Enhancement of moxidectin bioavailability in lamb by a natural flavonoid: quercetin

Moxidectin is an antiparasitic drug widely used in cattle, sheep and companion animals. Due to the involvement of P-glycoprotein (P-gp) and cytochrome P450 3A in the metabolism of moxidectin, we studied the influence of various P-gp interfering agents (ivermectin, quercetin and ketoconazole) on the metabolism of 14C moxidectin in cultured rat hepatocytes over 72 h. This in vitro study allowed selection of compounds which are able to increase the moxidectin bioavailability in lambs. From this, the modulation of moxidectin pharmacokinetics in plasma of lambs was studied after co-administration of 0.2 mg kg(-1) moxidectin (subcutaneously (SC)) and 0.2 mg kg(-1) ivermectin (SC), or 10 mg kg(-1) quercetin (SC), or 10 mg kg(-1) ketoconazole (orally). Ivermectin and quercetin increased significantly the quantity of 14C moxidectin in the rat hepatocytes. Ketoconazole co-administration led to a higher concentration of moxidectin in the rat hepatocytes. In vivo, only quercetin was able to modify the pharmacokinetics of moxidectin in plasma of lambs by increasing significantly the area under the plasma concentration-time curve. This study allowed the use of a natural agent, quercetin, to improve the bioavailability of moxidectin.     

莫西菌素在畜牧业中的应用研究进展

莫西菌素（moxidectin,MOX）是由链霉菌发酵产生的奈马菌素经衍生化得到,具有良好的驱虫活性且对哺乳动物安全,主要应用于畜牧业。莫西菌素相较于其他阿维菌素类药物具有更好的脂溶性和水溶性,在动物体内脂肪组织中分布最高。莫西菌素通过与γ-氨基丁酸（GABA）结合,使Cl^-大量内流造成神经膜电位超极化,导致虫体麻痹死亡。给药途径和动物生理状况的不同会影响其峰血浆浓度和药物半衰期。莫西菌素在牛、羊、犬等动物体内具有很好的驱虫活性,其应用范围从哺乳动物逐渐扩展到鸟类,防治对象从线虫逐渐扩展到螨虫和部分病原菌,研究方向也从驱虫活性延伸至治疗人类疾病。随着莫西菌素应用范围的扩大和时间的延长,耐药性开始出现,可以采用莫西菌素和其他药剂混合等方式降低耐药性的产生速度。探究其更广泛的作用,需要不同研究领域研究人员的共同努力。     

The effects of inhibiting cytochrome P450 3A, p-glycoprotein, and gastric acid secretion on the oral bioavailability of methadone in dogs

Methadone is an opioid, which has a high oral bioavailability (>70%) and a long elimination half-life (>20 h) in human beings. The purpose of this study was to evaluate the effects of ketoconazole [a CYP3A and p-glycoprotein (p-gp) inhibitor] and omeprazole (an H+,K(+)-ATPase proton-pump inhibitor) on oral methadone bioavailability in dogs. Six healthy dogs were used in a crossover design. Methadone was administered i.v. (1 mg/kg), orally (2 mg/kg), again orally following oral ketoconazole (10 mg/kg q12 h for two doses), and following omeprazole (1 mg/kg p.o. q12 h for five doses). Plasma concentrations of methadone were analyzed by high-pressure liquid chromatography or fluorescence polarization immunoassay. The mean +/- SD for the elimination half-life, volume of distribution, and clearance were 1.75 +/- 0.25 h, 3.46 +/- 1.09 L/kg, and 25.14 +/- 9.79 mL/min.kg, respectively following i.v. administration. Methadone was not detected in any sample following oral administration alone or following oral administration with omeprazole. Following administration with ketoconazole, detectable concentrations of methadone were present in one dog with a 29% bioavailability. MDR-1 genotyping, encoding p-gp, was normal in all dogs. In contrast to its pharmacokinetics humans, methadone has a short elimination half-life, rapid clearance, and low oral bioavailability in dogs and the extent of absorption is not affected by inhibition of CYP3A, p-gp, and gastric acid secretion.     

