Two-compartment Open Model Research Articles

Effect of three anticoccidials on pharmacokinetics of tilmicosin in broiler chickens

The disposition kinetic of tilmicosin (25mg/kg) was studied following oral administration alone, pretreated with amprolium (240 ppm), pretreated with diclazuril (2.5 ppm) and pretreated with toltrazuril (25 ppm) in broiler chickens. The serum tilmicosin concentrations were determined by microbiological assay technique using Bacillus subtilis (ATCC 6633) as the test organism. Following oral administration of tilmicosin, the disposition curve was best described by two-compartment open model. The maximum serum concentration (Cmax) was 1.90 ± 0.11, 1.27 ± 0.13, 1.50 ± 0.14 and 1.41 ± 0.11µg/ml for tilmicosin alone and in the presence of amprolium, diclazuril and toltrazuril, respectively. The elimination half-life (T0.5 (el)) was significantly decreased (5.28 ± 0.30, 5.88 ± 0.33, 6.03 ± 0.25 h, respectively) in amprolium, diclazuril and toltrazuril pretreated broiler chicken compared to tilmicosin alone (7.30 ± 0.41 h). The outcomes illustrated a significant decrease in the interval between doses in amprolium, diclazuril and toltrazuril pretreated broiler chicken compared to tilmicosin alone. Amprolium diclazuril and toltrazuril, resulted in a significance decrease in AUC (12.02 ± 1.14, 15.50 ± 1.26 and 14.56 ± 1.46 µg.h.ml-1, respectively) compared to tilmicosin alone (21.98±1.83 µg.h.ml-1). It is concluded that the administration of amprolium, diclazuril and toltrazuril before tilmicosin would altered its pharmacokinetic profile in broiler chicken.

Pharmacokinetics and distribution in interstitial and pulmonary epithelial lining fluid of danofloxacin in ruminant and preruminant calves.

The objective of this study was to compare active drug concentrations in the plasma vs. different effector compartments including interstitial fluid (ISF) and pulmonary epithelial lining fluid (PELF) of healthy preruminating (3-week-old) and ruminating (6-month-old) calves. Eight calves in each age group were given a single subcutaneous (s.c.) dose (8mg/kg) of danofloxacin. Plasma, ISF, and bronchoalveolar lavage (BAL) fluid were collected over 96h and analyzed by high-pressure liquid chromatography. PELF concentrations were calculated by a urea dilution assay of the BAL fluids. Plasma protein binding was measured using a microcentrifugation system. For most preruminant and ruminant calves, the concentration-time profile of the central compartment was best described by a two-compartment open body model. For some calves, a third compartment was also observed. The time to maximum concentration in the plasma was longer in preruminating calves (3.1h) vs. ruminating calves (1.4h). Clearance (CL/F) was 385.15 and 535.11mL/h/kg in preruminant and ruminant calves, respectively. Ruminant calves maintained higher ISF/plasma concentration ratios throughout the study period compared to that observed in preruminant calves. Potential reasons for age-related differences in plasma concentration-time profiles and partitioning of the drug to lungs and ISF as a function of age are explored.

Abstract 2036: A phase Ib pharmacokinetic drug-drug interaction evaluation of oral buparlisib in combination with lapatinib in HER2+/PI3K-activated, trastuzumab-resistant locally advanced, recurrent and metastatic breast cancer (MBC)

