Bioavailability of a commercial formulation of ivermectin after subcutaneous administration to sheep

OBJECTIVE: To evaluate bioavailability and other pharmacokinetic variables of a commercial formulation of ivermectin after IV administration to sheep. ANIMALS: 6 healthy adult sheep. PROCEDURES: A single dose of a commercial formulation of ivermectin (200 microg/kg) was administered IV to each sheep. After a washout period of 3 weeks, each sheep was administered ivermectin by SC injection. Plasma samples were obtained for up to 36 and up to 42 days after IV and SC administration, respectively. Ivermectin concentrations were quantified by use of high-performance liquid chromatography with fluorescence detection. RESULTS: Results obtained indicated that after IV administration, ivermectin is cleared slowly from plasma, tends to distribute and accumulate in the peripheral compartment, and is slowly eliminated from the body. After SC administration, noncompartmental analysis revealed that bioavailability of ivermectin is nearly complete (98.20%), has a slow mean absorption time of 0.96 days, and reaches a maximum plasma concentration of 19.55 ng/mL at 3.13 days. CONCLUSIONS AND CLINICAL RELEVANCE: The commercial formulation of ivermectin used in this study can be administered SC to sheep on the basis of a nearly complete bioavailability. In addition, the maximum plasma concentration and interval from SC injection until maximum plasma concentration is obtained are higher than those reported by other authors who used other routes of administration.     

Comparison of the pharmacokinetics of moxidectin (Equest®) and ivermectin (Eqvalan®) in horses

A study was undertaken in order to evaluate and compare plasma disposition kinetic parameters of moxidectin and ivermectin after oral administration of their commercially available preparations in horses. Ten clinically healthy adult horses, weighing 390-446 kg body weight (b.w.), were allocated to two experimental groups of five horses. Group I was treated with an oral gel formulation of moxidectin (MXD) at the manufacturers recommended therapeutic dose of 0.4 mg/kg bw. Group II was treated with an oral paste formulation of ivermectin (IVM) at the manufacturers recommended dose of 0.2 mg/kg b.w. Blood samples were collected by jugular puncture at different times between 0.5 h and 75 days post-treatment. After plasma extraction and derivatization, samples were analysed by HPLC with fluorescence detection. Computerized kinetic analysis was carried out. The parent molecules were detected in plasma between 30 min and either 30 (IVM) or 75 (MXD) days post-treatment. Both drugs showed similar patterns of absorption and no significant difference was found for the time corresponding to peak plasma concentrations or for absorption half-life. Peak plasma concentrations (Cmax) of 70.3+/-10.7 ng/mL (mean +/- SD) were obtained for MXD and 44.0+/-23.1 ng/mL for IVM. Moreover, the values for area under concentration-time curve (AUC) were 363.6+/-66.0 ng x d/mL for the MXD treated group, and 132.7+/-47.3 ng x d/mL for the IVM treated group. The mean plasma residence times (MRT) were 18.4+/-4.4 and 4.8+/-0.6 days for MXD and IVM treated groups, respectively. The results showed a more prolonged residence of MXD in horses as demonstrated by a four-fold longer MRT than for IVM. The longer residence and the higher concentrations found for MXD in comparison to IVM could possibly explain a more prolonged anthelmintic effect. It is concluded that in horses the commercial preparation of MXD presents a pharmacokinetic profile which differs significantly from that found for a commercial preparation of IVM. To some extent these results likely reflect differences in formulation and doses.     