Pharmacokinetics of phenoxymethyl penicillin (penicillin V) in calves

Phenoxymethyl penicillin (penicillin V) was administered intravenously (i.v.) and orally to pre-ruminant calves and the distribution and elimination kinetics, as well as the oral bioavailability, were determined. After i.v. injection, the drug was distributed rapidly in the body, the elimination half-life (t1/2 beta) was 34 min and the apparent volume of distribution at steady-state (Vd ss) was 0.30 l/kg. Mean peak serum drug concentrations were directly related to the oral dose administered, i.e. 0.22 microgram/ml, 1.06 micrograms/ml and 2.14 micrograms/ml after dosing at 10, 20 and 40 mg/kg, respectively. The elimination t1/2 of the drug after oral dosing varied between 90 and 110 min, and the oral bioavailability was approximately 30% of the dose. The co-administration of phenoxymethyl penicillin and probenecid resulted in elevation and prolongation of serum drug concentration. The percentage of drug bound to serum proteins was 78.8% +/- 8.2%. Phenoxymethyl penicillin was probably inactivated and degraded in the gastrointestinal tract of 6-week-old calves fed exclusively hay, silage and concentrates as very low and erratic serum drug concentrations were measured after these calves were dosed orally with the drug at 40 mg/kg. In view of the narrow antibacterial spectrum of the drug and the relatively high dose required, it appears that phenoxymethyl penicillin can only be of limited practical value for the treatment of bacterial infections in preruminant calves.     

Clinical presentation and management of moxidectin toxicity in two dogs

Moxidectin is a macrocyclic lactone related to ivermectin used in horses and dogs for endoparasite treatment and prophylaxis. The clinical and neurological presentation of moxidectin toxicity in two dogs following inadvertent poisoning with a moxidectin-containing equine de-worming medication is reported here. In both the dogs, the predominant clinical signs were generalised tremors and ataxia. Moxidectin exerts its neurotoxic effects in mammals by potentiating the effect of gamma-aminobutyric acid and, consistent with this, both the dogs demonstrated a poor response to treatment with diazepam. It would be more appropriate to avoid gamma-aminobutyric acid agonists, such as benzodiazepines and barbiturates, in dogs with moxidectin toxicity and consider using anaesthetic agents with a different mode of action, such as propofol. The prognosis in dogs accidentally exposed to moxidectin-containing equine de-worming medication appears to be excellent if the cause of the neurotoxicity is correctly identified and the case is appropriately managed.     

Analytical determination and pharmacokinetics of robenacoxib in the dog

An analytical method was developed and validated for the measurement of the novel analgesic and anti-inflammatory drug robenacoxib in blood and plasma of dogs and cats. To prevent nonreproducible carry-over effects, an initial solid phase extraction procedure was followed by high pressure liquid chromatography analysis for samples with concentrations in the range 500 to 20 000 ng/mL. To improve accuracy, samples of concentration 3 to 100 ng/mL were analyzed by liquid chromatography-mass spectrometry. Applying these methods, blood concentration-time profiles and pharmacokinetic variables of robenacoxib in dogs were determined in a four-phase cross-over study, which compared different routes of administration of the drug, including intravenous (i.v.) injection, oral application with and without feed, and subcutaneous (s.c.) application. After i.v. administration the mean clearance from blood was 0.81 L/kg/h, the volume of distribution was 0.77 L/kg for the elimination phase and 0.24 L/kg for steady-state, and the terminal half-life in blood was 0.63 h. Maximum blood concentrations were obtained in less than 1 h following oral or s.c. application. Absolute bioavailability was 88% after s.c. injection, 84% after oral administration to fasted dogs, but was reduced to 62% when applied orally to fed dogs. In canine and feline plasma the degree of binding of robenacoxib to plasma protein in vitro was greater than 98%. The blood:plasma concentration ratio was 0.44:1 in the dog and 0.65:1 in the cat. In conclusion analytical methods for the quantification of robenacoxib in blood and plasma in the dog and cat were developed and validated. In dogs, robenacoxib has good bioavailability after oral (84%) and subcutaneous (88%) administration.     