Abstract Background: A novel combination of oral lapatinib (LPT), a selective dual ErbB1/ErbB2 targeted drug, + oral buparlisib (B) a pan-class I PI3K inhibitor, could provide a synergestic antitumor activity in trastuzumab resistant disease. LPT has been shown to be a potent CYP3A4 inhibitor which is also mainly involved in BKM120 metabolism. In this study we investigated the potential pharmacokinetic (PK) drug-drug interactions (DDI) related to the association of B and LPT. Methods: Trastuzumab-resistant HER2 + metastatic breast cancer (MBC) patients were treated with a continuous once daily dosing schedule of LPT + B. Dose levels [DL, LPT (mg)/B (mg)] ranged from 750/40 to 1,250/80. For PK analysis, 2 time point samples were collected on D1 and D8 and 10 time point samples were collected on D15 of cycle 1 for LPT and B assays. Plasma concentrations of B and LPT, were measured using UPLC coupled with tandem mass spectrometry validated methods. Population PK was modeled using a non linear mixed effect model program (Monolix version 4.3s) by computing the maximum likelihood estimator of the parameters without any approximation of the model (no linearization). Results: 343 and 322 plasma concentrations were available for PK analysis of LPT and B respectively. A two-compartment open model adequately described B concentration versus time courses. The inter-individual variabilities (ISV) could be well estimated for all stuctural parameters (clearance: CL, volume of distribution: V, inter-compartmental clearance: Q) except for absorption constant: Ka. The population PK parameters obtained for the structural model were: Ka = 0.985 h−1, CL/F = 10.5L/h, V1/F = 54.8 L, Q/F = 46.3 L/h, V2/F = 582 L. Mean AUC0-24h(CV%) values for B were 10130 (34%), 15450 (29%), and 20560 (38%) ng*hr/mL for 40 mg, 60 mg and 80 mg dose level respectively. A one-compartment model adequately fitted the LPT plasma concentration-time data. The population PK parameters were CL/F = 25.7 L/h, V/F = 291 L and the absorption constant, Ka = 0.214 h−1. B has no significant effect on the PK of LPT and vice versa. Conclusions: B AUC increased proportionally with increasing dose. LPT PK parameters are consistent with those already published. There is no significant evidence for drug-drug PK interaction between LPT and B. Intra-occasion variabilities will be discussed. Citation Format: François Lokiec, Anthony Goncalves, Fanny Bret, Jihane Pakradouni, Magali Provansal, Renaud Sabatier, Jean-Marc Extra, Carole Tarpin, Nicolas Isambert, Mario Campone, Keyvan Rezai. A phase Ib pharmacokinetic drug-drug interaction evaluation of oral buparlisib in combination with lapatinib in HER2+/PI3K-activated, trastuzumab-resistant locally advanced, recurrent and metastatic breast cancer (MBC). [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 2036.

Population pharmacokinetics of arbekacin in different infectious disease settings and evaluation of dosing regimens.

The efficacy of arbekacin in patients with MRSA infections is influenced by the peak concentration (Cpeak)/MIC ratio (≧8). A daily arbekacin dose of 4-6mg/kg is primarily used for the treatment of MRSA infection. However, clinical pharmacokinetic studies of arbekacin that evaluate changes in patients with different infectious diseases have been limited. This study was to evaluate the pharmacokinetics of arbekacin in different infectious diseases and to evaluate its dosing regimens. This work describes a single-centre, retrospective study. The pharmacokinetic parameters of arbekacin were calculated from individual serum-concentration data using WinNonlin ver. 6.3. A total of 331 serum samples were obtained from 170 patients. Our drug concentration-time data were well described by a two-compartment open model. The final model showed that drug clearance was related to creatinine clearance and that the total distribution volume (Vd) was related to actual body weight and the presence of bacteremia. The individual Vd in bacteremia patients was significantly higher than those of other patients (bacteremia: 29.7±0.5L, pneumonia: 20.8±0.4L, other infections: 21.4±0.4L; p<0.05). Additionally, Monte Carlo simulation showed that target (Cpeak/MIC≧8) attainment was only 10.1%, even at a dose of 6mg/kg, especially for MRSA bacteremia patients with an arbekacin MIC=2μg/mL. In conclusion, our study revealed that the Vd may be higher in bacteremia patients than in patients with other infectious diseases. Therefore, an increase in the daily dose of arbekacin should be considered for bacteremia patients.