Pharmacokinetics of ivermectin in llamas (Lama glama)

The pharmacokinetic behaviour of ivermectin was investigated in adult llamas (Lama glama) by using high performance liquid chromatography with a lower limit of quantification of 2 ng/ml to measure its concentration in serum. Llamas were treated with one of three commercial formulations (injectable, pour-on or oral paste) at dosages recommended by the manufacturer, or with an experimental injectable sustained-release formulation. In five llamas given 1 per cent ivermectin subcutaneously at 200 microg/kg, the median peak serum concentration (Cmax) was 3 ng/ml and the area under the serum concentration-time curve (AUC) was 13.5 ng x day/ml. In six llamas treated topically with 0.5 per cent ivermedin pour-on at 500 microg/kg, Cmax was 2.5 ng/ml or less and the AUC was 7.75 ng x day/ml or less. In seven llamas with measurable concentrations of ivermedin, the median times to peak serum concentration (tmax) were six days after subcutaneous injection and seven days after treatment with the pour-on formulation. In six llamas, the serum concentration of ivermectin remained less than 2 ng/ml for 124 hours after treatment with a 1.87 per cent oral paste at 200 microg/kg. In five llamas treated subcutaneously with 25 per cent ivermectin sustained-release microspheres at 1500 microg/kg, the median Cmax was 5 ng/ml and the median AUC was 224 ng x day/ml.     

Breed differences in the pharmacokinetics of ivermectin administered subcutaneously to Holstein and Belgian Blue calves

Belgian Blue (BB) cattle are very sensitive to mange caused by Psoroptes ovis and, in contrast to the case in Holstein cattle, single treatments with ivermectin do not result in complete elimination of the parasite. The objective of the present study was to determine the concentration of ivermectin in plasma, skin and hair following subcutaneous administration to Holstein and BB calves and to assess the influence of breed on drug pharmacokinetics and availability. Two groups of six healthy female Holstein and BB calves were treated with ivermectin (SC formulation) at a dose of 0.2 mg/kg. Blood, skin and hair were collected before treatment and up to 21 days after treatment. Ivermectin was analyzed in plasma and tissue by high-performance liquid chromatography (HPLC). The peak concentrations (Cmax), time-peak concentrations (Tmax), the area under the plasma concentration-time curves (AUC) and the mean residence time (MRT) were determined. The patterns of plasma and tissue ivermectin concentrations were similar in the two breeds of animals, however, the AUC and Cmax levels for plasma and skin were significantly higher in the BB calves. In hair, ivermectin was detected later than in plasma and skin, with the Tmax ranging between 4 days (Holstein group) and 6 days (BB group). The possible reasons for the significantly higher levels in plasma and skin in BB calves compared to Holstein calves are discussed.     

Efficacy of injectable and pour-on microdose ivermectin in the treatment of goat warble fly infestation by Przhevalskiana silenus (Diptera, Oestridae)

The prophylactic efficacy of microdoses of injectable and pour-on ivermectin formulations against larval stages of Przhevalskiana silenus was assessed in naturally infected goats in the region of Calabria (southern Italy).Sixty-eight goats from two goat farms were divided into five groups: one group remained untreated, while the other four groups were treated with microdoses of ivermectin (5 and 10 microg/kg injectable formulation and 10 and 20 microg/kg pour-on formulation).The microdoses of ivermectin were fully effective in the treatment of goat warble fly infestation (GWFI) as no larvae emerged from the warbles in the treated groups, while all the larvae emerged in the control groups. Irrespective of the type of formulation used, the difference between the treated groups and the control group was statistically significant (P< 0.001). By contrast, no statistical differences were found between the goats treated with the injectable formulation and those receiving the pour-on applications, and between the two doses of the injectable and pour-on formulations used. Given the plasma concentrations it attains at its lowest dose (0.052 - 0.042 ng/ml for the injectable formulation and 0.030 ng/ml for the pour-on) the injectable formulation seems to offer the most reliable route for the administration of ivermectin microdoses and it is acceptable for milk consumption. The introduction of ivermectin in the early eighties and the use of microdoses in some cases have made it possible to control cattle hypodermosis in large areas of Europe. As with cattle hypodermosis, the administration of ivermectin microdoses in goats is particularly interesting because of the low costs involved and the low levels of residues found in goat milk; it may thus constitute the basis for GWFI control campaigns in areas where the disease is prevalent.     

