Evaluation of bioequivalence after oral, intramuscular, and intravenous administration of racemic ketoprofen in pigs

OBJECTIVE: To assess bioequivalence after oral, IM, and IV administration of racemic ketoprofen in pigs and to investigate the bioavailability after oral and IM administration. ANIMALS: 8 crossbred pigs. PROCEDURES: Each pig received 4 treatments in a randomized crossover design, with a 6-day washout period. Ketoprofen was administered at 3 and 6 mg/kg, PO; 3 mg/kg, IM; and 3 mg/kg, IV. Plasma ketoprofen concentrations were measured by use of high-performance liquid chromatography for up to 48 hours. To assess bioequivalence, a 90% confidence interval was calculated for the area under the time-concentration curve (AUC) and maximum plasma concentration (C(max)). RESULTS: Equivalence was not detected in the AUCs among the various routes of administration nor in C(max) between oral and IM administration of 3 mg/kg. The bioavailability of ketoprofen was almost complete after each oral or IM administration. Mean +/- SD C(max) was 5.09 +/- 1.41 microg/mL and 7.62 +/- 1.22 microg/mL after oral and IM doses of 3 mg/kg, respectively. Mean elimination half-life varied from 3.52 +/- 0.90 hours after oral administration of 3 mg/kg to 2.66 +/- 0.50 hours after IV administration. Time to peak C(max) after administration of all treatments was approximately 1 hour. Increases in AUC and C(max) were proportional when the orally administered dose was increased from 3 to 6 mg/kg. Conclusions and Clinical Relevance: Orally administered ketoprofen was absorbed well in pigs, although bioequivalence with IM administration of ketoprofen was not detected. Orally administered ketoprofen may have potential for use in treating pigs.     

Pharmacokinetics and metabolism of ketoprofen after intravenous and intramuscular administration in camels

The pharmacokinetics of ketoprofen were determined after an intravenous (i.v.) and intramuscular (i.m.) dose of 2.0 mg/kg body weight in five camels (Camelus dromedarius) using gas chromatography/mass spectrometry (GC/MS). The data obtained (median and range) following i.v. administration was as follows: the elimination half-life (t(1/2beta)) was 4.16 (2.65-4.29) h, the steady state volume of distribution (Vss) was 130.2 (103.4-165.3) mL/kg, volume of distribution (area method) (Vd(area)) was 321.5 (211.4-371.0) mL/kg, total body clearance (Cl) was 1.00 (0.88-1.08) mL/min x kg and renal clearance was 0.01 (0.003-0.033) mL/min x kg. Following i.m. administration, the drug was rapidly absorbed with peak serum concentration of 12.2 (4.80-14.4) microg/mL at 1.50 (1.00-2.00) h. The systemic availability of ketoprofen was complete. The apparent half-life was 3.28 (2.56-4.14) h. A hydroxylated metabolite of ketoprofen was identified by (GC/MS) under electron impact (EI) and chemical ionization (CI) scan modes. The detection times for ketoprofen and hydroxy ketoprofen in urine after an intravenous (i.v.) dose of 3.0 mg/kg body weight was 24.00 and 70.00 h, respectively. Serum protein binding of ketoprofen at 20 microg/mL was extensive; (99.1+/-0.15%).     

Dispersion of a fluorescein dye-ampicillin mixture after intratracheal administration in calves

The pulmonary and systemic dispersion of a dye mixture after intratracheal (i.t.) administration was characterized in young dairy calves. Five calves were given i.t. injections of a fluorescein and ampicillin mixture, and were then killed at 2, 5 or 15 min after treatment. The respiratory system, nasal pharynx area, nose, liver, kidney, stomach and esophagus were removed and examined. Sections were taken from lung areas for histopathological examinations and all tissues were photographed, using floodlight and ultraviolet light. There was uniform low-grade fluorescence throughout the lung, but the greatest fluorescence followed an anterior ventral dispersion. The dye was readily absorbed from the lung into the bloodstream, causing fluorescence in the liver, bile, kidney and urine. Coughing of the calves during the injection caused some of the mixture to be expectorated and swallowed, resulting in fluorescence in the esophagus, stomach contents, and nasal pharanges, turbinates and nostrils.     