Pharmacokinetics of Lornoxicam in rabbits after single intravenous bolus and intramuscular administrations

The pharmacokinetics of lornoxicam (a non-steroidal anti-inflammatory drug) at a dose of 0.4 mg/Kg body weight was evaluated after single intravenous (i.v.) and intramuscular (i.m.) bolus administrations in rabbits. An HPLC assay using pure lornoxicam base as a standard was used to measure its concentrations in plasma at prefixed time points up to 12 hours post administration. Following an i.v. bolus injection, the plasma concentration-time curves of lornoxicam were best represented by two-compartment open model. The drug was rapidly distributed and moderately eliminated with half-lives of distribution (t1/2α) and elimination (t1/2β) of 0.238 and 2.611 h, respectively. The volume of distribution was large with (Vdss) value of 1.499 L. The total body clearance (ClB) was 0.413 L/h. After i.m. bolus administration of the same dose, lornoxicam was moderately and completely absorbed in rabbits with an absorption half-life (t½ab) of 1.228 h with peak plasma concentration (Cmax) of 0.463 μg/mL attained at 1.512 h (Tmax) and systemic bioavailability of 99.79%. The elimination half-life following i.m. administration was 2.283 h. The extent of plasma protein binding percent was 98.9%. The study recommends the use of lornoxicam in rabbits because of its good pharmacokinetic profile indicated by good absorption, bioavailability and plasma concentrations.

Pharmacokinetics of clarithromycin after single intravenous and intracrop bolus administrations to broiler chickens

&lt;p&gt;The pharmacokinetics of clarithromycin at a dose of 7.5 mg/kg body weight was evaluated after single intravenous (i.v.) and intracrop (i.c.) bolus administrations in broilers. An HPLC assay using pure clarithromycin base as a standard was used to measure its concentrations in plasma. Following an i.v. bolus injection, the plasma concentration-time curves of clarithromycin were best represented by two-compartment open models. The drug was rapidly distributed and moderately eliminated with half-lives of distribution (&lt;em&gt;t&lt;/em&gt;&lt;sub&gt;1/2α&lt;/sub&gt;) and elimination (&lt;em&gt;t&lt;/em&gt;&lt;sub&gt;1/2β&lt;/sub&gt;) of 0.38 and 4.58 h, respectively. The volume of distribution was large with (V&lt;sub&gt;dss&lt;/sub&gt;) value of 6.89 L. The total body clearance (&lt;em&gt;Cl&lt;/em&gt;&lt;sub&gt;B&lt;/sub&gt;) was 1.2 L/h. After i.c. bolus administration of the same dose, clarithromycin was moderately absorbed in broilers with an intermediate absorption half-life (&lt;em&gt;T&lt;/em&gt;&lt;sub&gt;½ab&lt;/sub&gt;) of 0.72 h with peak plasma concentration (&lt;em&gt;C&lt;/em&gt;&lt;sub&gt;max&lt;/sub&gt;) of 1.69 μg/ml attained at 1.7 h (&lt;em&gt;T&lt;/em&gt;&lt;sub&gt;max&lt;/sub&gt;) and systemic bioavailability of 66.54%. The elimination half-life following i.c. administration was 2.11 h. The extent of plasma protein binding percent was 52%. The study recommends the use of clarithromycin in broilers because of its good pharmacokinetic profile indicated by good absorption, bioavailability and plasma concentrations ≥ MICs of many sensitive microorganisms.&lt;/p&gt;

Pharmacokinetics and Tissue Residues of Tylosin in Broiler Chickens

The pharmacokinetics and tissue residue of tylosin in broiler chickens were studied after I.V. and oral administrations in a dose of 50 mg tylosin/kg.b.wt. Tylosin was obeyed a two-compartment open model following I.V. administration at a dose of 50 mg/kg.b.wt. The disposition kinetics of tylosin following I.V. administration revealed that tylosin was highly distributed with Vd(area) of 6 L/kg and eliminated with half-life (t1/2β) equal to 7.29 hours. The disposition kinetics of tylosin following oral administration revealed that the maximum blood concentration (Cmax) was 3.40 μg/ml attained at (tmax) of 1.08 hour. Tylosin was eliminated with half-life (t1/2β) equal to 5.78 hours. The mean systemic bioavailability of tylosin after oral administration was 90.29%. Following repeated oral administration of 50 mg tylosin base/kg.b.wt once daily for 5 consecutive days, the blood (μg/ml) and tissue (μg/g) residues of tylosin showed that liver, kidney and lung contained the highest tylosin residues and completely disappeared from those tissues at 6 days after the last oral dose. Chickens should not be slaughtered for human consumption within the treatment and 6 days after the last oral administrations of tylosin.