Field efficacy of moxidectin in dogs and rabbits naturally infested with Sarcoptes spp., Demodex spp. and Psoroptes spp. mites

The efficacy of moxidectin 1% injectable for cattle was evaluated in dogs and rabbits with naturally acquired sarcoptic, demodectic or psoroptic mites. Twenty-two dogs with generalised demodicosis were orally treated with 0.4mg/kg moxidectin daily. Forty-one dogs suffering from sarcoptic mange were treated with 0.2-0.25mg/kg moxidectin either orally or subcutaneously every week for three to six times. Seven rabbits were treated orally with 0.2mg/kg moxidectin twice 10 days apart. Of the 22 dogs with demodicosis, 14% were stopped treatment because of side effects, 14% were lost and of the remaining 72% all were cured (mean therapy duration 2.4 months). Thirty-seven of the sarcoptic mange-infected dogs finished treatment and were cured. In 17% of dogs, side effects were noted. All seven rabbits treated for psoroptic mange were cured and did not show any side effect. Our results indicate that moxidectin is effective and a good alternative for the treatment of demodicosis and scabies in dogs and psoroptic mange in rabbits. Side effects seem to occur more frequently if applied subcutaneously, therefore the oral route should be preferred.     

Pharmacokinetics of oral morphine sulfate in dogs: a comparison of sustained release and conventional formulations.

The pharmacokinetics and bioavailability (F) of single dose sustained release morphine sulfate (OSRMS) and nonsustained release morphine sulfate (NSRMS) were compared to each other and to a bolus injection of morphine sulfate (MS) intravenously (i.v.) in dogs. Beagles (n = 6) were randomly assigned to 3 treatment groups: namely, OSRMS 15 mg orally, NSRMS 15 mg orally, and 15 mg i.v. Serum samples were drawn at intervals up to 480 min following oral and 420 min following i.v. administration. Serum was analysed for morphine concentration using a radioimmunoassay. Data were analysed using non-compartmental pharmacokinetics. The only statistically significant difference between OSRMS and NSRMS was maximum serum concentration (Cmax). There were trends toward longer time to maximum serum concentration (Tmax) and longer mean absorption time (MAT) for OSRMS when compared to NSRMS, but the differences were not statistically significant (P < 0.05). Pharmacokinetic parameters for both oral formulations exhibited large variability in the rate of absorption of MS from the gastrointestinal tract. Bioavailability of both OSRMS and NSRMS was low (15%-17%). As expected, the area under the concentration vs time curve (AUC) and Cmax for the i.v. data was significantly greater than for both oral groups, and Tmax and mean residence time (MRT) were significantly less following i.v. administration. There were no statistically significant differences among the 3 treatment groups for apparent volume of distribution at steady state (Vdss) or elimination parameters. The OSRMS formulation used in this study provided equivalent bioavailability to NSRMS in dogs, accompanied by large individual variability in drug absorption. It also did not appear that the sustained release formulation provided sufficiently prolonged release of morphine sulfate from the tablet matrix in dogs to allow prolonged dosing intervals compared to NSRMS.     

Pharmacokinetics of the insulin-sensitizing agent troglitazone in cats

OBJECTIVE: To determine pharmacokinetics of troglitazone in healthy cats after i.v. and oral administration of a single dose of the drug. ANIMALS: 5 healthy ovariohysterectomized adult cats. PROCEDURE: Using a randomized crossover design, cats were given 5 mg of troglitazone/kg of body weight i.v. and 40 mg of troglitazone/kg orally. Blood and urine samples were collected after drug administration, and concentrations of troglitazone in plasma and urine were determined by use of high-performance liquid chromatography. RESULTS: Area-moment analysis was used to calculate pharmacokinetic variables. Terminal phase half-life was 1.1 +/- 0.1 hours. Steady-state volume of distribution was 0.23 +/- 0.15 L/kg. After i.v. administration, clearance was 0.33 +/- 0.04 L/h/kg. Drug was not detected in urine samples. Mean bioavailability of orally administered troglitazone was 6.9%. CONCLUSIONS AND CLINICAL RELEVANCE: The overall disposition of troglitazone in cats was similar to that reported in other species, including humans. Troglitazone has low and variable oral bioavailability. Clearance of the compound is moderate. Little if any unchanged troglitazone is excreted in urine; thus, metabolism and biliary excretion play predominant roles in elimination of the drug. On the basis of troglitazone pharmacokinetics in healthy cats, as well as on the basis of pharmacodynamics of the drug in humans and other animals, a regimen that uses a dosage of 20 to 40 mg/kg administered orally once or twice per day to cats will produce plasma concentrations of the insulin-sensitizing agent that have been documented to be effective in humans.     