Disposition of cyclosporine after intravenous and multi-dose oral administration in cats

The aim of this study was to evaluate the disposition of cyclosporine after intravenous (i.v.) and oral administration and to evaluate single sampling times for therapeutic monitoring of cyclosporine drug concentrations in cats. Six adult male cats (clinically intact) were used. Two treatments consisting of a single i.v. cyclosporine (1 mg/kg) and multiple oral cyclosporine (3 mg/kg b.i.d p.o. for 2 weeks) doses. Whole blood cyclosporine concentrations were measured at fixed times by high performance liquid chromatography and pharmacokinetic values were calculated. Mean values for the i.v. data included AUC (7413 ng/mL.h), t1/2 distribution and elimination (0.705 and 9.7 h, respectively), Cmax (1513 ng/mL), and Vd(ss) (1.71 L/kg). Mean values for the oral data included AUC (6243 ng/mL.h), t1/2 of absorption and elimination (0.227 and 8.19 h, respectively), and Cmax (480.0 ng/mL). Bioavailability of orally administered cyclosporine was 29 and 25% on days 7 and 14 respectively. Whole blood comment cyclosporine concentration 2 h after administration (C2) better correlated with AUC on days 7 and 14 than trough plasma concentration (C12). The rate of oral cyclosporine absorption was less than expected and there was substantial individual variation. Therapeutic drug monitoring strategies for cyclosporine in cats should be re-evaluated.     

Plasma pharmacokinetics and synovial fluid concentrations after oral administration of single and multiple doses of celecoxib in greyhounds

OBJECTIVE: To determine the plasma pharmacokinetics and synovial fluid concentrations after oral administration of single and multiple doses of celecoxib in Greyhounds. ANIMALS: 7 adult Greyhounds. PROCEDURES: Dogs received celecoxib (median dose, 11.8 mg/kg [range, 11.5 to 13.6 mg/kg], PO, q 24 h) for 10 days. Blood samples were collected prior to administration of celecoxib and serially for 24 hours after the 1st and 10th doses were administered. A synovial joint catheter was placed into a stifle joint in each dog for collection of synovial fluid samples. Concentrations of celecoxib in plasma and synovial fluid were quantified by use of a validated liquid chromatography/mass spectrometry method. Identification of hydroxy- and carboxyl-celecoxib in plasma and synovial fluid was also performed. Pharmacokinetic parameters were determined by use of noncompartmental analysis. RESULTS: Administration of multiple doses of celecoxib resulted in a significant decrease (40%) in median area under the curve (AUC) values and a corresponding decrease in median maximum concentrations (Cmax; 2,620 to 2,032 ng/mL) between the 1st and 10th doses. Synovial fluid concentrations were less than the corresponding plasma concentrations at all times except 24 hours after administration of the 10th dose of celecoxib. CONCLUSIONS AND CLINICAL RELEVANCE: Celecoxib distributes into the synovial fluid of Greyhounds. Although the exact mechanism for the decreases in AUC and Cmax is not known, results suggested that the plasma pharmacokinetics of celecoxib are different after administration of multiple doses in Greyhounds. These findings warrant further investigation on the absorption, distribution, metabolism, and elimination of celecoxib in Greyhounds and other breeds of dogs.     

