Compartment Open Model Research Articles

Pharmacokinetics of Marbofloxacin following Intramuscular Administration in Rabbits

Pharmacokinetic study of marbofloxacin was carried out in healthy rabbits following intramuscular administrations for five days. Blood samples were collected on 1st and 5th day of marbofloxacin administration. Concentrations of the marbofloxacin in blood plasma were estimated by microbiological assay. Kinetic parameters were calculated by using one compartment open model. Apparently higher plasma concentrations of the drug appeared at all intervals from 2.5 min to 24 h on 5th day as compared to 1st day of marbofloxacin administration with significant differences at 10.0 min and 12 h only. The minimum therapeutic concentration (≥ 0.25 µg/mL) of marbofloxacin was maintained up to 12 h and all kinetic parameters differ non-significantly between 1st and 5th day of marbofloxacin administration. On the basis of present findings, a satisfactory dosage regimen of marbofloxacin @ 2.14 mg/kg body weight followed by 2.04 mg/kg body weight intramuscular route at 24 h intervals can be recommended to maintain the minimum therapeutic concentration (≥ 0.25 µg/mL) during the treatment of bacterial infections in rabbit.

Pharmacokinetics of ceftiofur sodium after intravenous and subcutaneous administration in pre-weaned calves

The current work was outlined to decide kinetic profile and bioavailability of ceftiofur sodium at measurements of 2.2 mg/kg. b.wt. after a single intravenous and subcutaneous injection in pre-weaned calves. Five clinically typical pre-weaned calves were utilized in this work. Serum ceftiofur concentrations were decided by utilizing high performance liquid chromatography (HPLC) strategy. The serum concentration-time curve has shown a two compartment open model. Taking after a single intravenous injection, distribution half-life (t0.5α) was 0.11 ± 0.01h, volume of distribution (Vdss) was 0.16 ± 0.004 L/kg, elimination half-life (t0.5β) was 11.07 ± 0.12h and total body clearance (CLtot) was 0.013 ± 0.005 L/kg/h. Taking after a single subcutaneous organization, ceftiofur had a peak serum concentration (Cmax) 6.64 ± 0.08 μg/ml at a time (tmax) of 3.38 ± 0.069 h, disposal half-life (t0.5el) was 2.11 ± 0.25h demonstrating the propensity of calves to eliminate ceftiofur in slow rate. Bioavailability was 77.04 ± 1.64% after subcutaneous injection indicating a good absorption of ceftiofur. Ceftiofur serum concentrations along 36 h following subcutaneous injection in the current work were exceeding the MICs of different susceptible microorganisms responsible for serious disease problems. These results demonstrating successful use of ceftiofur in pre-weaned calves.

Systematically Optimized Imiquimod-Loaded Novel Hybrid Vesicles by Employing Design of Experiment (DoE) Approach with Improved Biocompatibility, Stability, and Dermatokinetic Profile.

The present research work explored the possibility of harnessing the benefits of vesicular carriers for overcoming imiquimod-associated complaints or side effects. Hybrid vesicles were prepared by the most common and easily scalable method, i.e., thin film hydration. The chaffing of myriad of factors, both process and material related, affecting the desirable attributes of conceived vesicles, was performed through Taguchi design. Based upon the analysis of Pareto chart and prior experiences, concentration of phospholipid and poloxamer 407 was selected for optimization by 2 levels, 13 run central composite design (CCD). The optimized hybrid vesicles contained 1% w/v phospholipid and 3% w/v poloxamer 407. The optimized hybrid vesicles were incorporated into the 3% w/v carbopol 940 gel and characterized for morphology, physicochemical properties, and rheological behavior. The release (%) and skin retention (% of total dose) across rat skin from gel at same amount of formulation was more than Imiquad®. The gel delivered the loaded cargo, preferably, in the viable region of skin and formed local depot in confocal microscopic studies. The gel followed one compartment open body dermatokinetic model in rat skin. There was not any harmful effect on the mice skin after repeated applications. The gel was stable at room conditions for 1year.