Pharmacokinetics of morphine and plasma concentrations of morphine-6-glucuronide following morphine administration to dogs

The purpose of this study was to evaluate the pharmacokinetics of morphine and morphine-6-glucuronide (M-6-G) following morphine administered intravenously and orally to dogs in a randomized crossover design. Six healthy 3–4-year-old Beagle dogs were administered morphine sulfate (0.5 mg/kg) as an i.v. bolus and extended release tablets were administered orally as whole tablets (1.6 ± 0.1 mg/kg) in a randomized crossover design. Plasma concentrations of morphine and M-6-G were determined using high-pressure liquid chromatography and electrochemical coulometric detection. Following i.v. administration all dogs exhibited dysphoria and sedation, and four or six dogs vomited. Mean ± SE values for half-life, apparent volume of distribution, and clearance after i.v. administration were 1.16 ± 0.15 h, 4.55 ± 0.17 L/kg, and 62.46 ± 10.44 mL/min/kg, respectively. One dog vomited following oral administration and was excluded from the oral analysis. Oral bioavailability was 5% as determined from naïve-averaged analysis. The M-6-G was not detected in any plasma samples following oral or i.v. administration of morphine at a 25 ng/mL the limit of quantification. Computer simulations concluded morphine sulfate administered 0.5 mg/kg intravenously every 2 h would maintain morphine plasma concentrations consistent with analgesic plasma concentrations in humans. Oral morphine is poorly and erratically absorbed in dogs.     

Efficacy of oral,injectable and pour-on formulations of moxidectin against gastrointestinal nematodes in cattle in New Zealand

The efficacy of moxidectin administered by different routes, against naturally acquired infections of gastrointestinal nematode parasites of cattle, was compared using faecal egg count reduction tests on 14 commercial farms throughout New Zealand. On each farm, groups of 15 calves were sampled for faecal nematode egg count and then treated with ivermectin administered orally, or with moxidectin administered either by the oral, subcutaneous injection or topical (pour-on) route. Samples were again collected 14 days after treatment and efficacy was calculated as the percentage reduction in-group mean egg count between the pre- and post-treatment samples. In addition, efficacy was calculated for individual animals, in order to compare the variability of the different treatments. On four farms untreated control groups were run and five animals from each of the control and all of the moxidectin-treated groups were bled over time to estimate plasma–moxidectin concentrations.Averaged across all tests, the reduction in faecal egg count was significantly greater after treatment with moxidectin oral (91.1%) than following treatment with moxidectin injection (55.5%) or with moxidectin pour-on (51.3%). Low efficacies were invariably against Cooperia oncophora. The oral treatments were significantly less variable in efficacy than the injection and pour-on treatments. Moxidectin concentrations in plasma were highest following subcutaneous injection and lowest following pour-on administration. Plasma levels following oral administration were intermediate, being significantly lower than post-injection and significantly higher than post-pour-on. There was no evidence of transfer of moxidectin to untreated animals through licking. Based on these results, along with those of other studies, it is proposed that oral administration of macrocyclic lactone anthelmintics results in higher concentrations of active reaching the target worms in the gastrointestinal tract than following either administration by injection or by pour-on.     

Pharmacokinetics of moxidectin and doramectin in goats.