联合应用阿苯达唑和伊维菌素在线虫感染鄂尔多斯细毛羊体内的药动学研究

为阐明联合应用阿苯达唑(ABZ)和伊维菌素(IVM)在胃肠道线虫感染鄂尔多斯细毛羊体内的药动学互作关系,以感染胃肠道线虫的鄂尔多斯细毛羊为研究对象,比较研究了单独或联合应用阿苯达唑和伊维菌素后的药物动力学特征。通过粪便虫卵检查法,选取感染胃肠道线虫的鄂尔多斯细毛羊15只,随机分成3组,每组5只。第1组口服给予阿苯达唑(15mg/kg),第2组皮下注射伊维菌素(0.2mg/kg),第3组皮下注射伊维菌素(0.2mg/kg)的同时口服阿苯达唑(15mg/kg)。于给药后不同时间,由颈静脉采集血样,分离血浆,并用高效液相色谱法测定各时间点血浆阿苯达唑、阿苯达唑亚砜、阿苯达唑砜和伊维菌素浓度,并用PK Solution 2.0药物动力学软件计算出各药动学参数。结果表明,联合用药组绵羊血浆伊维菌素峰浓度(Cmax)、药时曲线下面积(AUC)和平均滞留时间(MRT)分别为44.80ng/mL±6.12ng/mL、5 007.46ng.h/mL±1 301.42ng.h/mL和85.47h±5.03h,均显著(P<0.05)小于单独用药组的对应参数值67.62ng/mL±9.06ng/mL、7 125.08ng.h/mL±908.52ng.h/mL和113.39h±9.00h。口服阿苯达唑组绵羊血浆中仅检测到了阿苯达唑砜和阿苯达唑亚砜,而未检测到阿苯达唑母药。联合用药后,除阿苯达唑砜的达峰时间(T max)显著推迟外,阿苯达唑砜和阿苯达唑亚砜的其他各参数之间均无显著性差异。因此,联合应用IVM和ABZ可影响它们在胃肠道线虫感染鄂尔多斯细毛羊体内的药动学特征,且对伊维菌素药动学特征的影响尤为明显,在临床联合用药过程中应予以重视。     

Pharmacokinetics of ivermectin in zebu Gobra (Bos indicus)

Plasma disposition kinetics of ivermectin was evaluated in a West African cattle breed. Five clinically healthy zebu Gobra cattle (Bos indicus) weighing 220-270 kg were treated (0.2 mg kg-1) with a commercially available ivermectin formulation for cattle. Blood samples were collected by jugular puncture at different times between 0.5 h and 40 days post-treatment. After plasma extraction and derivatization, samples were analysed by HPLC with fluorescence detection. Ivermectin was detected in plasma between 30 min and 20 days post-treatment. The observed peak plasma concentration (Cmax) was 46.3+/-13.8 ng ml-1 and the time to reach Cmax (t(max)) was 0.9+/-0.2 day. The values for the absorption half-life (t1/2ab) and the elimination half-life (t1/2el) were 0.3+/-0.2 and 2.8+/-0.7 days, respectively. The calculated area under the concentration-time curve (AUC) was 185.2+/-12.1 ng day ml-1 and the mean residence time (MRT) was 4.2+/-1.3 days. The availability of ivermectin is low in zebu Gobra in comparison to other breeds cattle but equivalent to that reported in the yak and is likely to be due to physiological characteristics of this breed.     

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.     

Breed-related plasma disposition of ivermectin following subcutaneous administration in Kilis and Damascus goats

Many factors related with drug and animals affect the plasma disposition of endectocides including ivermectin (IVM). The aim of the present study was to investigate the breed differences in pharmacokinetics of IVM in goats following subcutaneous administration. Two different goat breeds (Kilis and Damascus goats) were allocated into two treatment groups with respect to breed. The injectable formulation of IVM was administered subcutaneously at a dose rate of 0.2 mg/kg bodyweight. Blood samples were collected before treatment and at various times between 1 h and 40 days after treatment and the plasma samples were analysed by high performance liquid chromatography (HPLC) using fluorescence detection. The results indicated that the plasma disposition of IVM was substantially affected by breed differences following subcutaneous administration in goats. The last detectable plasma concentration (t_last) of IVM was significantly later in Kilis goats (38.33 days) compared with Damascus goats (22.50 days). Although, there were no significant differences on C_max (10.83 ng/ml vs. 10.15 ng/ml) and t_max (2.75 days vs. 2.33 days) values; the area under the concentration–time curve-AUC (110.26 ng.d/ml vs. 73.38 ng.d/ml) the terminal half-life-t_1/2λz (5.65 days vs. 3.81 days) and the mean plasma residence time-MRT (9.31 days vs. 6.35 days) were significantly different in Kilis goats compared with Damascus goats, respectively. The breed-related difference observed on the plasma disposition of IVM between Kilis and Damascus goats could be attributable to different excretion pattern or specific anatomical and/or physiological characteristics such as body fat composition of each breed.     