Enantiospecific ketoprofen concentrations in plasma after oral and intramuscular administration in growing pigs

Background

Ketoprofen is a non-steroidal anti-inflammatory drug which has been widely used for domestic animals. Orally administered racemic ketoprofen has been reported to be absorbed well in pigs, and bioavailability was almost complete. The objectives of this study were to analyze R- and S-ketoprofen concentrations in plasma after oral (PO) and intra muscular (IM) routes of administration, and to assess the relative bioavailability of racemic ketoprofen for both enantiomers between those routes of administration in growing pigs.

Methods

Eleven pigs received racemic ketoprofen at dose rates of 4 mg/kg PO and 3 mg/kg IM in a randomized, crossover design with a 6-day washout period. Enantiomers were separated on a chiral column and their concentrations were determined by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated and relative bioavailability (F_rel) was determined for S and R –ketoprofen.

Results

S-ketoprofen was the predominant enantiomer in pig plasma after administration of the racemic mixture via both routes. The mean (± SD) maximum S-ketoprofen concentration in plasma (7.42 mg/L ± 2.35 in PO and 7.32 mg/L ± 0.75 in IM) was more than twice as high as that of R-ketoprofen (2.55 mg/L ± 0.99 in PO and 3.23 mg/L ± 0.70 in IM), and the terminal half-life was three times longer for S-ketoprofen (3.40 h ± 0.91 in PO and 2.89 h ± 0.85 in IM) than R-ketoprofen (1.1 h ± 0.90 in PO and 0.75 h ± 0.48 in IM). The mean (± SD) relative bioavailability (PO compared to IM) was 83 ± 20% and 63 ± 23% for S-ketoprofen and R-ketoprofen, respectively.

Conclusions

Although some minor differences were detected in the ketoprofen enantiomer concentrations in plasma after PO and IM administration, they are probably not relevant in clinical use. Thus, the pharmacological effects of racemic ketoprofen should be comparable after intramuscular and oral routes of administration in growing pigs.     

The pharmacokinetics of diminazene aceturate after intramuscular administration in healthy dogs

The pharmacokinetics of diminazene aceturate following intramuscular (i.m.) administration at 4.2 mg/kg was evaluated in 8 healthy German Shepherd dogs. Blood samples were collected at 19 intervals over a period of 21 days. Diminazene plasma concentrations were measured using a validated HPLC method with UV detection and a sensitivity of 25 ng/ml. The in vitro and in vivo binding of diminazene to blood elements was additionally determined. Diminazene pharmacokinetics showed a large inter-individual variation after i.m. administration. It had a short absorption half-life (K01-HL of 0.11 +/- 0.18 h), resulting in a C(max) of 1849 +/- 268.7 ng/ml at T(max) of 0.37 h and a mean overall elimination half-life (T1/2beta) of 5.31 +/- 3.89 h. A terminal half-life of 27.5 +/- 25.0 h was measured. At 1 h after i.m. injection, 75% of the diminazene in whole blood was in the plasma fraction. The results of this study indicate that diminazene is rapidly distributed and sequestered into the liver, followed by a slower terminal phase during which diminazene is both redistributed to the peripheral tissues and/or renally excreted. It is recommended that diminazene administered i.m. at 4.2 mg/kg should not be repeated within a 21-day period.     

Enantioselective pharmacokinetics of racemic carprofen in New Zealand white rabbits

The enantioselective pharmacokinetics of single dose (2 mg/kg) racemic carprofen (CPF) were evaluated in adult New Zealand white rabbits after intravenous (i.v.) and subcutaneous (s.c.) dose. Six rabbits were utilized in a two‐way randomized crossover study and serial blood samples were collected. Plasma CPF concentrations were determined by high‐performance liquid chromatography. After i.v. and s.c. racemic CPF administration, plasma concentration–time curves were best described by a two‐compartment open model and a one‐compartment model, respectively. The S(+) CPF enantiomer predominated in plasma following both routes of administration. Mean observed clearance of R(?)‐CPF (82.17 ± 13.70 mL/h·kg) was more rapid than for S(+)‐CPF (27.92 ± 7.07 mL/h·kg; P < 0.001). T_1/2λz was shorter for R(?)‐CPF than S(+)‐CPF after both i.v. (1.03 and 2.99 h, respectively) and s.c. (1.94 and 4.14 h, respectively) dosing. Mean AUC_0→∞ ratios for R(?):S(+)‐CPF were approximately 1:3 for both routes of administration. Mean residence time of R(?)‐CPF was shorter than of S(+)‐CPF (1.06 ± 0.29 h, 3.45 ± 0.50 h; P < 0.001) and R(?)‐ and S(+)‐CPF volumes of distribution at steady state were 85.00 ± 14.42 and 94.39 ± 18.66 mL/kg, respectively after i.v. administration. The mean s.c. bioavailability [F (%)] for both R(?)‐ and S(+)‐CPF was high, 94.4 ± 22.8 and 91.0 ± 35.7%, respectively.     

