Paritaprevir and Ritonavir Liver Concentrations in Rats as Assessed by Different Liver Sampling Techniques

ABSTRACT The liver is crucial to pharmacology, yet substantial knowledge gaps exist in the understanding of its basic pharmacologic processes. An improved understanding for humans requires reliable and reproducible liver sampling methods. We compared liver concentrations of paritaprevir and ritonavir in rats by using samples collected by fine-needle aspiration (FNA), core needle biopsy (CNB), and surgical resection. Thirteen Sprague-Dawley rats were evaluated, nine of which received paritaprevir/ritonavir at 30/20 mg/kg of body weight by oral gavage daily for 4 or 5 days. Drug concentrations were measured using liquid chromatography-tandem mass spectrometry on samples collected via FNA (21G needle) with 1, 3, or 5 passes (FNA1, FNA3, and FNA5); via CNB (16G needle); and via surgical resection. Drug concentrations in plasma were also assessed. Analyses included noncompartmental pharmacokinetic analysis and use of Bland-Altman techniques. All liver tissue samples had higher paritaprevir and ritonavir concentrations than those in plasma. Resected samples, considered the benchmark measure, resulted in estimations of the highest values for the pharmacokinetic parameters of exposure (maximum concentration of drug in serum [C max] and area under the concentration-time curve from 0 to 24 h [AUC0–24]) for paritaprevir and ritonavir. Bland-Altman analyses showed that the best agreement occurred between tissue resection and CNB, with 15% bias, followed by FNA3 and FNA5, with 18% bias, and FNA1 and FNA3, with a 22% bias for paritaprevir. Paritaprevir and ritonavir are highly concentrated in rat liver. Further research is needed to validate FNA sampling for humans, with the possible derivation and application of correction factors for drug concentration measurements.

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Pharmacokinetic Interaction between Asari Radix et Rhizoma and Dried Ginger (Zingiber officinalis) in Rats

Current Pharmaceutical Analysis ◽

10.2174/1573412917999210111225509 ◽

2021 ◽

Vol 17 ◽

Author(s):

Xingxing Zhuang ◽

Li Zhou ◽

Renhua Miao ◽

Shoudong Ni ◽

Meng Li

Keyword(s):

High Performance ◽

Pharmacokinetic Interaction ◽

Raw Material ◽

Pharmacokinetic Parameters ◽

Sprague Dawley ◽

Active Components ◽

Sprague Dawley Rats ◽

Liquid Chromatography Tandem Mass ◽

Student’S T ◽

Student’S T Test

Introduction:: Asari Radix et Rhizoma (ARR) and dried ginger (Zingiber officinalis) (DG) are often used together in drug preparations in traditional Chinese medicine (TCM) to treat respiratory diseases including cold, bronchitis and pneumonia. Previous studies suggested that ARR and/or DG may influence the pharmacokinetics of other herbal components. In the current study, we examined pharmacokinetic interactions between ARR and DG in rats after oral administration. Methods:: We developed a method based on ultra-high-performance liquid chromatography-tandem mass spectrometry to simultaneously measure serum concentrations of two active components each in ARR (L-asarinin and sesamin) and DG (6-gingerol and 6-shogaol). Adult Sprague-Dawley rats were starved overnight, then given ARR extract, DO extract, or a co-decoction of ARR and DG by gastric gavage (6 g raw material per kg body weight; n = 6 per group). Blood samples were collected prior to drug administration and at the following times (h) afterward: 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0 and 24.0. Pharmacokinetic parameters were compared using Student’s t test for independent samples. Results:: A simple, rapid, sensitive analytical method has been developed to detect four bioactive components simultaneously in the ARR-DG herbal pair. Pharmacokinetic parameters including Cmax, Tmax, T1/2 and AUC(0~t) were calculated using the non-compartmental model with the DAS 2.0 pharmacokinetic software. For L-asarinin, Tmax was 2.00 ± 0.00 h in ARR animals and 1.67±0.26 h in ARR-DG animals (P<0.05), T1/2 was 8.58 ± 1.75 h in ARR and 11.93 ± 2.13 h in ARR-DG (P<0.05). For 6-gingerol, Cmax was 350.48 ± 23.85 ng/mL in DG animals and 300.21 ± 20.02 ng/mL in ARR-DG (P<0.01), Tmax was 2.83 ± 0.41 h in DG and 2.17 ± 0.41 h in ARR-DG (P<0.05) and AUC(0~t) was 1.93 ± 0.15 mg/mL•h in ARR and 1.70 ± 0.15 mg/mL•h in ARR-DG (P<0.05). For 6-shogaol, Cmax was 390.28 ± 26.02 ng/mL in DG animals and 455.63 ± 31.01 ng/mL in ARR-DG (P<0.01), Tmax was 2.93 ± 0.10 h in DG and 1.92 ± 0.10 h in ARR-DG (P<0.01), T1/2 was 3.74 ± 0.29 h in DG and 3.28 ± 0.22 h in ARR-DG (P<0.01), and AUC(0~t) was 2.15 ± 0.18 mg/mL•h in DG and 2.73 ± 0.15 mg/mL•h in ARR-DG (P<0.01). Conclusions:: Pharmacokinetic interations between ARR and DG decrease Tmax, increase T1/2 but do not affect overall bioavailability of L-asarinin in ARR. The interactions in ARR-DG decrease Cmax and Tmax but increase T1/2 and AUC(0~t) of 6-gingerol in DG. The interactions increase Cmax and AUC(0~t) but decrease Tmax and T1/2 of 6- shogaol in DG. Interactions in ARR-DG do not affect the pharmacokinetics of sesamin.