Ivermectin disposition kinetics after subcutaneous and intramuscular administration of an oil-based formulation to cattle.

Slight differences in formulation may change the plasma kinetics and ecto-endoparasiticide activity of endectocide compounds. This work reports on the disposition kinetics and plasma availability of ivermectin (IVM) after subcutaneous (SC) and intramuscular (IM) administration as an oil-based formulation to cattle. Parasite-free Aberdeen Angus calves (n = 24; 240-280 kg) were divided into three groups (n = 8) and treated (200 microg/kg) with either an IVM oil-based pharmaceutical preparation (IVM-TEST formulation) (Bayer Argentina S.A.) given by subcutaneous (Group A) and intramuscular (Group B) injections or the IVM-CONTROL (non-aqueous formulation) (Ivomec, MSD Agvet) subcutaneously administered (Group C). Blood samples were taken over 35 days post-treatment and the recovered plasma was extracted and analyzed by HPLC using fluorescence detection. IVM was detected in plasma between 12 h and 35 days post-administration of IVM-TEST (SC and IM injections) and IVM-CONTROL formulations. Prolonged IVM absorption half-life (p < 0.05) and delayed peak plasma concentration (p < 0.001) were obtained following the SC administration of the IVM-TEST compared to the IVM-CONTROL formulation. No differences in total plasma availability were observed among treatments. However, the plasma residence time and elimination half-life of IVM were significantly longer after injection of the IVM-TEST formulation. IVM plasma concentrations were above 0.5 ng/ml for 20.6 (CONTROL) and 27.5 days (IVM-TEST SC), respectively (p < 0.05). The modified kinetic behaviour of IVM obtained after the administration of the novel oil-based formulation examined in this trial, compared to the standard preparation, may positively impact on its strategic use in cattle.     

Influence of the route of administration on efficacy and tissue distribution of ivermectin in goat

The tissue concentration and efficacy of ivermectin after per os and subcutaneous administration were compared in goats experimentally infected with Trichostrongylus colubriformis (ivermectin-susceptible strain, INRA). Infected goats (n = 24) were treated per os (n = 9) or subcutaneously (n = 9) with ivermectin, 0.2 mg/kg, or kept as not treated controls. The faecal egg counts and small intestine worm counts were determined. Ivermectin concentration was measured in the plasma, gastrointestinal tract, lung, skin or hair, liver and adipose tissues at 0, 2, 7 and 17 days post-treatment. The efficacy of ivermectin against T. colubriformis infection in goat was 98.7 and 99.9% for subcutaneous and oral administration, respectively. Ivermectin concentration declined with time and only residual concentration was measured at 17 days post-treatment in plasma and gastrointestinal tract. Ivermectin concentration was higher after subcutaneous compared to per os injection in most of the tissue examined. In skin, hair and subcutaneous adipose tissue ivermectin persisted at significant concentrations 17 days post-treatment for both routes of administration. In our experimental conditions, ivermectin provides similar efficacy against T. colubriformis after subcutaneous or per os administration in goat. However, the lower ivermectin levels in tissues after per os administration suggest that the lasting of efficacy may be shortened after per os compared to subcutaneous administration especially in animals with poor body condition in pasture where re-infection occurs quickly after anthelmintic treatment.     

A comparative kinetic study of ivermectin and moxidectin in lactating camels (Camelus dromedarius).

The plasma and milk kinetics of ivermectin (IVM) and moxidectin (MXD) was evaluated in lactating camels treated subcutaneously (0.2 mg kg(-1)) with commercially available formulations for cattle. Blood and milk samples were taken concurrently at predetermined times from 12 h up to 60 days post-administration. No differences were observed between plasma and milk kinetics of IVM, while substantial differences were noted between plasma and milk profiles of MXD in that both the maximal concentration (Cmax) and the area under concentrations curves (AUC) were three to four-fold higher for milk than for plasma. The time (Tmax) to reach Cmax was significantly faster for MXD (1.0 day) than that for IVM (12.33 days). The Cmax and the AUC were significantly higher for MXD (Cmax = 8.33 ng ml(-1); AUC = 70.63 ng day ml(-1)) than for IVM (Cmax = 1.79 ng ml(-1); AUC = 30.12 ng day ml(-1)) respectively. Drug appearance in milk was also more rapid for MXD (Tmax = 3.66 days) compared to IVM (Tmax = 17.33 days). The extent of drug exchange from blood to milk, expressed by the AUCmilk/AUCplasma ratio, was more than three-fold greater for MXD (4.10) compared to that of IVM (1.26), which is consistent with the more lipophilic characteristic of MXD. However, the mean residence time (MRT) was similar in both plasma and milk for each drug.     