Pharmacokinetic Study of Florfenicol in Healthy and Vibriosis-infectedPseudosciaena croceaafter Oral Administration

The pharmacokinetics of florfenicol were studied in healthy and vibriosis-infected large yellow croaker (Pseudosciaena crocea) following administration of a single oral dose of at . After oral administration, florfenicol levels in tissues (liver, kidney, muscle, serum, and skin) were analyzed using high-performance liquid chromatography. A two-compartment open model was used to describe the pharmacokinetics of florfenicol following oral administration. Compared to the healthy group, the absorption rate of vibriosis-infected fish significantly decreased, peak-time () delayed, maximum concentration () declined, total body clearance decreased, the elimination half-life () was extended, and the area under the curve increased. These results indicate that a oral dose of florfenicol administered once daily continuously for 4 or 5 days can be used for the treatment of Vibrio alginolyticus infection in large yellow croaker (Pseudosciaena crocea).

Pharmacokinetics of vancomycin and dosing recommendations for trauma patients.

The objectives of this study were to characterize the population pharmacokinetics of vancomycin in trauma patients and to propose dosing schemes to optimize therapy. Trauma patients from Hospital Universitario Severo Ochoa (Spain) receiving intravenous vancomycin and routine therapeutic drug monitoring were included. Concentrations and time data were retrospectively collected, and population modelling was performed with NONMEM 7.2; internal and external validations were performed to probe the final model. Finally, several simulations were executed to propose dosing guidelines to reach expected vancomycin concentrations. A total of 118 trauma patients were included; the population was 45% males, with a mean age of 77 years (range 37-100 years) and a mean total body weight (TBW) of 72 kg (range 38-110 kg). The pharmacokinetics of vancomycin was best described by a two-compartment open model; creatinine clearance (CLCR) was related to vancomycin clearance (0.49 ± 0.04 L/h), being diminished by the presence of furosemide (0.34 ± 0.05 L/h). TBW influenced both the central volume of distribution (V1 = 0.74 ± 0.1 L/kg) and peripheral volume of distribution (V2 = 5.9 ± 2 L/kg), but patients with age >65 years showed a larger V1 (1.07 ± 0.1 L/kg). Bootstrapping was performed to internally validate the stability of the final model. External validation was developed using an alternate population of 40 patients with the same characteristics. The validated model was compared with population pharmacokinetic models previously published and showed better predictive performance for trauma patients than the current one. This final model allowed us to propose a new practical dose guideline to reach higher trough concentrations (15-20 mg/L) and AUC0-24/MIC ratios of more than 400 after 4 days of vancomycin treatment. A new population model was described for trauma patients to optimize vancomycin therapy, showing precise predictive performance to be applied for therapeutic drug monitoring and providing a new practical dose guideline that considers CLCR and concomitant administration of furosemide for these patients.

Pharmacokinetics of sarafloxacin in allogynogenetic silver crucian carp, Carassius auratus gibelio.