Pharmacokinetics of cefquinome after single intramuscular administration in dromedary camel (Camelus dromedarius)

The objective of this study was to investigate the pharmacokinetics of cefquinome in 5 healthy male dromedary camels following a single intramuscular (IM) administration at the dose rate of 1 mg/kg body weight in the caudal cervical epiaxial muscles. Blood samples were collected prior to drug administration and up to 48 h after drug administration. No clinical symptoms or signs suggestive of adverse drug reaction could be recorded in any animal. Plasma cefquinome concentration was estimated by high-performance liquid chromatography. The disposition kinetics of cefquinome best fitted to a 2 compartment open model. The peak plasma cefquinome concentration (Cmax cal) of 1.013 ± 0.038 μg/ml−1 was achieved at 5.257 ± 0.067 h (tmax cal). The absorption half-life (t½ka), elimination half-life (t½β), area under plasma drug concentration-time curve (AUC) and apparent volume of distribution (Vdarea) of cefquinome were 3.401 ± 0.042 h, 3.754 ± 0.072 h, 14.417 ± 0.621 μg/ml−1 h and 0.379 ± 0.016 l/kg−1, respectively. The results of the present study suggested that an intramuscular dosage regimen of 1 mg/kg body weight at 24 h interval would maintain the plasma drug levels required to be effective against the common bacterial pathogens in dromedary camel.

The distribution and excretion of 1-Methylnaphthalene in rats exposed to 1-Methylnaphthalene by inhalation

1-Methylnaphthalene (1-MN) is a constituent of polycyclic aromatic hydrocarbons, the chemicals that have become ubiquitous in the environment as result of natural and industrial process. This paper reports a study on the distribution and excretion of 1-MN in rats after single and repeated inhalation exposure to 1-MN vapor. Male Wistar rats were exposed to 1-MN vapor at nominal concentrations of 50 mg/m3 or 200 mg/m3 in the dynamic inhalation chambers (TSE Systems Head Nose Only Exposure) for 6 h (single exposure) or 5 days (6 h/day, repeated exposure). Blood, urine and tissue samples were collected during and after the exposure. Blood, urine and tissue concentrations of 1-MN were estimated by gas chromatography using the headspace technique. The elimination of 1-MN from blood followed an open 2-compartment model. The concentration in rat tissues was dependent on the magnitude and time of exposure. After repeated exposure, the concentration 1-MN in tissue decreased in comparison to single exposure. The elimination of 1-MN with urine after single and repeated exposure to 1-MN occurred mainly in the samples collected during the first day of collection. 1-Methylnaphthalene was rapidly eliminated from the blood and tissues of animals exposed by inhalation to 1-MN. In repeated exposure, there was probably a significant increase of 1-MN metabolism in rats exposed to low and high 1-MN doses. Under conditions of repeated 1-MN exposure, no significant systemic 1-MN accumulation could be observed. Int J Occup Med Environ Health 2018;31(6):763-770.

A Deeper Insight into Pharmacokinetics of Drugs Following one Compartment Model

This article discusses the mathematical pharmacokinetic models with reference to one open compartment model in detail. Four types of models, IV, bolus, extravascular 1st and 0 order, have been studied. Mathematical approaches to predict the pharmacokinetic parameters, including elimination half-life, rate constant and drug clearance, have been included. This article focuses on the significance of one open compartment model to study the distribution and elimination of drugs in the body beforehand, to determine whether the drugs under study should proceed to clinical trials or not. Thus, the prediction of the pharmacokinetics of the drug at an earlier stage with the help of this mathematical model saves time and cost during drug and discovery and drug development.

Population pharmacokinetics of teicoplanin in hospitalized elderly patients using cystatin C as an indicator of renal function

Serum cystatin C (CysC) has recently been proposed as an alternative marker to serum creatinine (SCR) for estimating renal clearance. In the present study, we performed a population pharmacokinetic analysis of teicoplanin (TEIC), which is mainly eliminated through the kidneys, using CysC as a predictor for renal clearance. Thirty-six patients with MRSA infections who were administrated to the National Hospital Organization Beppu Medical Center between January 2012 and December 2013 were enrolled and gave 123 sets of blood TEIC concentration data. Renal clearance was estimated by the Hoek equation using CysC, by creatinine clearance predicted by the Cockcroft-Gault equation using SCR, or directly by CysC. One compartment open model with inter-individual variabilities for renal clearance and the volume of distribution as well as an additional residual error model was used to estimate population pharmacokinetic parameters for TEIC. The model with the best predictability was that with CysC as a predictor for renal clearance; it showed better significance than the models using estimated the glomerular filtration rate by the Hoek equation or CLcr. The final model was as follows: CL (L/hr)=0.510×(CysC/1.4)-0.68×Total body weight/600.81, omega (CL)=19.8% CV, VC (L)=78.1, omega (V)=42.7% CV. The present results show the usefulness of CysC to more accurately predict the pharmacokinetics of drugs mainly eliminated through the kidneys, such as TEIC. However, since the sample size in this study was relatively small, further investigations on renal clearance predictability using CysC are needed.