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Effect of the Phragmitis Rhizoma Aqueous Extract on the Pharmacokinetics of Docetaxel in Rats

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207322666190419110724 ◽

2019 ◽

Vol 22 (5) ◽

pp. 326-332

Author(s):

Sarah Shin ◽

No Soo Kim ◽

Young Ah Kim ◽

Hea Ry Oh ◽

Ok-Sun Bang

Keyword(s):

Aqueous Extract ◽

Statistical Significance ◽

Ultra Performance Liquid Chromatography ◽

Pharmacokinetic Parameters ◽

Control Group ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Liquid Chromatography Tandem Mass ◽

Mass Spectrometry System ◽

Phragmitis Rhizoma

Background: Traditionally, Phragmitis rhizoma has been prescribed to relive a fever, vomiting, dysuria, and constipation, and to promote secretion of fluids. In addition, recent studies have reported its efficacy as a diuretic and antiemetic. Our previous study demonstrated that the Phragmitis rhizoma aqueous extract (EPR) ameliorates docetaxel (DTX)-induced myelotoxicity. Aim and Objective: This study was aimed to investigate the effects of EPR on the pharmacokinetics of DTX in Sprague–Dawley rats. Materials & Methods: The animals received an intravenous injection of DTX (5 mg/kg) with or without oral EPR (100 mg/kg) pretreatment for 1 or 6 days. The pharmacokinetics of plasma DTX was analyzed using an ultra-performance liquid chromatography-tandem mass spectrometry system, and pharmacokinetic parameters were estimated via noncompartmental analysis. Results: Relative to the control group (DTX alone), EPR pretreatment did not affect significantly the overall profiles of plasma DTX levels. Consecutively pretreated EPR for 6 days slightly altered AUC0-t and Cmax of DTX by 122 and 145.9%, respectively, but these data did not reach the threshold of statistical significance (p > 0.05). Conclusion: These results indicate that DTX exposure may not be affected by EPR treatment at the dose level used in this study, suggesting that oral EPR can be used safely when taken with intravenously injected DTX. However, further studies under the stringent conditions are needed when chronic treatment of EPR and anticancer drug.

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The Herb-Drug Pharmacokinetic Interaction of Fluoxetine and Its Metabolite Norfluoxetine with a Traditional Chinese Medicine in Rats by LC-MS/MS

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/2471870 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Lijing Yan ◽

Sheng Wang ◽

Linlin Zhao ◽

Juan Qiu ◽

Lu Zhou ◽

...