Bioavailability of racemic ketoprofen in healthy horses following rectal administration.

Ketoprofen (KTP) is a chiral non-steroidal anti-inflammatory drug (NSAID) of the propionic acid class, approved by the FDA for the allevation of pain associated with musculoskeletal disorders in horses. The present study was designed to examine the bioavailability of ketoprofen enantiomers after rectal administration of the racemate to healthy horses. One gram of racemic ketoprofen was injected intravenously and administered rectally as a fat based suppository in a cross-over design study (n = 4). Blood samples were analysed for KTP enantiomers using HPLC. After IV administration, the S(+) enantiomer concentrations in plasma were higher than the R(-) enantiomer concentrations and the AUC(0-12 h) for the S(+) enantiomer was significantly higher than for the R(-) enantiomer. Following rectal administration C(max) and AUC(0-12 h) were significantly higher for the S(+) than for the R(-) enantiomer. Bioavailability after rectal administration was low. Since there was no significant difference in bioavailability between the two enantiomers, it is assumed that no pre-systemic inversion from R(-) to S(+) occurred after rectal administration of racemic KTP to horses.     

The pharmacokinetics of primaquine in calves after subcutaneous and intravenous administration

The pharmacokinetics of primaquine was studied in calves of 180–300 kg live weight. Primaquine was injected at 0.29 mg/kg (0.51 mg/kg as primaquine diphosphate) intravenously (IV) or subcutaneously (SC) and the plasma concentrations of primaquine and its metabolite carboxyprimaquine were determined by high-performance liquid chromatography. The extrapolated concentration of primaquine at zero time after IV administration was 0.50±0.48 µg/ml (mean ±SD) which decreased with an elimination half-life of 0.16±0.07 h. Primaquine was rapidly converted to carboxyprimaquine after either route of administration. The peak concentration of carboxyprimaquine was 0.50±0.08 µg/ml at 1.67±0.15 h after IV administration. The corresponding value was 0.47±0.07 µg/ml at 5.05±1.20 h after SC administration. The elimination half-lives of carboxyprimaquine after IV and SC administration were 15.06±0.99 and 12.26±3.06 h, respectively. The areas under the concentration-time curve for carboxyprimaquine were similar following either IV or SC administration of primaquine; the values were 11.85±2.62 µg.h/ml after the former and 10.95±2.65 µg.h/ml after the latter. The mean area under the concentration-time curve for primaquine was less than 0.1 µg.h/ml after either route of administration.Abbreviations AUC area under the concentration-time curve - CPRQ carboxyprimaquine - IV intravenous - 6M8AQ 6-methoxy-8-aminoquinoline - PRQ primaquine - SC subcutaneous     

Combined pharmacokinetics of gentamicin in pony mares after a single intravenous and intramuscular administration

Healthy mature pony mares (n = 6) were given a single dose of gentamicin (5 mg/kg of body weight) IV or IM 8 days apart. Venous blood samples were collected at 0, 5, 10, 20, 30, and 45 minutes and at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, 24, 30, 36, 40, and 48 hours after IV injection of gentamicin, and at 10, 20, 30, and 45 minutes and at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, 24, and 30 hours after IM injection of gentamicin. Gentamicin serum concentration was determined by a liquid-phase radioimmunoassay. The combined data of IV and IM treatments were analyzed by a nonlinear least-square regression analysis program. The kinetic data were best fitted by a 2-compartment open model, as indicated by residual trends and improvements in the correlation of determination. The distribution phase half-life was 0.12 +/- 0.02 hour and postdistribution phase half-life was 1.82 +/- 0.22 hour. The volume of the central compartment was 115.8 +/- 6.0 ml/kg, volume of distribution at steady state was 188 +/- 9.9 ml/kg, and the total body clearance was 1.27 +/- 0.18 ml/min/kg. Intramuscular absorption was rapid with a half-life for absorption of 0.64 +/- 0.14 hour. The extent of absorption was 0.87 +/- 0.14. Kinetic calculations predicted that IM injections of 5 mg of gentamicin/kg every 8 hours would provide average steady-state serum concentrations of 7.0 micrograms/ml, with maximum and minimum steady-state concentrations of 16.8 and 1.1 micrograms/ml, respectively.     