The pharmacokinetic properties of sarafloxacin were investigated after single intravenous (i.v.) and oral (p.o.) administration of 10 mg/kg body weight (b.w.) in allogynogenetic silver crucian carp at 24-26 °C. The plasma concentrations of sarafloxacin were determined by high-performance liquid chromatography. After i.v. administration, the plasma concentration-time data were described by an open two-compartment model. The elimination half-life (T(1/2β)) was estimated to be 22.58 h. The volume of distribution, V(d(area)), was estimated to be 5.95 L/kg, indicating good tissue penetration of sarafloxacin in the fish. Area under the concentration-time curve (AUC) and total body clearance of sarafloxacin were 56.86 µg·h/mL and 0.18 L/h/kg, respectively. Following p.o. administration, the maximum plasma concentration (C(max)), T(1/2β), and AUC of sarafloxacin were 0.79 µg/mL, 46.68 h, and 16.58 µg·h/mL, respectively. Absorption of the drug was not good with a bioavailability (F) of 29.15%. Based on a minimum inhibitory concentration (MIC) of 0.00625 to 0.045 μg/mL for susceptible strains, sarafloxacin p.o. administration at a dose 10 mg/kg could be efficacious against common pathogenic bacteria of fish.

Prediction of in-vivo iontophoretic drug release data from in-vitro experiments–insights from modeling

A strategy was developed to predict in-vivo plasma drug levels from data collected during in-vitro transdermal iontophoretic delivery experiments. The method used the principle of mass conservation and the Nernst–Planck flux equation to describe molecular transport across the skin. Distribution and elimination of the drug in the body followed a one- or two-compartment open model. Analytical expressions for the relaxation constant and plasma drug concentration were developed using Laplace transforms. The steady-state dermal flux was appropriate for predicting drug absorption under in-vivo conditions only when the time constant in the skin was far greater than its value in the blood compartment. A simulation study was conducted to fully assess the performance of estimations based on the equilibrium flux approximation. The findings showed that the normalized integral of squared error decreased exponentially as the ratio of the two time constants (blood/skin) increased. In the case of a single compartment, the error was reduced from 0.15 to 0.016 when the ratio increased from 10 to 100. The methodology was tested using plasma concentrations of a growth-hormone releasing factor in guinea pigs and naloxone in rats.

Metabolism and pharmacokinetics of 8-hydroxypiperidinylmethyl-baicalein (BA-j) as a novel selective CDK1 inhibitor in monkey

Cyclin-dependent kinase 1 (CDK1) is the only necessary CDK in the cell proliferation process and a new target in the research and development of anti-cancer drugs. 8-Hydroxypiperidinemethyl-baicalein (BA-j) is a Mannich base derivative of baicalein (BA) isolated from Scutellaria baicalensis, as a novel selective CDK1 inhibitor. 12 metabolites of BA-j in the monkey urine were identified by LC–MS–MS and 1H NMR. The major metabolic pathways of BA-j, by capturing oxygen free radicals (.O2−) and releasing peroxides (H2O2), are degraded into active intermediate metabolite dihydroflavonol, then into main metabolite M179 by Shiff reaction, second metabolite M264 by sulfation, trace amount of metabolite M559 by glucuronidation UGT1A9, and without metabolism by CYP3A4. The metabolic process of BA-j by regulating intracellular reactive oxygen species (ROS) was related with BA-j selectively inducing apoptosis in cancer cells. Pharmacokinetics of 10mg/kg oral BA-j in monkey by HPLC-UV was best fitted to a two-compartment open model, with t1/2(β) of 4.2h, Cmax 25.4μM at 2h, and Vd 12.6L, meaning the drug distributing widely in body fluids with no special selectivity to certain tissues, and being able to permeate through the blood–brain barrier. The protein binding rate of BA-j was 91.8%. BA-j has excellent druggability for oral administration or injection, and it may be developed into a novel anti-cancer drug as a selective CDK1 inhibitor.

Pharmacokinetics of enrofloxacin in snakehead fish, Channa argus.

