scholarly journals Altered Pharmacokinetics of Daunorubicin in Rats with CCl4-Induced Hepatic Injury

2007 ◽  
Vol 10 (4) ◽  
pp. 443 ◽  
Author(s):  
Min-Koo Choi ◽  
Im-Sook Song ◽  
Dae-Duk Kim ◽  
Suk-Jae Chung ◽  
Chang-Koo Shim
Keyword(s):  
Hepatic Injury ◽  
Hepatic Metabolism ◽  
Isolated Hepatocytes ◽  
Fasting Period ◽  
Time Curve ◽  
Concentration Time ◽  
Single Intraperitoneal Injection ◽  
In Vivo Pharmacokinetics

PURPOSE. The effect of CCl4-induced experimental hepatic injury (CCl4-EHI) on the pharmacokinetics of daunorubicin was investigated systemically in rats, in an attempt to elucidate the major determinants of the effect of CCl4-EHI on the pharmacokinetics of the drug. METHODS. CCl4-EHI was induced in rats by a single intraperitoneal injection of CCl4 (1mL/kg rat), and a 24 h fasting period. Daunorubicin was administered intravenously to control and EHI rats at a dose of 11.3 mg/mL/kg and the in vivo pharmacokinetics was studied. The in vitro uptake of the drug into isolated hepatocytes and canalicular liver plasma membrane (cLPM) vesicles, as well as the liver microsomal degradation of the drug, were also determined. RESULTS. The area under the plasma concentration-time curve (AUC) of daunorubicin was increased by 1.6 times, resulting in a 34% decrease in the systemic clearance (CL) in rats with CCl4-EHI. The apparent biliary (CLbile) and urinary (CLurine) clearance of the drug were unchanged, whereas the AUC of daunorubicinol, the major metabolite of daunorubicin, was decreased by 66% in rats with CCl4-EHI. EHI seemed to affect the hepatobiliary elimination of the drug in several ways: the in vitro intrinsic sinusoidal uptake clearance was decreased by 20%; the in vitro intrinsic canalicular excretion clearance of the drug was increased by 1.7 times; and the in vitro liver microsomal degradation of daunorubicin was significantly retarded. CONCLUSIONS. CCl4-EHI appears to impair the hepatic metabolism of daunorubicin, thereby decreasing the CL and increasing the AUC of daunorubicin.

In vitro and in vivo antifungal activities of ER-30346, a novel oral triazole with a broad antifungal spectrum.

1996 ◽  
Vol 40 (10) ◽  
pp. 2237-2242 ◽  
Author(s):  
K Hata ◽  
J Kimura ◽  
H Miki ◽  
T Toyosawa ◽  
T Nakamura ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Candida Glabrata ◽  
Candida Parapsilosis ◽  
Good Activity ◽  
Time Curve ◽  
Concentration Time ◽  
Wide Range ◽  
Systemic Infections

ER-30346 is a novel oral triazole with a broad spectrum of potent activity against a wide range of fungi. ER-30346, with MICs at which 90% of the strains tested are inhibited (MIC90s) ranging from 0.025 to 0.78 microgram/ml, was 4 to 32 times more active than itraconazole, fluconazole, and amphotericin B against Candida albicans, Candida parapsilosis, and Candida glabrata. Against Candida tropicalis, ER-30346, with an MIC90 of 12.5 micrograms/ml, was 2 to > 8 times more active than itraconazole and fluconazole, but was 16 times less active than amphotericin B. ER-30346 (MIC90, 0.78 microgram/ml) was four to eight times more active than fluconazole and amphotericin B and had activity comparable to that of itraconazole against Trichosporon beigelli. The MIC90s of ER-30346 were 0.10 microgram/ml for Cryptococcus neoformans and 0.39 microgram/ml for Aspergillus fumigatus. ER-30346 was 2 to 8 times more active than itraconazole and amphotericin B and 32 to > 256 times more active than fluconazole. ER-30346 also showed good activity against dermatophytes, with MICs ranging from 0.05 to 0.39 microgram/ml, and its activity was comparable to or 2 to 16 times higher than those of itraconazole and amphotericin B and > 32 times higher than that of fluconazole. In vivo activity was evaluated with systemic infections in mice. Against systemic candidiasis and cryptococcosis, ER-30346 was comparable in efficacy to fluconazole and was more effective than itraconazole. Of the drugs tested, ER-30346 was the most effective drug against systemic aspergillosis. We studied the levels of ER-30346 in mouse plasma. The maximum concentration of drug in plasma and the area under the concentration-time curve for ER-30346 showed good linearity over a range of doses from 2 to 40 mg/kg of body weight.