Keyword(s):

Multiple Dose ◽

Dose Group ◽

Pharmacokinetic Interaction ◽

Primary Objective ◽

Pharmacokinetic Parameters ◽

Sprague Dawley ◽

Time Curve ◽

Liquid Chromatography Tandem Mass ◽

Healthy Adult Male ◽

Group B

Background. Fluoxetine (FLU) is the first-line and widely used medication for depression. The combination of Chaihu Shugan san (CSGS) and FLU is commonly used to enhance antidepressant effects and reduce side effects. Objective. The primary objective of this study was to investigate the potential pharmacokinetic effect of CSGS on FLU. Materials and Methods. Thirty-two healthy adult male Sprague-Dawley (SD) rats were randomly divided into four groups, the fluoxetine group and multiple dose groups A, B, and C. The rats in the different groups were orally administered with a combination of FLU and different doses of CSGS for 14 d. On the fifteenth day, serial blood samples were taken from the caudal vein before the administration and at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24, 36, and 48 h after the administration. A liquid-liquid extraction method was applied to extract the analytes from serum. Then, the concentrations of FLU and its metabolite, norfluoxetine (NOF), were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters were calculated by DAS 3.2.8 program and compared by statistic analysis. Results. Compared with the FLU group, the FLU and NOF area under the plasma concentration-time curve (AUC) (0–∞) in multiple dose group C was significantly increased, while the NOF AUCs (0–∞) in multiple dose group A and multiple dose group B were decreased. Compared with the FLU group, the NOF clearance (CL) in multiple dose group C was decreased, while the CL in multiple dose groups A and B was increased. Discussion and Conclusion. There were some differences in pharmacokinetic parameters between the FLU group and multiple dose groups, and CSGS can affect the pharmacokinetics of fluoxetine.

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Assessment of Liver Function Using Pharmacokinetic Parameters of Gd-EOB-DTPA: Experimental Study in Rat Hepatectomy Model

Contrast Media & Molecular Imaging ◽

10.1155/2018/6321316 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Myung-Won You ◽

Hyoung Jung Kim ◽

Hyeong-Seok Lim ◽

So Yeon Kim ◽

Jae Ho Byun ◽

...

Keyword(s):

Liver Function ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Control Group ◽

Sprague Dawley ◽

Time Curve ◽

Blood Samples ◽

The Difference ◽

Hepatectomy Group ◽

Group Comparisons

Objectives. To determine whether the pharmacokinetic parameters of Gd-EOB-DTPA can identify the difference in liver function in a rat hepatectomy model. Methods. A total of 56 eight-week-old male Sprague-Dawley rats were divided into the following groups: control group without hepatectomy (n=16), 70% hepatectomy group (n=14), and 90% hepatectomy group (n=26). On postoperative day 2, Gd-EOB-DTPA (0.1 mmol/kg) was injected intravenously and serial blood samples were obtained. Pharmacokinetic analysis was performed using a noncompartmental method. Statistical analysis was performed using one-way analysis of variance and post hoc pairwise group comparisons. Results. After excluding 6 rats that died unexpectedly, blood samples were obtained from 16, 14, and 20 rats in the control group, 70% hepatectomy group, and 90% hepatectomy group. There was a significant increase in area under the concentration-time curve from time zero to the time of the last measurable concentration between the 70% and 90% hepatectomy group (P<0.001). The volume of distribution at steady state was significantly decreased between the control and 70% hepatectomy group (P<0.001). The clearance was significantly different in all pairwise group comparisons (P<0.001). Conclusions. The vascular clearance of Gd-EOB-DTPA can identify the difference in liver function in a rat hepatectomy model.

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Phase I, Open-Label, Safety and Pharmacokinetic Study To Assess Bronchopulmonary Disposition of Intravenous Eravacycline in Healthy Men and Women

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02036-13 ◽

2014 ◽

Vol 58 (4) ◽

pp. 2113-2118 ◽

Cited By ~ 54

Author(s):

Kevin P. Connors ◽

Seth T. Housman ◽

J. Samuel Pope ◽

John Russomanno ◽

Edward Salerno ◽

...