Penicillin concentrations in serum, milk, and urine following intramuscular and subcutaneous administration of increasing doses of procaine penicillin G in lactating dairy cows.

Eight healthy, non-pregnant, crossbred Holstein dairy cows (557-682 kg) within their first 3 months of lactation (13-21.5 kg of milk/day) were used. Cows were kept in tie stalls for the whole experiment. The 8 cows were randomly assigned to 2 (IM and SC) 4 x 4 balanced Latin square design experiments. Doses of procaine penicillin G (PPG) (300000 IU/mL) in each square were 7000, 14000, 21000 and 28000 IU/kg and were injected IM or SC once daily for 5 consecutive days. Volumes of PPG per site of injection never exceeded 20 mL. Blood was collected to determine the Cmax, Tmax, and AUC; urine and milk were also taken to measure the persistence of PPG in these fluids. Results show that serum Cmax and Tmax were only slightly affected by increasing the doses or the route of administration, whereas the AUC was linearly increased in relation to the dose injected in both modes of injection. In the urine, Cmax varied from 160 to 388 IU/mL and Tmax from 72-120 h during 5 consecutive days of PPG injection. A dose effect in Cmax was observed only for the IM route of administration and no variation (P > 0.05) was found between the IM and SC routes. Milk Cmax concentrations were only increased by the dose regimen in the IM group. At doses of 21000 and 28000 IU/kg, the IM group had a higher (P > 0.05) Cmax when compared with the SC groups. Milk PPG residues were not detectable over 96 h following the last IM injection, independently of the dose injected. However milk PPG residues were detected for up to 132 h following the last SC injection. These results show that when PPG is injected IM once daily in volumes not exceeding 20 mL/site at doses as high as 28000 IU/kg, the withdrawal period should be at least 96 h. Therefore, in the present model, there was no advantage to inject PPG by SC route to improve PPG kinetic parameters as the AUC, Cmax, or Tmax.     

The comparative plasma pharmacokinetics of intravenous cefpodoxime sodium and oral cefpodoxime proxetil in beagle dogs

The pharmacokinetic properties of cefpodoxime, and its prodrug, cefpodoxime proxetil, were evaluated in two separate studies, one following intravenous (i.v.) administration of cefpodoxime sodium and the second after oral (p.o.) administration of cefpodoxime proxetil to healthy dogs. After cefpodoxime administration, serial blood samples were collected and plasma concentrations were determined by high performance liquid chromatography (HPLC). A single i.v. administration of cefpodoxime sodium at a dose of 10 mg cefpodoxime/kg body weight resulted in a cefpodoxime average maximum plasma concentration (Cmax) of 91 (+/-17.7) microg/mL, measured at 0.5 h after drug administration, an average half-life (t1/2) of 4.67 (+/-0.680) h, an average AUC(0-infinity) of 454 (+/-83.1) h.microg/mL, an average V(d(ss)) of 151 (+/-27) mL/kg, an average Cl(B) of 22.7 (+/-4.2) mL/h/kg and an average MRT(0-infinity) of 5.97 (+/-0.573) h. When dose normalized to 10 mg cefpodoxime/kg body weight, cefpodoxime proxetil administered orally resulted in Cmax of 17.8 +/- 11.4 microg/mL for the tablet formulation and 20.1 +/- 6.20 microg/mL for the suspension formulation and an average AUC(0-LOQ) of 156 (+/-76.1) h.microg/mL for the tablet formulation and 162 (+/-48.6) h.microg/mL for the suspension formulation. Relative bioavailability of the two oral formulations was 1.04 (suspension compared with tablet), whereas the absolute bioavailability of both oral formulations was estimated to be approximately 35-36% in the cross-study comparison with the i.v. pharmacokinetics. Combined with previous studies, these results suggest that a single daily oral dose of 5-10 mg cefpodoxime/kg body weight as cefpodoxime proxetil maintains plasma concentrations effective for treatment of specified skin infections in dogs.     