Pharmacokinetics of thiamphenicol in normal and pasteurella multocida infected lactating goats

The pharmacokinetic parameters of thiamphenicol following intravenous and intramuscular (single & repeated) administrations were estimated in normal and experimentally pasteurella multocida infected goats. Following a single intravenous injection of 30 mg thiamphenicol /kg b.wt. in normal goats, thiamphenicol could be detected therapeutically for 24 hours post intravenous injection. The serum concentration – time curve of thiamphenicol following intravenous injection showed that the drug obeyed a two compartments open model. The intramuscular bioavailability of thiamphenicol in normal goats was 66.63 %. Intramuscular injection of 30 mg thiamphenicol per kilogram body weight once daily for five consecutive days in normal and pastreulla multocida infected goats revealed a lower significant serum thiamphenicol concentration in pastreulla multocida infected goats compared with normal goats, also it’s found that: marked significant decrease in ( k1, K12, K21, T0.5(α) , T0.5(β), Tmax and CLtot in normal compared with infected goats, on the other hand a significant increase in Cmax,AUC, C0,B and β in normal compared with infected goats. Thiamphenicol was cleared by all clearance processes (Cltot) in the body at significant faster rates in Pasteurella multocida infected goats than in normal goats. The concentrations of thiamphenicol in milk were significantly lower in Pasteurella multocida infected goats than in normal goats. The mean peak urine concentrations of thiamphenicol were reached 4 hours after each intramuscular dose with a lower significant concentration in Pasteurella multocida infected goats than in normal goats.

Bioequivalence study of two oral amoxicillin formulations (Biocillin® and Atcomox 87%®) in broiler chickens

Background: The present study was designed to assess the comparative bioequivalence of Biocillin® and Atcomox87%® in healthy broiler chickens after oral administration of both products in a dose of 20 mg amoxicillin base/kg.b.wt.Methods: Twenty-four broiler chickens were divided into two groups. The first group was designed to study the pharmacokinetics of Biocillin®, while the 2nd group was designed to study the pharmacokinetics of Atcomox87%®. Each broiler chicken in both groups was injected intravenously with 20 mg amoxicillin pure standard/kg.b.wt. After 15 days both groups taken orally Biocillin® and Atcomox87%®, respectively. Blood samples were obtained from the wing vein and collected immediately before and at 0.08, 0.16, 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours after a single intravenous or oral administration.Results: Amoxicillin in both products obeyed a two compartments open model following I.V. injection. The disposition kinetics of Biocillin® and Atcomox87%® following oral administration of 20 mg amoxicillin base/kg.b.wt. revealed that the maximum blood concentration [Cmax] were 10.79 and 10.30 μg/ml and attained at [tmax] of 0.90 and 0.86 hours, respectively. The mean systemic bioavailability of amoxicillin in Biocillin® and Atcomox 87%® after oral administration in healthy chickens was 64.15 and 65.54%, respectively.Conclusions: Atcomox 87%® is bioequivalent to Biocillin® since the ratios of Cmax, AUC0-24 and AUC0-∞ (T/R) were 0.95, 0.91 and 0.90 respectively. These are within the bioequivalence acceptance range. Biocillin® and Atcomox87%® are therefore bioequivalent and interchangeable.

Bioavailability, pharmacokinetics and tissue residues of cephradine (Atocef Forte®) in healthy and colisepticemic broiler chickens

The pharmacokinetics (after single intravenous and oral dose) and tissue residues (orally and daily for five days) of cephradine (20 mg/kg b.wt.) were investigated in healthy and experimentally E.coli infected broiler chickens. Following single intravenous injection to healthy chickens, cephradine obeyed a two compartments open model and the elimination half-life (t1/2β), volume of distribution (Vdss) and total body clearance (CLtot) of cephradine were 2.93 h, 321.5 ml/kg and 0.08 L/h/kg, respectively. Following single oral administration of cephradine to healthy chickens, the peak serum concentration (Cmax) of it was 26.7 µg/mL and achieved (Tmax) at 2.41 h. The oral bioavailability of cephradine was 87.7%. Cephradine was assayed in kidney, liver, heart, gizzard, spleen, breast muscle, thigh muscle and skin after 24, 48, 72, 96 and 120 h after last dose. On conclusion, cephradine is a good choice for treatment of colisepticemia in chickens due to its higher oral bioavailability and distribution.