The pharmacokinetic behaviour of doramectin after a single subcutaneous administration and moxidectin following a single subcutaneous or oral drench were studied in goats at a dosage of 0.2 mg kg(-1). The drug plasma concentration-time data were analysed by compartmental pharmacokinetics and non-compartmental methods. Maximum plasma concentrations of moxidectin were attained earlier and to a greater extent than doramectin (shorter t(max) and greater C(max) and AUC than doramectin). MRT of doramectin (4.91 +/- 0.07 days) was also significantly shorter than that of moxidectin (12.43 +/- 1.28 days). Then, the exposure of animals to doramectin in comparison with moxidectin was significantly shorter. The apparent absorption rate of moxidectin was not significantly different after oral and subcutaneous administration but the extent of absorption, reflected in the peak concentration (C(max)) and the area under the concentration-time curve (AUC), of the subcutaneous injection (24.27 +/- 1.99 ng ml(-1) and 136.72 +/- 7.35 ng d ml(-1) respectively) was significantly greater than that of the oral administration (15.53 +/- 1.27 ng ml(-1) and 36.72 +/- 4.05 ng d ml(-1) respectively). The mean residence time (MRT) of moxidectin didn't differ significantly when administered orally or subcutaneously. Therefore low oral bioavailability and the early emergence of resistance in this minor species may be related. These results deserve to be correlated with efficacy studies for refining dosage requirements of endectocides in this species.     

Pharmacokinetics and pharmacodynamics of clemastine in healthy horses

Clemastine is an H1 antagonist used in certain allergic disorders in humans and tentatively also in horses, although the pharmacology of the drug in this species has not yet been investigated. In the present study we determined basic pharmacokinetic parameters and compared the effect of the drug measured as inhibition of histamine-induced cutaneous wheal formation in six horses. The most prominent feature of drug disposition after intravenous dose of 50 microg/kg bw was a very rapid initial decline in plasma concentration, followed by a terminal phase with a half-life of 5.4 h. The volume of distribution was large, Vss = 3.8 L/kg, and the total body clearance 0.79 L/h kg. Notably, oral bioavailability was only 3.4%. There was a strong relationship between plasma concentrations and effect. The effect maximum (measured as reduction in histamine-induced cutaneous wheal formation) was 65% (compared with controls where saline was injected) and the effect duration after i.v. dose was approximately 5 h. The effect after oral dose of 200 microg/kg was minor. The results indicate that clemastine is not appropriate for oral administration to horses because of low bioavailability. When using repeated i.v. administration, the drug has to be administered at least three to four times daily to maintain therapeutic plasma concentrations because of the short half-life. However, if sufficient plasma concentrations are maintained the drug is efficacious in reducing histamine-induced wheal formations.     

Effect of dietary fat on oral bioavailability of tepoxalin in dogs

A pharmacokinetic study was conducted to compare the oral bioavailability of tepoxalin and its pharmacologically active acid metabolite in fasted dogs and dogs fed either a low-fat or high-fat commercial diet. Using a cross-over design, six beagles were administered tepoxalin (10 mg/kg) intravenously (i.v.) and orally (p.o.) after being fed one of three diets (fasted, low-fat, or high-fat). Thereafter, blood samples were collected at frequent intervals, concentrations of tepoxalin and acid metabolite in plasma were determined by high performance liquid chromatography, and pharmacokinetic parameters were estimated. After i.v. dosing, the mean (+/-SD) half-life of elimination (t(1/2(beta))) was 2.45 +/- 1.47 h. After p.o. administration, plasma concentrations of acid metabolite were consistently higher than corresponding concentrations of the parent tepoxalin, indicating that tepoxalin is subject to a substantial first-pass effect. Mean (+/-SD) peak concentrations of tepoxalin were significantly higher after feeding of low-fat (1.08 +/- 0.37 microg/mL) and high-fat (1.19 +/- 0.29 microg/mL) diets than in fasted dogs (0.53 +/- 0.20 microg/mL), suggesting that feeding improves oral bioavailability.     