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

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

两种头孢噻呋注射液在猪体内的比较药动学研究

研究了两种头孢噻呋注射液给猪肌注后的比较药物动力学特征。选用12头健康猪随机分为两组,每组6头,分别肌注上海公谊兽药厂生产的长效盐酸头孢噻呋注射液和美国辉瑞生产的盐酸头孢噻呋注射液（速解灵注射液）,每头5mg／kg。采用超高效液相色谱法测定猪血浆中头孢噻呋的的药物浓度,用Winnonlin5．2药动学分析软件非房室模型处理药时数据,模型200处理肌注给药后的药代动力学参数。结果表明：健康猪肌注两种注射液后,参数MRT、Cmax、tmax统计差异极显著（P〈0．01）,长效盐酸头孢噻呋注射液单剂量肌注给药较速解灵注射液吸收慢,达峰时间显著延迟,达峰浓度显著降低,平均驻留时间显著延长;参数AUC、Kel、t1/2允统计无显著性差异（P〉0．05）,长效盐酸头孢噻呋注射液的相对生物利用度为98．41％,与速解灵注射液的生物利用度相当。本研究可为头孢噻呋注射液的临床合理用药提供参考。     

Enantioselective pharmacokinetics of ketoprofen in piglets: the significance of neonatal age

Following intravenous dose of 6mg/kg racemic ketoprofen, the chiral pharmacokinetics of ketoprofen was investigated in eight piglets aged 6 and 21days old. S-ketoprofen predominated over R-ketoprofen in plasma of the piglets in both age groups. The volumes of distribution of S-ketoprofen for the 6- and 21-day-old piglets were 241.7 (211.3-276.5) mL/kg and 155.0 (138.7-173.1) mL/kg, respectively, while the corresponding parameters for R-ketoprofen were 289.2 (250.3-334.2) mL/kg and 193.0 (168.7-220.8) mL/kg. The clearances of R-ketoprofen [948.4 (768.0-1171.2) mL/h/kg and 425 (319.1-566.0) mL/h/kg for the 6- and 21-day-old piglets, respectively] were significantly higher compared to the clearances of S-ketoprofen [57.3 (46.6-70.4) mL/h/kg and 33.8 (27.0-42.2) mL/h/kg for 6- and 21-day-old piglets, respectively]. The elimination half-life of S-ketoprofen was 3.4h for both age groups, while the elimination half-life of R-ketoprofen was 0.2h for the 6-day-old and 0.4h for the 21-day-old piglets. The clearances of both R- and S-ketoprofen were significantly higher in the 6-day-old piglets compared to when they were 21 days old. Furthermore, the volumes of distribution were larger in the youngest age group.     

Florfenicol pharmacokinetics in lactating cows after intravenous, intramuscular and intramammary administration

Pharmacokinetics of florfenicol 30% injectable solution was determined in lactating cows after intravenous, intramammary and intramuscular administration. Serum concentration-time data generated in the present study were analysed by non-compartmental methods based on statistical moment theory. Florfenicol half-life was 176 min, mean residence time 129 min, volume of distribution at steady-state 0.35 L/kg, and total body clearance 2.7 mL/min·kg after intravenous administration at 20 mg/kg. The absorption after intramuscular administration appeared slow and the kinetic parameters and the serum concentration vs. time curve were characteristic of absorption rate-dependent elimination. The absorption after intramammary administration of florfenicol at 20 mg/kg was good (53.9%) and resulted in serum concentrations with apparent clinical significance. The intramammary administration resulted in serum florfenicol concentrations that were significantly higher than the respective serum concentrations following Intravenous administration 4 h after administration and thereafter. Florfenicol absorption was faster from the mammary gland than from the muscle. The maximum serum concentrations ( C _max) were 6.9 μg/mL at 360 min after intramammary administration and 2.3 μg/mL at 180 min after intramuscular administration. The bioavailability of florfenicol was 54% and 38% after intramammary and intramuscular administration, respectively. The C _max in milk was 5.4 μg/mL at 180 min after intravenous and 1.6 μg/mL at 600 min after intramuscular administration.     