Prophylactic Effect Of Aqueous Propolis Extract Against Acute Experimental Hepatotoxicity In Vivo

2002 ◽  
Vol 57 (3-4) ◽  
pp. 379-385 ◽  
Author(s):  
Aiman S. El-Khatib ◽  
Azza M. Agha ◽  
Laila G. Mahran ◽  
Mohamed T. Khayyal
Keyword(s):  
Reduced Glutathione ◽  
Wide Spectrum ◽  
Folk Medicine ◽  
Lipid Peroxide ◽  
Isolated Hepatocytes ◽  
Propolis Extract ◽  
Single Intraperitoneal Injection ◽  
Liver Homogenates

Propolis has been extensively used in folk medicine for the management of a wide spectrum of disorders. In a previous study, we demonstrated the protective effect of the aqueous propolis extract (APE) against the injurious effects of carbon tetrachloride (CCl4) on hepatocytes in vitro. The present investigation was carried out to show whether the hepatoprotective effect of the extract could also be manifested in vivo. Rats were given APE orally for 14 consecutive days, before being subjected to a single intraperitoneal injection of CCl4. One day after the CCl4 injection, the animals were sacrificed, hepatocytes were isolated and liver homogenates were prepared for the assessment of liver injury. In isolated hepatocytes, APE afforded protection against CCl4-induced injury as manifested by a decrease in the leakage of the cytosolic enzyme lactate dehydrogenase (LDH), decreased generation of lipid peroxide and maintenance of cellular reduced glutathione (GSH) content. In principle, similar findings were observed in liver homogenates. The present findings show that APE has in vivo hepatoprotective potential which could be attributed at least in part to the maintenance of cellular GSH content. The latter effect seems to play an important role in conserving the integrity of biomembranes as it was associated with a decrease in lipid peroxidation and reduced leakage of cytosolic LDH

scholarly journals Comparative Efficacies of Tedizolid Phosphate, Vancomycin, and Daptomycin in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Endocarditis

2015 ◽  
Vol 59 (6) ◽  
pp. 3252-3256 ◽  
Author(s):  
Liana C. Chan ◽  
Li Basuino ◽  
Etyene C. Dip ◽  
Henry F. Chambers
Keyword(s):  
Staphylococcus Aureus ◽  
Rabbit Model ◽  
Time Curve ◽  
Methicillin Resistant ◽  
Content Type ◽  
Treatment Groups ◽  
Concentration Time ◽  
Dose Ranging

ABSTRACTTedizolid, the active component of the prodrug tedizolid phosphate, is a novel oxazolidinone that is approximately 4 times more active by weight than linezolid againstStaphylococcus aureusin vitro. Thein vivoefficacy of tedizolid phosphate (15 mg/kg body weight intravenous [i.v.] twice a day [b.i.d.]) was compared to those of vancomycin (30 mg/kg i.v. b.i.d.) and daptomycin (18 mg/kg i.v. once a day [q.d.]) in a rabbit model of aortic valve endocarditis (AVE) caused by methicillin-resistantS. aureusstrain COL (infection inoculum of 107CFU). Median vegetation titers of daptomycin-treated rabbits were significantly lower than those of rabbits treated with tedizolid phosphate (15 mg/kg b.i.d.) (P= 0.016), whereas titers for vancomycin-treated compared to tedizolid-treated rabbits were not different (P= 0.984). The numbers of organisms in spleen and kidney tissues were similar for all treatment groups. A dose-ranging experiment was performed with tedizolid phosphate (2, 4, and 8 mg/kg b.i.d.) compared to vancomycin (30 mg/kg b.i.d.), using a higher infecting inoculum (108CFU) to determine the lowest efficacious dose of tedizolid phosphate. Tedizolid phosphate (2 mg/kg) (equivalent to 60% of the area under the concentration-time curve from 0 to 24 h (AUC0–24) for the human 200-mg dose approved by the U.S. Food and Drug Administration) was not efficacious. Tedizolid phosphate at 4 mg/kg (equivalent to 75% of the AUC0–24for the human 400-mg dose) and 8 mg/kg produced lower vegetation titers than the control, but neither was as efficacious as vancomycin.

scholarly journals Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Dose Selection for ME1100, an Arbekacin Inhalation Solution

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Sujata M. Bhavnani ◽  
Jeffrey P. Hammel ◽  
Elizabeth A. Lakota ◽  
M. Courtney Safir ◽  
Brian D. VanScoy ◽  
...  
Keyword(s):  
Compartment Model ◽  
Simulated Patients ◽  
Population Pharmacokinetic ◽  
Total Drug ◽  
Target Attainment ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time