A review of the use of moxidectin in horses

Moxidectin has broad‐spectrum anti‐nematodal and anti‐arthropodal activities in the horse but is not effective against tapeworms or flukes. Moxidectin and ivermectin have the same efficacy against internal, adult parasites of horses. Moxidectin, however, is highly effective in eliminating encysted and hypobiotic larval stages of cyathostomins, whereas ivermectin is not. Treatment of horses with moxidectin results in an egg‐reappearance period (ERP) of 15–24 weeks. Because of its long ERP, moxidectin is labelled to be used at 12 week intervals. Moxidectin may provide protection against infection by ingested cyathostomin larvae for 2–3 weeks after it is administered. The larvicidal activity of moxidectin has often been compared to that of fenbendazole administered at either 7.5 or 10 mg/kg bwt for 5 consecutive days. The efficacy of fenbendazole, when administered daily for 5 consecutive days at 7.5 or 10 mg/kg bwt, against all stages of cyathostomins is often less than that of moxidectin because resistance of cyathostomins to benzimidazoles is prevalent worldwide, and the 5 day course of fenbendazole does not overcome this resistance. There are now reports of resistance of ascarids to moxidectin. Overt resistance of cyathostomins and a shortened egg re‐emergence period after treatment with moxidectin have been reported. Rapid removal of manure by natural fauna can significantly reduce larval nematode concentrations and thereby reduce intervals of anthelmintic treatment. Of the macrocyclic lactones, moxidectin has the least deleterious effect on faecal fauna.     

Pharmacokinetics of methimazole in normal cats and cats with hyperthyroidism

The intravenous and oral disposition of the antithyroid drug methimazole was determined in 10 clinically normal cats and nine cats with naturally occurring hyperthyroidism. After intravenous administration of 5 mg methimazole, the mean residence time was significantly (P less than 0.05) shorter in the cats with hyperthyroidism than in the normal cats, but there was no significant difference between the mean values for total body clearance (CL), steady state volume of distribution (Vdss), terminal elimination rate constant (ke), or serum terminal half-life (t1/2) in the two groups of cats. After oral administration, the mean bioavailability of methimazole was high in both the normal cats (77.6 per cent) and cats with hyperthyroidism (79.5 per cent). The values for mean residence time, ke and serum terminal t1/2 after oral dosing were significantly shorter in the cats with hyperthyroidism than in the normal cats. However, after oral administration of methimazole there were no significant differences between the mean values for CL, Vdss, bioavailability and maximum serum concentrations or the time for maximal concentrations to be reached in the two groups of cats. Overall, most pharmacokinetic parameters for methimazole were not altered by the hyperthyroid state. However, the cats with hyperthyroidism did show a trend toward faster elimination of the drug compared with the normal cats, similar to what has been previously described for the antithyroid drug propylthiouracil in cats. These results also indicate that methimazole is well absorbed when administered orally and has a higher bioavailability than that of propylthiouracil in cats with hyperthyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical pharmacokinetics of flumequine in calves

The minimal inhibitory concentration (MIC) of flumequine for 249 Salmonella, 126 Escherichia coli, and 22 Pasteurella multocida isolates recovered from clinical cases of neonatal calf diarrhoea, pneumonia and sudden death was less than or equal to 0.78 microgram/ml. The pharmacokinetics of flumequine in calves was investigated after intravenous (i.v.), intramuscular (i.m.) and oral administration. The two-compartment open model was used for the analysis of serum drug concentrations measured after rapid i.v. ('bolus') injection. The distribution half-life (t1/2 alpha) was 13 min, elimination half-life (t1/2 beta) was 2.25 h, the apparent area volume of distribution (Vd(area)), and the volume of distribution at steady state (Vd(ss)) were 1.48 and 1.43 l/kg, respectively. Flumequine was quickly and completely absorbed into the systemic circulation after i.m. administration of a soluble drug formulation; a mean peak serum drug concentration (Cmax) of 6.2 micrograms/ml was attained 30 min after treatment at 10 mg/kg and was similar to the concentration measured 30 min after an equal dose of the drug was injected i.v. On the other hand, the i.m. bioavailability of two injectable oily suspensions of the drug was 44%; both formulations failed to produce serum drug concentrations of potential clinical significance after administration at 20 mg/kg. The drug was rapidly absorbed after oral administration; the oral bioavailability ranged between 55.7% for the 5 mg/kg dose and 92.5% for the 20 mg/kg dose. Concomitant i.m. or oral administration of probenecid at 40 mg/kg did not change the Cmax of the flumequine but slightly decreased its elimination rate. Flumequine was 74.5% bound in serum. Kinetic data generated from single dose i.v., i.m. and oral drug administration were used to calculate practical dosage recommendations. Calculations showed that the soluble drug formulation should be administered i.m. at 25 mg/kg every 12 h, or alternatively at 50 mg/kg every 24 h. The drug should be administered orally at 30 and 60 mg/kg every 12 and 24 h, respectively. Very large, and in our opinion impractical, doses of flumequine formulated as oily suspension are required to produce serum drug concentrations of potential clinical value.     