Pharmacokinetics and residues in milk of oxytetracyclines administered parenterally to dairy goats

OBJECTIVE: To determine for two commercial preparations of oxytetracycline (OTC) the pharmacokinetic behaviour, the presence of detectable milk residues and the penetration in milk of OTC administered by intravenous (IV) (conventional formulation [CF]) and intramuscular (IM) routes (CF and long-acting [LA] formulations) in goats producing milk. The effects of these formulations on plasma activity values of creatine kinase (CK) and lactate dehydrogenase (LDH) were also determined as indicators of tissue damage. PROCEDURE: Five healthy lactating goats producing 1.5+/-0.5 L/d milk and weighing 56.0+/-4.8 kg were used. Single doses of OTC chlorhydrate (CF) were administered (20 mg OTC/kg) by IV (Trial 1 IV) and IM (Trial 1 IM) routes and OTC dehydrate (LA) by the IM route. The same goats were first given IV CF, then IM CF followed by IM LA with 3 weeks between each treatment. Blood and milk samples were taken. The quantification of OTC was performed by HPLC and the plasma activities of CK and LDH enzymes were determined by spectrophotometry. The presence of OTC residues in milk was determined by a commercial reagent. The plasma pharmacokinetic parameters were calculated using a two-compartment model. RESULTS: Estimates of kinetic variables following IV administration were: Vss= 400.0+/-120.0 mL/kg and CL= 110.0+/-14.0 (mL/h)/kg. The t(fi) for IV= 3.0+/-0.3 h; IM, CF = 10.5+/-2.1 h and IM, LA = 15.1+/-3.1 h. The concentration of OTC in milk at 48 h was: IV= 0.6+/-0.4; IM CF= 1.1+/-0.2 and at 72 h (IM LA)= 0.6+/-0.1 microg/mL and the penetration in milk of OTC was: IV= 70.0+/-18.0; IM CF= 79.0+/-14.0 and IM LA= 66.0+/-6.0%. The areas under the curve of CK and LDH activities in plasma were calculated by the trapezoidal method. Values of CK and LDH IM, LA were greater (P < 0.05) than those observed for IM, CF at 2 and 3 days after administration of the antibiotic. Finally, the bioavailability of OTC CF = 92.0+/-22.0 and LA= 78.0+/-23.0% was suitable for its usage by the IM route in lactating goats. CONCLUSION: Plasma concentration-time values of OTC administered parenterally in production dairy goats showed similar bioavailability for the two pharmaceutical preaprations. The presence of detectable residues in milk indicates that milk should not be used for human consumption for 2 and 3 days after administration of conventional and long-acting formulations, respectively. The increments in CK and LDH activities after the IM administration of LA are consistent with the presence of tissue damage provoked by the pharmaceutical preparations at the injection site.     

Single dose pharmacokinetics of piroxicam in cats

Piroxicam (PIRO) is a nonsteroidal anti-inflammatory drug (NSAID) recognized for its value as a chemopreventative and anti-tumor agent. Eight cats were included in this study. PIRO was administered in a single oral (p.o.) and intravenous (i.v.) dose of 0.3 mg/kg. The study was designed as a randomized complete crossover with a 2-week washout period. Serial blood samples were collected after each dose and plasma was analyzed for PIRO. Pharmacokinetic parameters of PIRO were determined using noncompartmental analysis. PIRO is well absorbed in the cat with a median bioavailability (F) of 80% (range 64-124%). The median i.v. t1/2 was 12 h (range 8.6-14 h). The median Cmax was 519 ng/mL with a corresponding Tmax of 3 h. PIRO appears to be rapidly absorbed following p.o. administration in cats with a higher Cmax and AUC than in dogs.     