Keyword(s):

Respiratory Infections ◽

Correction Method ◽

Pharmacokinetic Parameters ◽

Open Label ◽

Time Curve ◽

Epithelial Lining Fluid ◽

Drug Concentrations ◽

Penetration Ratio ◽

Liquid Chromatography Tandem Mass ◽

Adult Volunteers

ABSTRACTThis study evaluated the pulmonary disposition of eravacycline in 20 healthy adult volunteers receiving 1.0 mg of eravacycline/kg intravenously every 12 h for a total of seven doses over 4 days. Plasma samples were collected at 0, 1, 2, 4, 6, and 12 h on day 4, with each subject randomized to undergo a single bronchoalveolar lavage (BAL) at 2, 4, 6, or 12 h. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography-tandem mass spectrometry, and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods. Penetration for ELF and AM was calculated by using a ratio of the area under the concentration time curve (AUC0–12) for each respective parameter against free drug AUC (fAUC0–12) in plasma. The total AUC0–12in plasma was 4.56 ± 0.94 μg·h/ml with a meanfAUC0–12of 0.77 ± 0.14 μg·h/ml. The eravacycline concentrations in ELF and AM at 2, 4, 6, and 12 h were means ± the standard deviations (μg/ml) of 0.70 ± 0.30, 0.57 ± 0.20, 0.34 ± 0.16, and 0.25 ± 0.13 with a penetration ratio of 6.44 and 8.25 ± 4.55, 5.15 ± 1.25, 1.77 ± 0.64, and 1.42 ± 1.45 with a penetration ratio of 51.63, respectively. The eravacycline concentrations in the ELF and AM achieved greater levels than plasma by 6- and 50-fold, respectively, supporting further study of eravacycline for patients with respiratory infections.

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Pulmonary Disposition of Tedizolid following Administration of Once-Daily Oral 200-Milligram Tedizolid Phosphate in Healthy Adult Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05354-11 ◽

2012 ◽

Vol 56 (5) ◽

pp. 2627-2634 ◽

Cited By ~ 56

Author(s):

Seth T. Housman ◽

J. Samuel Pope ◽

John Russomanno ◽

Edward Salerno ◽

Eric Shore ◽

...

Keyword(s):

Correction Method ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Epithelial Lining Fluid ◽

Once Daily ◽

Dosing Interval ◽

Drug Concentrations ◽

Liquid Chromatography Tandem Mass ◽

Adult Volunteers

ABSTRACTThis study assessed the pulmonary disposition of tedizolid, an oxazolidinone, in adult volunteers receiving 200 mg of the prodrug tedizolid phosphate orally every 24 h for 3 days to steady state. Plasma samples were collected over the dosing interval, and participants were randomized to undergo bronchoalveolar lavage (BAL) at 2, 6, 12, or 24 h after the last dose. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods followed by compartmental population pharmacokinetics. Penetration was calculated as the area under the concentration-time curve during the dosing interval (AUC0–24) for ELF and AM relative to the free AUC0–24(fAUC0–24) in plasma. The half-life and volume of distribution in plasma were 9.23 ± 2.04 h and 108.25 ± 20.53 liters (means ± standard deviations), respectively. Total AUC0–24in plasma was 25.13 ± 5.78 μg · h/ml. Protein binding was 89.44% ± 1.58%, resulting in a meanfAUC0–24of 2.65 ± 0.72 μg · h/ml in plasma. Mean concentrations (μg/ml) at 2, 6, 12, and 24 h were 9.05 ± 3.83, 4.45 ± 2.18, 5.62 ± 1.99, and 1.33 ± 0.59 in ELF and 3.67 ± 1.02, 4.38 ± 2.18, 1.42 ± 0.63, and 1.04 ± 0.52 in AM. ELF and AM penetration ratios were 41.2 and 20.0. The mean ELF penetration ratio after population analyses was 39.7. This study demonstrates that tedizolid penetrates into ELF and AM to levels approximately 40-fold and 20-fold, respectively, higher than free-drug exposures in plasma.