Pharmacokinetics and tissue residues of josamycin in fowls.

Josamycin is a macrolide antibiotic which is produced by fermentation of cultures of Streptomyces narbonensis. It was once administrated (18 mg/kg b. wt.) in fowls via intravenous, oral and intramuscular routes for determination of blood concentration, kinetic behaviour and bioavailability. Following a single intravenous injection, the blood concentration-time-curve indicated a two compartments open model with an elimination half life value (t1/2 beta) of 1.83 +/- 0.06 hours. Both oral and intramuscular routes showed higher values, i.e. 2.33 +/- 0.13 and 2.85 +/- 0.17 hours. The lower apparent volume of distribution of Josamycin in fowls than one liter/kg elucidate higher distribution in blood than in tissues. Systemic bioavailability after both oral and intramuscular administration, i.e. 33.88 +/- 2.4 and 27.28 +/- 1.46% respectively, showed lower absorption from site of i.m. application. Josamycin was administered (18 mg/kg b. wt.) intramuscularly and orally once daily for 5 consecutive days. The drug peaked in serum 1 hour (intramuscular) and 2 hours (orally) after each dose. The recorded results revealed that serum level of Josamycin was higher after oral application (29.98 +/- 1.92 micrograms/ml) than after i.m. application. The drug persisted in the lung tissues and fat for 72 hours after administration and disappeared from all body tissues 96 hours after the last dose of repeated administration.     

Pharmacokinetics of Amoxicillin Trihydrate in Desert Sheep and Nubian Goats

The pharmacokinetics of amoxicillin were studied in five Desert sheep and five Nubian goats after intravenous (i.v.) or intramuscular (i.m.) administration of a single dose of 10 mg/kg body weight. Following i.v. injection, the plasma concentration-versus-time data were best described by a two-compartment open model. The kinetic variables were similar in both species except for the volume of the central compartment (V_c), which was larger in sheep (p<0.05). Following i.m. injection, except for the longer half-life time of absorption in goats (p<0.05), there were no significant differences in other pharmacokinetic parameters between sheep and goats. The route of amoxicillin administration had no significant effect on the terminal elimination half-life in either species. The bioavailability of the drug (F) after i.m. administration was high (>0.90) in both species. These results indicate that the pharmacokinetics of amoxicillin did not differ between sheep and goats; furthermore, because of the high availability and short half-life of absorption, the i.m. route gives similar results to the i.v. route. Therefore, identical intramuscular and intravenous dose regimens should be applicable to both species.     

Enrofloxacin-theophylline interaction: influence of enrofloxacin on theophylline steady-state pharmacokinetics in the Beagle dog

Enrofloxacin, a quinolone antibiotic developed exclusively for use in animals, was investigated for its effects on the steady-state pharmacokinetics of theophylline in six healthy Beagle dogs. A sustained-release theophylline formulation was given alone (20 mg/kg per os twice daily at 12 h intervals) for 9 days and then co-administered with enrofloxacin (5 mg/kg i.v. once a day) for 5 days. Mean trough theophylline concentrations progressively and significantly increased during the five days of enrofloxacin co-administration. Theophylline clearance and concentration-time profile were significantly changed by enrofloxacin co-administration. No significant change was observed in enrofloxacin pharmacokinetics. The kinetic interaction between theophylline and enrofloxacin could be of clinical significance and may require plasma drug concentration monitoring and adjustment of theophylline dosage.