Pharmacodynamics and pharmacokinetics of flumequine in pigs after single intravenous and intramuscular administration

The pharmacokinetics and intramuscular (IM) bioavailability of flumequine (15 mgkg(-1)) were investigated in healthy pigs and the findings related to published minimal inhibitory concentrations (MICs) for susceptible bacteria of animal origin, and to experimentally determined MICs for susceptible strains of porcine origin. We found MICs for Escherichia coli, Salmonella spp., Pasteurella spp. and Bordetella spp. in the range 0.5 to >64 microg mL(-1) isolated from infected pigs in the Forli area of Italy; only the Pasteurella multocida strains were sensitive (MIC(90)=0.5 microg mL(-1)). After intravenous (IV) injection, flumequine was slowly distributed and eliminated (t(1/2lambda(1))1.40+/-0.16 h and t(1/2lambda(2))6.35+/-1.69 h). The distribution volume at steady state (V(dss)) was 752.59+/-84.03 mL kg(-1) and clearance (Cl(B)) was 237.19+/-17.88 mL kg(-1)h(-1). After IM administration, peak serum concentration (4.99+/-0.92 microg mL(-1)) was reached between the 2nd and the 3rd hour. The results on MIC of isolated bacteria, although only indicative, suggest that the efficacy of flumequine on Gram-negative bacteria may be impaired by the emergence of less sensitive or resistant strains.     

Clinical pharmacokinetics of norfloxacin-glycine acetate after intravenous and intramuscular administration to horses

The pharmacokinetic properties of norfloxacin-glycine acetate (NFLXGA) were determined in six horses following a single intravenous (i.v.) and intramuscular (i.m.) dose of 4 mgkg(-1) body weight. Following i.v. and i.m. administration, the plasma drug concentrations were best fitted by an open two-compartment model with a rapid distribution phase. After i.v. NFLXGA administration, the distribution (t(1/2alpha)) and elimination half-life (t(1/2beta)) were 0.42 (0.05) and 5.44 (1.36)h. The volume of distribution of NFLXGA at steady state (Vd(ss)) was 2.19 (0.53) Lkg(-1). After NFLXGA i.m. administration, the maximal absorption concentration (C(max)) was 0.44 (0.04) microgml(-1) at 0.86 (0.15)h (T(max)). The mean absorption (t(1/2ka)) and elimination half-life (t(1/2beta)) of NFLXGA were 0.27 (0.07) and 9.47 (2.24)h, respectively. The mean systemic bioavailability (F) following i.m. administration was 55 (12)%. The optimal dosage for each administration route was calculated from the pharmacokinetic data on the basis of the area under the inhibitory plasma concentration-time curve (AUIC) every 24h and was found to be 13.36 and 7.35 mgkg(-1) for i.m. and i.v. administration, respectively.     

Pharmacokinetics of an ampicillin-sulbactam combination after intravenous and intramuscular administration to neonatal calves

The pharmacokinetics of a 2:1 ampicillin-sulbactam combination after intravenous (i.v.) and intramuscular (i.m.) injection at a single dose rate of 20 mg/kg bodyweight (13.33 mg/kg of sodium ampicillin and 6.67 mg/kg of sodium sulbactam) were studied in 10-day-old neonatal calves (n = 10). The plasma concentration-time data of both antibiotics were best fitted to an open two-compartment model after i.v. administration. After i.m. administration, an open two-compartment model demonstrated first order absorption. The apparent volumes of distribution of ampicillin and sulbactam, calculated by the area method, were 0.20+/-0.01 and 0.18+/-0.01 L/kg, respectively, and the total body clearances were 0.51+/-0.03 and 0.21+/-0.01 L/kg h. The elimination half-lives of ampicillin after i.v. and i.m. administration were 0.99+/-0.03 and 1.01+/-0.02 h, respectively, whereas for sulbactam the half-lives were 2.24+/-0.02 and 3.44+/-0.94 h. The bioavailability after i.m. injection was high and similar for both drugs (70.31+/-0.2% for ampicillin and 68.62+/-4.44% for sulbactam). The mean peak plasma concentrations of ampicillin and sulbactam were reached at similar times (0.47+/-0.02 and 0.72+/-0.01 h, respectively) and peak concentrations were also similar but not proportional to the dose administered (17.88+/-0.91 mg/L of ampicillin and 12.92+/-0.79 mg/L of sulbactam). Both drugs had similar pharmacokinetic behaviour after i.m. administration. Since the plasma concentrations of sulbactam were consistently higher during the elimination phase of their disposition, consideration could be given to formulating the ampicillin-sulbactam combination in a ratio higher than 2:1.