The pharmacokinetics of enrofloxacin (EF) was investigated after single intravenous (i.v.) and oral (p.o.) dose of 10mg/kg body weight (b.w.) in snakehead fish at 24-26°C. The plasma concentrations of EF and its metabolite ciprofloxacin (CF) were determined by high-performance liquid chromatography. The plasma concentration-time data were described by an open two-compartment model for both routes. After intravenous administration, the elimination half-life (T1/2β ), area under the concentration-time curve (AUC) and total body clearance of EF were 19.82h, 75.79μgh/mL and 0.13L/h/kg, respectively. Following p.o. administration, the maximum plasma concentration (Cmax ), T1/2β and AUC of EF were 1.86μg/mL, 35.8h and 49.98μgh/mL, respectively. Absorption of EF was good with a bioavailability (F) of 65.82%, which was higher than that calculated in most seawater fish. CF, an active metabolite of EF, was detected occasionally in this study, which indicates a low extent of deethylation of EF in snakehead fish.

Population Pharmacokinetic Analysis of the Oral Absorption Process and Explaining Intra-Subject Variability in Plasma Exposures of Imatinib in Healthy Volunteers.

Imatinib mesylate is presently the first-line treatment for chronic myeloid leukemia (CML). The aim of this study was to investigate the absorption and distribution kinetics of imatinib in healthy Iranian volunteers using nonlinear mixed effects modeling (NLMEM) to assess the overall, intra- and inter-subject variabilities in pharmacokinetic parameters after oral administration. This analysis was based on data from 24 healthy subjects who participated in a bioequivalence study after administering a single dose of 200mg of each formulation. Imatinib concentrations were quantified using a validated liquid chromatography method. To simultaneously describe the imatinib pharmacokinetic profiles obtained with both formulations, a population pharmacokinetic model was applied to data using SAEM algorithm implemented in MONOLIX, whilst simulations were used by numerical solving of ordinary differential equations to calculate secondary parameters in individuals for bioequivalence studies. According to goodness-of-fit criteria, a two-compartment open model with sequential zero- then first-order absorption and first-order elimination was used as the structural pharmacokinetic model. Inter-individual variability (IIV) was considered for all parameters. Typical population estimates (% IIV) were fraction of the drug absorbed with a zero-order kinetic (Fr) of 0.153 (47.9%) in period (Tk0) of 0.714h (47.4%), first-order absorption rate constant (k a) of 0.94h(-1)(31.2%), oral clearance of 19L/h (27.9%), central volume of distribution (V c/F) of 139 L (21.5%), apparent peripheral volume of distribution (V p/F) of 130 L (29.7%) and the apparent inter-compartment clearance (Q/F) of 29.6L/h (41.8%). Body mass index (BMI) was the only covariate found to significantly affect V p /F. The coefficient of variation for intra-individual plasma exposure (AUC0-∞) was 27.8%. Analyses using NLMEM for imatinib exhibited absorption complexities such as two input rates and medium to high intra-individual variability in drug exposure.

Pharmacokinetics of florfenicol following intravenous and intramuscular administration in dogs

Florfenicol is a synthetic broad-spectrum antibiotic used to treat infectious diseases in veterinary medicine. Limited information is available on the pharmacokinetics and bioavailability of florfenicol in dogs. This study was conducted in six healthy dogs to determine the bioavailability and pharmacokinetics of florfenicol following a single intravenous (i.v.) and intramuscular (i.m.) dose of 30 mg/kg body weight (b.w.). Blood samples were taken over the course of 24 h post-treatment and the recovered plasma was extracted and analysed using high-performance liquid chromatography (HPLC). Pharmacokinetic analysis was performed using a two-compartment open model. After i.v. administration of florfenicol, elimination half-life (t1/2b), volume of distribution at steady state (Vdss), total body clearance (ClT) and area under curve (AUC0-24) were 3.09 ± 0.13 h, 1.19 ± 0.15 l/kg, 0.37 ± 0.04 l/h/kg, and 59.44 ± 5.27 µg/h/ml, respectively. The peak plasma concentration (Cmax), time to maximum concentration (tmax) and bioavailability (F) were 3.05 ± 0.43 µg/ml, 1.50 ± 0.35 h, and 44.70 ± 6.75%, respectively, following i.m. administration. In this study the time that plasma concentration exceed the concentration of 1 µg/ml was approximately 8 h. Therefore, florfenicol should be given twice daily at a dosage of 30 mg/kg b.w. to maintain therapeutic concentration. The pharmacokinetic profile of florfenicol in dogs reveals that it may be therapeutically useful against susceptible microorganisms involved in most common infections in dogs.

