whitney U-test.The mean plasma concentrations of DRM and IVM after oral administration in horses were detected until 30 and 20 days, respectively. Both drugs showed similar patterns of absorption and no significant differences were found for peak concentration, the time to peak concentration, or for absorptive half-life. The terminal elimination half-life was significantly (P<0.05) longer in the DRM treated group than for the IVM treated group. The differences observed in the elimination half-life explain the longer mean residence time and high values of area under the concentration time curve for the group treated with DRM, which are 30% higher than those of the IVM group. Considering its pharmacokinetics, tolerance and anthelmintic efficacy, the oral administration of DRM, could be an alternative to IVM for the control of parasitic diseases of horses.     

Plasma profile and pharmacokinetics of dextromethorphan after intravenous and oral administration in healthy dogs

Dextromethorphan is an N-methyl-D-aspartate (NMDA) noncompetitive antagonist which has been used as an antitussive, analgesic adjunct, probe drug, experimentally to attenuate acute opiate and ethanol withdrawal, and as an anticonvulsant. A metabolite of dextromethorphan, dextrorphan, has been shown to behave pharmacodynamically in a similar manner to dextromethorphan. The pharmacokinetics of dextromethorphan were examined in six healthy dogs following intravenous (2.2 mg/kg) and oral (5 mg/kg) administration in a randomized crossover design. Dextromethorphan behaved in a similar manner to other NMDA antagonists upon injection causing muscle rigidity, ataxia to recumbency, sedation, urination, and ptyalism which resolved within 90 min. One dog repeatedly vomited upon oral administration and was excluded from oral analysis. Mean +/- SD values for half-life, apparent volume of distribution, and clearance after i.v. administration were 2.0 +/-0.6 h, 5.1 +/- 2.6 L/kg, and 33.8 +/- 16.5 mL/min/kg. Oral bioavailability was 11% as calculated from naive pooled data. Free dextrorphan was not detected in any plasma sample, however enzymatic treatment of plasma with glucuronidase released both dextromethorphan and dextrorphan indicating that conjugation is a metabolic route. The short half-life, rapid clearance, and poor bioavailability of dextromethorphan limit its potential use as a chronic orally administered therapeutic.     

Pharmacokinetic analysis of mosapride following intravenous and oral administration in beagle dogs

The aim of this study was to investigate the pharmacokinetic properties of mosapride after intravenous and oral administration to beagle dogs. To obtain the advanced pharmacokinetic parameters of mosapride, both noncompartmental analysis and pharmacokinetic modeling were performed. Twenty beagle dogs were randomly sorted into intravenous (1 mg single administration of mosapride) and oral (5 mg once a day administration of mosapride) groups. Blood samples were collected according to the reported schedule for pharmacokinetics. The plasma concentration of mosapride was analyzed using liquid chromatography–tandem mass spectrometry. According to the pharmacokinetic analysis, the absorption rate of mosapride was 3.14 ± 1.14 hr⁻¹ and oral bioavailability of mosapride was approximately 1%. The one-compartment model well described the pharmacokinetics of mosapride after both intravenous and oral administration to dogs. These findings will help facilitate the determination of the optimal dose regimen of mosapride for dogs with gastrointestinal disorder.     

The effects of concurrent administration of cytochrome P-450 inhibitors on the pharmacokinetics of oral methadone in healthy dogs

ObjectiveThe objective was to examine the effects of inhibiting cytochrome P450 (CYP) on the pharmacokinetics of oral methadone in dogs.Study designProspective non-randomized experimental trial.AnimalsSix healthy Greyhounds (three male and three female).MethodsThe study was divided into two phases. Oral methadone (mean = 2.1 mg kg^?1 PO) was administered as whole tablets in Phase 1. In Phase 2 oral methadone (2.1 mg kg^?1 PO) was administered concurrently with ketoconazole (13.0 mg kg^?1 PO q 24 hours), chloramphenicol (48.7 mg kg^?1 PO q 12 hours), fluoxetine (1.3 mg kg^?1 PO q 24 hours), and trimethoprim (6.5 mg kg^?1 PO q 24 hours). Blood was obtained for analysis of methadone plasma concentrations by liquid chromatography with mass spectrometry. The maximum plasma concentration (C_max), time to C_max (T_max), and the area under the curve from time 0 to the last measurable time point above the limit of quantification of the analytical assay (AUC_0–LAST) were compared statistically.ResultsThe C_max of methadone was significantly different (p = 0.016) for Phase 1 (5.5 ng mL^?1) and Phase 2 (171.9 ng mL^?1). The AUC_0–LAST was also significantly different (p = 0.004) for Phase 1 (13.1 hour ng mL^?1) and Phase 2 (3075.2 hour ng mL^?1).Conclusion and clinical relevanceConcurrent administration of CYP inhibitors with methadone significantly increased the area under the curve and plasma concentrations of methadone after oral administration to dogs. Further studies are needed assessing more clinically relevant combinations of methadone and CYP inhibitors.