Pharmacokinetic studies of the recombinant chicken interferon-α in broiler chickens.

In this study, 24 male and female broiler chickens at 30-day-old were divided into three groups with 8 animals in each group. The animals were administered with recombinant chicken interferon-α (rChIFN-α) at a dose of 1.0 × 106 IU/kg intravenously, intramuscularly or subcutaneously, respectively. Serum samples were collected at different time points post administration, and the titers of rChIFN-α in the blood were determined by cytopathic effect inhibition assay. The results showed that the pharmacokinetic characteristics of rChIFN-α by intramuscular injection and subcutaneous injection were fitted to one compartment open model, and the Tmax was 3.21 ± 0.79 hr and 3.95 ± 0.85 hr, respectively, and the elimination half-life (T1/2) was 6.20 ± 2.77 hr and 5.03 ± 3.70 hr, respectively. In contrast, the pharmacokinetics of rChIFN-α via intravenous injection was in line with the open model of two-compartment and was eliminated in the first order, and the elimination half-life (T1/2) was 4.61 ± 0.84 hr. In addition, compared with those in the intravenous group and the subcutaneous group, the bioavailability of rChIFN-α in the intramuscular group was 82.80%. In conclusion, rChIFN-α was rapidly absorbed and slowly eliminated after intramuscular administration of single dose of rChIFN-α aqueous formulations. Thus, rChIFN-α can be used as a commonly-used therapeutic agent.

Pharmacokinetics of lincomycin following intravenousadministration in febrile goats

Disposition of antimicrobials is known to be altered during disease conditions and fever is one of the common manifestations of bacterial infections in animals. The disposition of lincomycin (10 mg/kg, IV) during Echerichia coli endotoxin-induced fever in goats followed two compartment open model and drug was detected in plasma up to 8 h. The high AUC (39.5±6.21 mg.h/mL) indicated good antibacterial activity of lincomycin in goats. The volume of distribution and total body clearance were 3.35±0.45 L/kg and 0.28±0.03 L/h/kg, respectively. The long elimination half life 9.93± 2.83 h indicated persistence of drug for longer period in body. Lincomycin, is suggested to be repeated at 24 h interval for organisms sensitive to lincomycin having MIC up to 0.6 µg/mL for the treatment of bacterial infections manifested with fever in goats.

Bioavailability pharmacokinetics and residues of marbofloxacin in normal and E.coli infected broiler chicken

The pharmacokinetics of marbofloxacin was studied following a single intravenous, oral administration in normal broiler chickens and repeated oral administrations in normal and experimentally E.coli infected broiler chickens. The pharmacokinetic parameters following a single intravenous injection of 2 mg/kg b.wt., revealed that marbofloxacin obeyed a two compartments open model, distribution half-life (t0.5(α)) was 0.25±0.02 h, volume of distribution (Vdss) was 0.76±0.08 L/kg, elimination half-life (t0.5(β)) was 5.43±0.87 h and total body clearance (CLtot) was 0.09±0.002 l/kg/h. Following a single oral administration, marbofloxacin was rapidly and efficiently absorbed through gastrointestinal tract of chickens as the absorption half-life (t0.5 (ab): 0.62±0.02 h). Maximum serum concentration (Cmax) was 1.15±0.01 μg/ml, reached its maximum time (tmax) at 2.53±0.04 h, elimination half-life (t0.5 (el)) was 7.36±0.20 h indicating the tendency of chickens to eliminate marbofloxacin in slow rate. Oral bioavailability was 73.57± 1.90 % indicating good absorption of marbofloxacin after oral administration. Serum concentrations of marbofloxacin following repeated oral administration of 2 mg/kg b.wt. once daily for five consecutive days, peaked 2 hours after each oral dose with lower significant values recorded in experimentally infected broiler chickens than in normal ones. Tissues residues of marbofloxacin in slaughtered normal chickens was highly in those tissues lung, liver, and kidneys in chickens and the chicken must not be slaughtered before 3 days of stopping of drug administration. It was concluded that the in- vitro protein binding was 12.33±0.82%.