Population pharmacokinetics of kahalalide F in advanced cancer patients

In this study, we characterize the population pharmacokinetics of kahalalide F (KF), a novel marine anticancer drug, after intravenous (i.v.) administration in advanced cancer patients. Data from 240 patients included in three Phase I and three Phase II trials receiving i.v. weekly and every 3 weeks infusions of KF, at doses ranging 266-6650 µg/m(2), were analyzed using NONMEM™ VII. The effect of demographics and/or pathophysiologically relevant factors on KF pharmacokinetic parameters was evaluated. Model evaluation was conducted using nonparametric bootstrap and visual predictive check (in both internal and external datasets). An open two-compartment model with linear distribution and elimination from central compartment was suitable to describe the data. Volume of distribution at steady state and its between-subject variability (CV%) was estimated to be 6.56 L (28 %). Plasma clearance was estimated to be 6.25 L/h (43 %). Within the range of covariates evaluated, age, weight, body surface area, gender, ECOG performance status, presence of liver metastases, creatinine clearance, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, total protein and serum albumin did not contribute to explain KF pharmacokinetic variability to a significant extent. The developed model was deemed appropriate to describe the time course of KF plasma concentrations and its variability in advanced cancer patients. The integration of pharmacokinetic data from six clinical studies demonstrated KF linear elimination from plasma, dose-proportional exposure and time-independent pharmacokinetics. Based on analyzed data, no clinically relevant covariates were identified as predictors of KF pharmacokinetics.

Pharmacokinetics of cefquinome in tilapia (Oreochromis niloticus) after a single intramuscular or intraperitonealadministration.

The pharmacokinetics of cefquinome was studied in plasma after a single dose (10mg/kg) of intramuscular (i.m.) or intraperitoneal (i.p.) administration to tilapia (Oreochromis niloticus) in freshwater at 30°C. Ten fish per sampling point were examined after treatment. The data were fitted to two-compartment open models following both routes of administration. The estimates of total body clearance (CL/F), volume of distribution (Vd/F), and absorption half-life (T1/2ka ) were 0.049 and 0.037L/h/kg, 0.41 and 0.33L/kg, and 0.028 and 0.035h following i.m. and i.p. administration, respectively. After i.m. injection, the elimination half-life (T1⁄2β ) was calculated to be 5.81h, the maximum plasma concentration (Cmax ) to be 49.40μg/mL, the time to peak plasma cefquinome concentration (Tmax ) to be 0.14h, and the area under the plasma concentration-time curve (AUC) to be 204.6μgh/mL. Following i.p. administration, the corresponding estimates were 6.05h, 44.39μg/mL, 0.17h and 267.8μgh/mL. The minimum inhibitory concentrations of cefquinome, determined for 30 strains of Streptococcus agalactiae isolated from diseased tilapia, ranged from 0.015 to 0.12μg/mL. Results from these studies support that 10mg cefquinome/kg body weight daily could be expected to control tilapia bacterial pathogens inhibited invitro by a minimal inhibitory concentration value of ≤2μg/mL.

Lack of gender effect on the pharmacokinetics of oxytetracycline in Fenneropenaeus chinensis after intramuscular administration