ABSTRACT ME1100 (arbekacin inhalation solution) is an inhaled aminoglycoside that is being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken to evaluate ME1100 regimens for the treatment of patients with HABP/VABP. The data used included a population pharmacokinetic (PPK) 4-compartment model with 1st-order elimination, nonclinical PK-PD targets from one-compartment in vitro and/or in vivo infection models, and in vitro surveillance data. Using the PPK model, total-drug epithelial lining fluid (ELF) concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr) (ml/min/1.73 m2) values. Percent probabilities of PK-PD target attainment by MIC were determined based on the ratio of total-drug ELF area under the concentration-time curve (AUC) to MIC (AUC/MIC ratio) targets associated with 1- and 2-log10 CFU reductions from baseline for Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. Percent probabilities of PK­PD target attainment based on PK-PD targets for a 1-log10 CFU reduction from baseline at MIC values above the MIC90 value for K. pneumoniae (8 μg/ml), P. aeruginosa (4 μg/ml), and S. aureus (0.5 μg/ml) were ≥99.8% for ME1100 600 mg twice daily (BID) in simulated patients with CLcr values >80 to ≤120 ml/min/1.73 m2. ME1100 600 mg BID, 450 mg BID, and 600 mg once daily in simulated patients with CLcr values >50 to ≤80, >30 to ≤50, and 0 to ≤30 ml/min/1.73 m2, respectively, provided arbekacin exposures that best matched those for 600 mg BID in simulated patients with normal renal function. These data provide support for ME1100 as a treatment for patients with HABP/VABP.

scholarly journals Pharmacokinetic Study of NADPH Oxidase Inhibitor Ewha-18278, a Pyrazole Derivative

Pharmaceutics ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 482
Author(s):  
Seul Gee Lee ◽  
Jaeok Lee ◽  
Kyung Min Kim ◽  
Kee-In Lee ◽  
Yun Soo Bae ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Oxidase Inhibitor ◽  
High Concentration ◽  
Time Curve ◽  
Suitable Candidate ◽  
Nadph Oxidase Inhibitor ◽  
Concentration Time ◽  
Zero Time

In a previous study, the specific NOX1/2/4 inhibitor Ewha-18278 was confirmed as a possible treatment for osteoporosis both in vitro and in vivo. Here, we investigated the pharmacokinetics (PK) of the compound by intravenous (IV) and oral administrations to rats. Dimethyl sulfoxide (DMSO)-based and diazepam injection-based formulations were used to dissolve the compound. In the latter formulation applicable to humans, the changes in PK parameters were monitored at two different concentrations (1 mg/mL and 2 mg/mL). The area under the plasma concentration-time curve from zero time to infinity (AUCinf) of Ewha-18278 was highest in the DMSO-based formulation (2 mg/mL). Also, the concentration was increased 1.6-fold at the low concentration of the diazepam injection-based formulation compared to the high concentration. There was no statistical significance in the AUCinf of the compound between DMSO-based formulation (2 mg/mL) and diazepam injection-based formulation (1 mg/mL). These results suggest that Ewha-18278 can be delivered to humans by both IV and oral routes. In addition, the diazepam injection-based formulation of Ewha-18278 appears to be a suitable candidate for dosage development for future toxicity test and clinical trial.

scholarly journals Effects of Silymarin on the In Vivo Pharmacokinetics of Simvastatin and Its Active Metabolite in Rats

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1666
Author(s):  
Ying Li ◽  
Yin Wu ◽  
Ya-Jing Li ◽  
Lu Meng ◽  
Cong-Yang Ding ◽  
...  
Keyword(s):  
Active Metabolite ◽  
Compartmental Model ◽  
Elimination Rate ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Simultaneous Quantification ◽  
Concentration Time ◽  
Significant Difference ◽  
In Vivo Pharmacokinetics

Herein, the effect of silymarin pretreatment on the pharmacokinetics of simvastatin in rats was evaluated. To ensure the accuracy of the results, a rapid and sensitive UPLC–MS/MS method was established for simultaneous quantification of simvastatin (SV) and its active metabolite simvastatin acid (SVA). This method was applied for studying the pharmacokinetic interactions in rats after oral co-administration of silymarin (45 mg/kg) and different concentrations of SV. The major pharmacokinetic parameters, including Cmax, tmax, t1/2, mean residence time (MRT), elimination rate constant (λz) and area under the concentration-time curve (AUC0–12h), were calculated using the non-compartmental model. The results showed that the co-administration of silymarin and SV significantly increased the Cmax and AUC0–12h of SVA compared with SV alone, while there was no significant difference with regards to Tmax and t1/2. However, SV pharmacokinetic parameters were not significantly affected by silymarin pretreatment. Therefore, these changes indicated that drug-drug interactions may occur after co-administration of silymarin and SV.