Determination of Ginkgolides A, B, C, J and Bilobalide in Plasma by LC-ESI (-)/MS/MS (QQQ) and its Application to the Pharmacokinetic Study of Ginkgo Biloba Extract in Rats.

A simple, rapid, and specific high-performance liquid chromatograph coupled with a tandem mass spectrometry method has been developed and validated for the quantification of ginkgolides in rat plasma, and the main pharmacokinetic parameters of ginkgolides after oral administration of Ginkgo biloba extract (GBE) was acquired. Methods: Plasma samples were pretreated with ethyl acetate extraction. Sulfamethoxazole was used as the internal standard (IS). Chromatographic separation was achieved on an Eclipse XDB-C18 column (2.1 mm×150 mm, 5 μm) with a mobile phase consisting of methanol/0.1% formic acid water (gradient elution: 0~25 min (77:23)→(60:40), V/V) at a flow rate of 0.3 mL·min-1. The detection was performed on a triple quadruple tandem mass spectrometer using an electrospray ionization (ESI) source for 25 min. The detection was operated by multiple reaction monitoring(MRM) under negative ionization mode of the transitions of m/z 325→163 for BB, 469→423 for GJ, 439→125 for GC, 453→351 for GA, 423→367 for GB and of m/z 252→156 for sulfamethoxazole (IS) respectively. Results: The pharmacokinetic properties of BB, GJ, GA, GB and GC were in line with the open 2-compartment model after oral administration of GBE in rats; The pharmacokinetic parameters of various lactones were calculated, and drugs-time curve and the curve fitting diagram of 5 ginkgolides were drew; The absorption and distribution rate of BB, GJ, GA, GB and GC were fast in rats in vivo, and half-life of absorption was less than 3 h. Conclusion: The developed LC-ESI (-)/MS/MS (QQQ) method was successfully applied to assess the pharmacokinetic parameters and oral bioavailability of ginkgolides in rats after administration of GBE, which can provide basis for further clinical efficacy studies.

Abstract 2049: Pharmacokinetic drug-drug interaction: a phase Ib dose escalation study of LY2780301 in combination with weekly paclitaxel

Abstract Introduction: LY2780301 is an orally available small molecule dual inhibitor of p70 S6 kinase and AKT. LY2780301 is an inhibitor of CYP3A4. By the one hand, Paclitaxel (PXL) undergoes extensive metabolism via CYP450 2C8 and CYP450 3A4 pathways. By the other hand, PXL induces weakly CYP3A4 activity. In this study we investigated for the first time, the potential pharmacokinetic (PK) drug-drug interaction (DDI) related to the combination of both drugs LY2780301 and PXL. Methods: Women with HER2- locally advanced or metastatic breast cancer, with and without PI3/AKT pathway activation, were treated with weekly administration of PXL on day1 (D1), D8 and D15. LY2780301 was administered by a daily flat dosing regimen starting at D3. Dose levels [DL, LY2780301 (mg/day)/PXL (mg/m2/week)] ranged from 400/70 to 500/80. For PK analysis, 7 time point samples were collected on D1 and D3 of cycle 1 for PXL and LY2780301 respectively. 7 samples were collected on D8 for both drugs. LY2780301 plasma concentrations were measured using Ultra Performance Liquid Chromatography (UPLC) coupled with tandem mass spectrometry validated method. PXL plasma concentrations were measured using UPLC coupled with UV validated method. A joint population PK (PK-POP) model has been developed for LY2780301 and its main metabolite. PK-POP modelling has been performed with a non linear mixed effect model program (Monolix version 4.3.2). Results: 12 patients, 35 to 67 years old, were treated. A total of 160 and 157 concentrations for LY2780301 and its metabolite were used respectively for PK-POP modeling. A one compartment open model adequately described LY2780301 and its metabolite concentration versus time courses respectively with the estimation of the fraction of absorbed dose (fm) of LY2780301 metabolised in that metabolite. The interindividual variabilities (ISV) could be well estimated for all structural parameters (clearance: CL, volume of distribution: V, L and the absorption constant: Ka). The population PK parameters obtained for the structural model were: Ka = 0.536 h−1, CL/F = 3.57 L/h, V/F = 85.2 L, CL/(F*fm) = 13.2 L/h, V2/(F*fm) = 13.2 L, fm = 0.747 for LY2780301 and its metabolite respectively. PXL increases LY2780301 CL from 3.57 to 4.4 L/h (p = 0.016). Conclusions: We have demonstrated a PK DDI between LY2780301 and PXL. PXL increases LY2780301 CL and decreases LY2780301 AUC. PXL PK modeling is ongoing in order to verify the effect of LY2780301 on PXL PK. Citation Format: Keyvan Rezai, Samuel Huguet, Olivier Madar, Jean-Marc Extra, Magali Provansal, Carole Tarpin, Nicolas Isambert, Jihane Pakradouni, Anthony Goncalves, François Lokiec. Pharmacokinetic drug-drug interaction: a phase Ib dose escalation study of LY2780301 in combination with weekly paclitaxel. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2049.