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Effect of aminophylline on the pharmacokinetics of amikacin in Sprague-Dawley rats

The Journal of Infection in Developing Countries ◽

10.3855/jidc.10514 ◽

2019 ◽

Vol 13 (03) ◽

pp. 251-254

Author(s):

Seth Kwabena Amponsah ◽

Kwabena Frimpong-Manso Opuni ◽

Kwabena Aboagye Antwi ◽

Victor Pouzuing Kunkpeh

Keyword(s):

Elimination Rate ◽

Test Group ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Control Group ◽

Sprague Dawley ◽

Serum Samples ◽

Sprague Dawley Rats ◽

Elimination Half ◽

Apnea Of Prematurity

Introduction: In most resource-poor settings, amikacin is normally co-administered with aminophylline among preterm newborns with infection and apnea of prematurity. There is the likelihood of an interaction between concurrently administered amikacin that is excreted almost solely via kidneys, and aminophylline, which is known to increase filtration fraction. The aim of this study was to evaluate the effect of aminophylline on the pharmacokinetics of amikacin using an animal model. Methodology: Twelve male Sprague-Dawley rats (7 – 8 weeks old) were put into 2 equal groups. The test group received amikacin (10 mg/kg/day) with aminophylline (5 mg/kg/day) via the intraperitoneal route, and the control group received only amikacin (10 mg/kg/day) via the same route. On Day 4, after daily administration of drugs, tail vein blood samples were collected at different time points. Serum samples at each time point for each group were pooled and analyzed by fluorescence polarization immunoassay. Non-compartment pharmacokinetic analysis was used to estimate pharmacokinetic parameters. Area under the concentration-time curves (AUCs) were extrapolated from time 0 to infinity (AUC0→∞). Elimination rate constant (Ke) and elimination half-life (t1/2e) were also estimated. Results: Pharmacokinetic parameters of the control group (amikacin only) vis-a-vis the test group were as follows: Cmax; 42.4 μmol/L vs 19.0 μmol/L, AUC0→∞; 84.9 μmol/L/h vs 41.4 μmol/L/h, Ke; 0.12 hours-1 vs 0.24 hours-1, and t1/2; 5.87 hours vs 2.88 hours, respectively. Conclusion: This study suggests possible interaction between aminophylline and amikacin. However, further studies need to be conducted in humans to ascertain this finding.

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Effect of Green Tea and (-)-Epigallocatechin Gallate on the Pharmacokinetics of Rosuvastatin

Current Drug Metabolism ◽

10.2174/1389200221666200514133355 ◽

2020 ◽

Vol 21 (6) ◽

pp. 471-478

Author(s):

Shenjia Huang ◽

Qingqing Xu ◽

Linsheng Liu ◽

Yicong Bian ◽

Shichao Zhang ◽

...

Keyword(s):

Green Tea ◽

Cell Model ◽

Hek293t Cell ◽

Epigallocatechin Gallate ◽

Drug Uptake ◽

Pharmacokinetic Parameters ◽

Control Group ◽

Sprague Dawley ◽

Time Curve ◽

Uptake And Transport

Background: Green tea can inhibit OATPs, so it may interact with the substrate of OATPs, such as rosuvastatin. Objective: This study aimed to investigate the effects of green tea on the pharmacokinetics of rosuvastatin and its mechanism. Methods: Male Sprague-Dawley rats received different doses of green tea extract (GTE) and (-)- epigallocatechin-3- gallate (EGCG). Caco-2 cells and OATP1B1-HEK293T cells were used in drug uptake and transport assay. The matrix concentrations of rosuvastatin and catechins were determined by ultra-performance liquid chromatographytandem mass spectrometry (UPLC-MS/MS). Results: GTE and EGCG were both found to increase the area under the plasma concentration-time curve (AUC0-∞) of rosuvastatin ((p<0.050). In the Caco-2 cell model, the uptake and transport of rosuvastatin in the GTE groups were 1.94-fold (p<0.001) and 2.11-fold (p<0.050) higher, respectively, than those of the control group. However, in the EGCG group, the uptake and transport of rosuvastatin were decreased by 22.62% and 44.19%, respectively (p<0.050). In the OATP1B1- HEK293T cell model, the OATP1B1-mediated rosuvastatin uptake was decreased by GTE to 35.02% of that in the control (p<0.050) and was decreased by EGCG to 45.61% of that in the control (p<0.050). Conclusion: GTE increased the systemic rosuvastatin exposure in rats. The mechanism may include an increase in rosuvastatin absorption and a decrease in liver distribution by inhibiting OATP1B1. EGCG may be the main ingredient of green tea that affects the pharmacokinetic parameters of rosuvastatin. Our results showed the importance of conducting green tea-rosuvastatin study.