Fenneropenaeus chinensis, an economically important shrimp species, currently suffers from epizootic diseases due to high density stocking and bacterial infections. Oxytetracycline (OTC) has been widely used to treat various systemic bacterial infections in shrimp farming. In the present study, the effect of gender on pharmacokinetics of OTC in F. chinensis was investigated. The OTC concentrations in hemolymph of shrimp after single intramuscular administration (75 mg OTC per kg body weight) were analyzed by high performance liquid chromatography and best described with a two-compartment open model which is characterized by a short elimination half-life, low clearance, and a relatively large apparent volume of distribution. The pharmacokinetic equations were C t = 58.54e−0.38t + 11.67e−0.04t for females; and C t = 27.94e−0.28t + 14.87e−0.04t for males. The distribution and elimination half-lives of OTC were 1.82 and 19.58 h, respectively, in females and 2.50 and 16.11 h, respectively, in males at 22°C. The areas under the drug concentration curve were 480 mg L−1 h−1 in females and 430 mg L−1 h−1 in males. The total body clearance of the drug was 157.11 mL kg−1 h−1 in females and 172.47 mL kg−1 h−1 in males. The apparent volume distribution was 4.44 in females and 4.01 L kg−1 in males. There was no significant difference in pharmacokinetic parameters between female and male shrimps, indicating that there is no need to consider the gender effect in clinical use of OTC in F. chinensis farming.

The role of equilibrium and kinetic properties in the dissociation of Gd[DTPA-bis(methylamide)] (Omniscan) at near to physiological conditions.

[Gd(DTPA-BMA)] is the principal constituent of Omniscan, a magnetic resonance imaging (MRI) contrast agent. In body fluids, endogenous ions (Zn(2+), Cu(2+), and Ca(2+)) may displace the Gd(3+). To assess the extent of displacement at equilibrium, the stability constants of DTPA-BMA(3-) complexes of Gd(3+), Ca(2+), Zn(2+), and Cu(2+) have been determined at 37 °C in 0.15 M NaCl. The order of these stability constants is as follows: GdL≈CuL>ZnL≫CaL. Applying a simplified blood plasma model, the extent of dissociation of Omniscan (0.35 mM [Gd(DTPA-BMA)]) was found to be 17% by the formation of Gd(PO4), [Zn(DTPA-BMA)](-) (2.4%), [Cu(DTPA-BMA)](-) (0.2%), and [Ca(DTPA-BMA)](-) (17.7%). By capillary electrophoresis, the formation of [Ca(DTPA-BMA)](-) has been detected in human serum spiked with [Gd(DTPA-BMA)] (2.0 mM) at pH 7.4. Transmetallation reactions between [Gd(DTPA-BMA)] and Cu(2+) at 37 °C in the presence of citrate, phosphate, and bicarbonate ions occur by dissociation of the complex assisted by the endogenous ligands. At physiological concentrations of citrate, phosphate, and bicarbonate ions, the half-life of dissociation of [Gd(DTPA-BMA)] was calculated to be 9.3 h at pH 7.4. Considering the rates of distribution and dissociation of [Gd(DTPA-BMA)] in the extracellular space of the body, an open two-compartment model has been developed, which allows prediction of the extent of dissociation of the Gd(III) complex in body fluids depending on the rate of elimination of the contrast agent.

Pharmacokinetic profile of cefquinome after oral subchronic flubendiamide exposure and in vitro plasma protein binding in buffalo calves

The disposition kinetics study of cefquinome was conducted following single intravenous (IV) administration of 2mg/kg bodyweight in buffalo calves after oral subchronic exposure to flubendiamide and to determine the in vitro plasma protein binding of cefquinome. Plasma concentrations of cefquinome were analyzed using reverse-phase high performance liquid chromatography (HPLC). The results were compared with our earlier study on the pharmacokinetics of cefquinome in untreated buffalo calves. Plasma concentration-time data for cefquinome following IV injection were best fit into a two-compartmental open model in flubendiamide-exposed buffalo calves. Following flubendiamide exposure, most of the pharmacokinetic parameters of cefquinome were significantly altered in buffalo calves. Cefquinome was bound to plasma proteins of buffalo calves to the extent of 11.4±0.66%. In flubendiamide-exposed animals an intravenous dose of 2mg/kg body weight would maintain the therapeutic plasma levels required to be effective against the bacterial pathogens with MIC values ≤0.39μg/mL for only 12h, whereas in untreated buffalo calves the same dose of 2mg/kg body weight would maintain the plasma levels up to 24h, The study revealed that subchronic flubendiamide exposure significantly alters the disposition of cefquinome in buffalo calves.