Relevance of the Pharmacokinetic and Pharmacodynamic Profiles of Puerariae lobatae Radix to Aggregation of Multi-Component Molecules in Aqueous Decoctions.

The complexity of traditional Chinese medicines (TCMs) is related to their multi-component system. TCM aqueous decoction is a common clinical oral formulation. Between molecules in solution, there exist intermolecular strong interactions to form chemical bonds or weak non-bonding interactions such as hydrogen bonds and Van der Waals forces, which hold molecules together to form “molecular aggregates”. Taking the TCM Puerariae lobatae Radix (Gegen) as an example, we explored four Gegen decoctions of different concentration of 0.019, 0.038, 0.075, and 0.30 g/mL, named G-1, G-2, G-3, and G-4. In order of molecular aggregate size (diameter) the four kinds of solution were ranked G-1 < G-2 < G-3 < G-4 by Flow Cell 200S IPAC image analysis. A rabbit vertebrobasilar artery insufficiency (VBI) model was set up and they were given Gegen decoction (GGD) at a clinical dosage of 0.82 g/kg (achieved by adjusting the gastric perfusion volume depending on the concentration). The HPLC fingerprint of rabbit plasma showed that the chemical component absorption into blood in order of peak area values was G-1 < G-2 > G-3 > G-4. Puerarin and daidzin are the major constituents of Gegen, and the pharmacokinetics of G-1 and G-2 puerarin conformed with the two compartment open model, while for G-3 and G-4, they conformed to a one compartment open model. For all four GGDs the pharmacokinetics of daidzin complied with a one compartment open model. FQ-PCR assays of rabbits’ vertebrobasilar arterial tissue were performed to determine the pharmacodynamic profiles of the four GGDs. GGD markedly lowered the level of AT1R mRNA, while the AT2R mRNA level was increased significantly vs. the VBI model, and G-2 was the most effective. In theory the dosage was equal to the blood drug concentration and should be consistent; however, the formation of molecular aggregates affects drug absorption and metabolism, and therefore influences drugs’ effects. Our data provided references for the rational use of Chinese medicines in the clinic, such as the best oral preparation and decoction concentration.

Influence of Circulation System on Estimation of Absorption and Elimination Constant after per oral Drug Administration: A Reanalysis.

This study aimed to identify the cause of atypical shape of measured concentration-time profile in the peak area by one compartment open model with a lag time (Bateman function with a lag) after single dose oral administration of drug published in "Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts and Application" by Gabrielsson and Weiner (1997) and two concentration profiles after frequent sampling oral glucose tolerance test. Following the oral administration of 100 μg of substance A to human volunteer, frequent sampling was carried out and concentration-time profiles were obtained. Our hemodynamic circulatory structural model capable of parameters estimation of circulation and gastrointestinal subsystem to explain the plateau within the interval 40-100 min (substance A) and 15-30 min (glucose) of the measured concentration-time profile was developed. The mean residence time, the rate constants of absorption and elimination parameters of our model were calculated. Comparing to the Bateman function, our results demonstrate better approximation of the substance A and glucose concentration-time profile and estimation of absorption rate constant by our structural model. Obtained model results indicate that the atypical shape of measured concentration-time profile of single dose oral administration of drug was probably caused by the gastrointestinal and circulation system with deep compartment. This applies to the substances with high coefficient of absorption.