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Changes in rat mesentery interstitial matrix due to superfusate

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1993.265.3.h852 ◽

1993 ◽

Vol 265 (3) ◽

pp. H852-H856 ◽

Cited By ~ 3

Author(s):

B. J. Barber ◽

R. A. Babbitt ◽

S. Dutta ◽

S. Parameswaran

Keyword(s):

Protein Content ◽

Normal Saline ◽

Protein Concentration ◽

Matrix Protein ◽

Protein Transport ◽

Albumin Concentration ◽

Sprague Dawley ◽

Tissue Samples ◽

Rat Mesentery ◽

Sprague Dawley Rats

Animal preparations for microscopy often require a superfusate solution to cover surgically exposed tissue. There are few, if any, data concerning the effects of this solution on extravascular protein concentration and hydration. The effect of superfusion on mesenteric tissue in anesthetized male Sprague-Dawley rats was studied. Tissue samples were taken from nonsuperfused and superfused tissue and analyzed for hydration, albumin, and transferrin content. The mesenteric tissue interstitial matrix was rapidly altered by normal saline superfusate. After superfusion, there was a decrease (P < 0.01) in tissue albumin concentration from 1.17 +/- 0.27 to 0.10 +/- 0.08 g/dl (n = 9). Tissue hydration increased from 4.98 +/- 0.8 micrograms water/microgram dry wt in controls to 7.38 +/- 1.2 micrograms water/micrograms dry wt after superfusion. When a range of superfusate albumin concentrations was used (0, 1, 2, and 3 g/dl), tissue albumin concentration changed 0.59 +/- 0.09 g/dl for each gram per deciliter change in superfusate concentration (P < 0.0001). The large changes in interstitial matrix protein content and hydration suggest that superfusate solution effects need to be considered in microvascular protein transport experiments.

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Withdrawal of cefoperazone with milk after intramammary administration in dairy cows – prospective and retrospective analysis

Polish Journal of Veterinary Sciences ◽

10.1515/pjvs-2017-0031 ◽

2017 ◽

Vol 20 (2) ◽

pp. 261-268

Author(s):

A. Burmańczuk ◽

T. Grabowski ◽

T. Błądek ◽

C. Kowalski ◽

P. Dębiak

Keyword(s):

Dairy Cows ◽

Half Life ◽

Drug Distribution ◽

Compartment Model ◽

Clinical Mastitis ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Lactation Period ◽

Milk Samples ◽

Drug Concentrations

Abstract The aim of the study was to carry out retrospective and prospective comparative analyses of the pharmacokinetics of CEF after single intramammary (IMM) administration in cows. The prospective study (study A) was conducted on 9 dairy cows of the Polish Black-White race with clinical mastitis during the lactation period. Milk samples were collected at 2, 4, 6, 8, 10, 24, 36, 48, 72 and 84 h after single IMM administration of 250 mg of CEF to one quarter. Drug concentrations in milk samples were determined by HPLC-MS/MS technique and the results of the pharmacokinetic analysis were compared to those obtained in previous studies based on the microbiological (study B) and HPLC-UV methods (study C and D). Pharmacokinetic parameters were calculated based on adapted two-compartment model of drug distribution. One of the findings of the comparison of the analysed investigations is that the CEF kinetics determined with the microbiological method is consistent with the results obtained by the authors of this paper. Both studies yielded similar results of the key pharmacokinetic parameters related to the level of the drug distribution to tissues and elimination half-life. In the pharmacodynamic analysis, the observations in all four studies were entirely consistent and have shown lower values of T>MIC90 in healthy animals and significantly higher values in infected dairy cows. The comparison of studies A, B, C, and D revealed that the time of complete CEF wash-out of 90.90% varied and amounted to 5.7, 8.0, 2.2, and 2.2 days after administration of the drug, respectively. It was confirmed that not only the type of the analytical method but also correct sampling have a significant impact on determination of the correct value of the drug half-life after IMM administration. The comparative analysis of studies in which the milk yield was high and low allows a conclusion that this parameter in the case of CEF has no significant effect on T>MIC90.

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