The steady-state pharmacokinetics and bioequivalence of carprofen administered orally and subcutaneously in dogs

Eighteen male Beagle dogs were randomized to oral (p.o.) or subcutaneous (s.c.) carprofen administration in a two-sequence, two-period crossover design with a 10-day washout between periods. Twenty-five milligrams of carprofen was administered p.o. or s.c. every 12 h for 7 days. Plasma concentrations of carprofen collected after the first and last treatments were determined by high-performance liquid chromatography. Carprofen concentration data were natural log transformed and geometric means were calculated for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0--12) following the first dose and Cmax and AUC0--12 following administration of the last dose. Formulations were considered bioequivalent if the 90% confidence interval (CI) of the mean difference for each variable between formulations were within -20% and 25% of the oral formulation. The mean Cmax and AUC0--12 were 16.9 microg/mL and 73.1 microg. h/mL, respectively, following a single oral dose and 8.0 microg/mL and 64.3 microg x h/mL, respectively, following a single s.c. injection. The 90% CI for Cmax (-56.8 to -48.7%) was outside of the bioequivalence criteria whereas the 90% CI for AUC0--12 (-16.3 to -7.5%) was within the bioequivalence criteria. At steady-state, the mean Cmax and AUC0--12 were 18.7 microg/mL and 101.9 microg x h/mL, respectively, following p.o. administration and 14.7 microg/mL and 111.0 microg x h/mL, respectively, following s.c. injection. The 90% CI was outside the bioequivalence criteria for Cmax (-30.8 to -10.8) but within the bioequivalence criteria for AUC0--12 (2.3-15.9%). The results of this study indicate that peak plasma concentrations of carprofen differ when administered p.o. and s.c., but that total drug exposure following a single dose and at steady-state are bioequivalent.     

喹烯酮及其主要代谢物在猪体内的药动学研究

本试验旨在研究喹烯酮及其主要代谢物在猪体内的药物代谢动力学过程。将喹烯酮按40 mg/kg的剂量对7头猪进行灌胃给药,采用HPLC-MS/MS法测定血浆中喹烯酮及其主要代谢物的浓度,药代动力学软件WinNonlin 5.2处理血浆中药物浓度－时间数据。灌胃给药后猪血浆中能检测到原药和N1-脱氧喹烯酮、脱二氧喹烯酮及3-甲基喹噁啉-2-羧酸(MQCA)3种代谢物。喹烯酮的浓度－时间数据符合一级吸收一室开放模型,其主要药代动力学参数为:T_1/2Ka＝(0.97±0.08)h,T_1/2λz＝(2.79±0.16)h,CL＝(26.03±0.65)L/h·kg,Cmax＝(0.26±0.01)μg/mL,Tmax＝(2.23±0.06)h,AUC＝(1.54±0.04)h·μg/mL;采用统计矩法处理N1-脱氧喹烯酮和脱二氧喹烯酮的浓度－时间数据,N1-脱氧喹烯酮主要药代动力学参数为:Tmax＝(6.33±1.37)h,Cmax＝(8.81±2.08) ng/mL,T_1/2λz＝(3.03±1.27)h,AUC＝(0.07±0.01)h·ng/mL,MRT＝(6.58±0.40)h;脱二氧喹烯酮的主要药动学参数:Tmax＝(10.29±0.29)h,Cmax＝(6.20±1.11)ng/mL,T_1/2λz＝(5.84±2.78)h,AUC＝(0.15±0.01)h·ng/mL,MRT＝(3.64±0.72)h。同时,在少数时间点检测到代谢物MQCA。猪口服喹烯酮后,吸收较快,消除较慢。血浆中检测到N1-脱氧喹烯酮、脱二氧喹烯酮及3-甲基喹噁啉-2-羧酸3种代谢物,且浓度较低、消除缓慢。