Pharmacokinetic Study of Ceftriaxone Alone and With Probenecid in Febrile Goats

Ceftriaxone (CTA), a third generation cephalosporin, is being used extensively in animal practice. CTApharmacokinetics has not been investigated with probenecid (PB) in febrile goats. In this investigation, pharmacokinetic properties and dosage regimen of CTA alone (50 mg/kg body weight) and with PB (1 g, orally) were studied in febrile goats. Blood samples were collected into heparinized tubes at predetermined time intervals after administration of the drug. Plasma concentrations of CTA were determined by the UV-detector, attached to high performance liquid chromatography. The plasma concentrations of CTA alone and with PB were detected up to 6 and 8 h, respectively. The plasma concentrations versus time data of CTA were adequately described by a two compartment open model. The pharmacokinetic properties (maximum plasma concentration-Cp max, totalbodyclearance-Cl, totalareaunderthetimeconcentrationcurve-AUC B and mean residence time-MRT) differed significantly (P<0.01) between CTA alone and with PB. The elimination of the drug tends to be faster in CTA alone treated goats. The Cp max of CTA alone and with PB in goats was 133.67±1.62 and 246.04±1.20 μg/ml, respectively. The elimination halflife (t½ β) of CTA alone was lower (0.98±0.02 h) as compared to PB (1.35±0.02 h) treated goats. A suitable intravenous dosage regimenfor CTA with PB was calculated as 1mg/kg bodyweight and repeated at 6 h intervals in febrile goats.

Comparative pharmacokinetics of cefoperazone following intravenous and intramuscular administration in goats

The pharmacokinetic profile of cefoperazone was studied in goats following intravenous and intramuscular administration of 20mg/kg body weight. Cefoperazone concentrations in serum were determined by microbiological assay technique using Escherichia coli (ATCC 10536) as test organism. Following i.v. administration, the cefoperazone serum concentration–time curve was best fitted in a two compartment open model. Cefoperazone has moderate distribution in the body of goats with Vdss of 0.44±0.03L/kg. The elimination half-life (T0.5(β)), area under curve (AUC) and total body clearance (Cltot) were 1.97±0.14h, 149.63±8.61μgml−1h−1, and 2.17ml/min/kg, respectively. Following i.m. administration, the drug was very rapidly absorbed, with an absorption half-life (T0.5(ab)) of 0.12±0.01h. The maximum serum concentration (Cmax) of 30.42±3.53μgml−1 was attained at (Tmax) 0.58±0.02h, with an elimination half-life (T0.5(el)) of 2.53±0.11h. The systemic bioavailability of cefoperazone in the goats after i.m. administration was 83.62% and in vitro protein binding was 20.34%. The serum concentrations of cefoperazone along 12h post i.m. injection in this study were exceeding the MIC of different susceptible micro-organisms responsible for serious disease problems. Consequently, a suitable intramuscular dosage regimen for cefoperazone was 20mg/kg repeated at 12h intervals in goats. The drug was detected in urine up to 12 and 18h following i.v. and i.m. administration, respectively.

Enrofloxacin kinetics in hemolymoh of the freshwater crayfish Astacus leptodactylus following bath administration

The purpose of this study was to investigate the hemolymph kinetics of enrofloxacin (ENR) following bath immersion administration in freshwater crayfish Astacus leptodactylus. A bath immersion concentration of 30 mg/l for 24h was used in this study. Hemolymph was collected from medicated crayfish prior to, and at 30 min, 1, 2, 4, 6, 12, 24, 48, 96, 144 and 192 h after bath exposure to the drug. The concentration of ENR in hemolymph was determined using a microbiological assay. The hemolymph concentrations of ENR after bath immersion dosing were best described by a two- compartment open model. The mean peak hemolymph concentration (C max) was 6 μg/ml. The elimination half-life of the terminal part of the elimination phase (T1/2β ) was obtained to be 38.5 h. The mean hemolymph concentration of enrofloxacin at 196 h post dosing easily exceeds the in vitro minimum inhibitory concentration (MIC) for most bacterial pathogens infecting fish and shrimp. Results from the present study suggest that it is possible and practical to obtain therapeutic hemolymph concentration of ENR in the Astacus leptodactylus using bath immersion administration.