scholarly journals Pharmacokinetics and Pharmacodynamics of Minocycline against Acinetobacter baumannii in a Neutropenic Murine Pneumonia Model

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Jian Zhou ◽  
Kimberly R. Ledesma ◽  
Kai-Tai Chang ◽  
Henrietta Abodakpi ◽  
Song Gao ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Multidrug Resistant ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Dose Linearity ◽  
Unit Reduction ◽  
The Relationship

ABSTRACT Multidrug-resistant (MDR) Acinetobacter baumannii is increasingly more prevalent in nosocomial infections. Although in vitro susceptibility of A. baumannii to minocycline is promising, the in vivo efficacy of minocycline has not been well established. In this study, the in vivo activity of minocycline was evaluated in a neutropenic murine pneumonia model. Specifically, we investigated the relationship between minocycline exposure and bactericidal activity using five A. baumannii isolates with a broad range of susceptibility (MIC ranged from 0.25 mg/liter to 16 mg/liter). The pharmacokinetics of minocycline (single dose of 25 mg/kg of body weight, 50 mg/kg, 100 mg/kg, and a humanized regimen, given intraperitoneally) in serum and epithelial lining fluid (ELF) were characterized. Dose linearity was observed for doses up to 50 mg/kg and pulmonary penetration ratios (area under the concentration-time curve in ELF from 0 to 24 h [AUCELF,0–24]/area under the concentration time curve in serum from 0 to 24 h [AUCserum,0–24]) ranged from 2.5 to 2.8. Pharmacokinetic-pharmacodynamics (PK-PD) index values in ELF for various dose regimens against different A. baumannii isolates were calculated. The maximum efficacy at 24 h was approximately 1.5-log-unit reduction of pulmonary bacterial burdens from baseline. The AUC/MIC ratio was the PK-PD index most closely correlating to the bacterial burden (r 2 = 0.81). The required AUCELF,0–24/MIC for maintaining stasis and achieving 1-log-unit reduction were 140 and 410, respectively. These findings could guide the treatment of infections caused by A. baumannii using minocycline in the future. Additional studies to examine resistance development during therapy are warranted.

Time course of changes in hepatic metabolism in response to sepsis in the rat: Impairment of gluconeogenesis and ketogenesis in vitro

1987 ◽  
Vol 72 (6) ◽  
pp. 683-691 ◽  
Author(s):  
Paulo R.L. De Vasconcelos ◽  
Michael G. W. Kettlewell ◽  
Dermot H. Williamson
Keyword(s):  
Time Course ◽  
Ketone Bodies ◽  
Hepatic Metabolism ◽  
Isolated Hepatocytes ◽  
Hepatic Lipogenesis ◽  
Chain Acyl ◽  
Caecal Ligation And Puncture ◽  
Caecal Ligation

1. The time course (12, 24 and 48 h) of changes in blood metabolites, and in gluconeogenesis and ketogenesis, in isolated hepatocytes from rats made septic by caecal ligation and puncture was measured. 2. Blood glucose was not significantly different in septic rats, but lactate was increased at 12, 24 and 48 h; pyruvate and alanine were increased at 48 h. The blood ketone body concentrations were decreased at all times studied after induction of sepsis. These changes were accompanied by increased plasma insulin in the septic rats. 3. The rate of hepatic lipogenesis in vivo was increased at 24 and 48 h. 4. There were appreciable increases in the hepatic concentrations of alanine (200%), lactate (200%) and pyruvate (100%) as well as other intermediates in the gluconeogenic pathway. The hepatic concentrations of acetyl-CoA and ketone bodies were decreased. 5. The rate of gluconeogenesis from added lactate, pyruvate, alanine and glutamine was depressed in isolated hepatocytes from septic rats at 24 and 48 h. 6. The basal rate of ketogenesis or the rate from butyrate in isolated hepatocytes was not significantly altered by sepsis, whereas the rate from oleate was decreased at all time points. 7. It is concluded that there is an impairment of the capacity for gluconeogenesis and ketogenesis in livers of septic rats. The latter may be due to decreased entry of long-chain acyl-CoA into the mitochondria for oxidation. The possibility that these changes are in part brought about by the hyperinsulinaemia associated with the sepsis is discussed.

Effect of Carbonized Herba schizonepetae on the Bioavailability of Eight Active Components from Pulsatillae Decoction in Its Particular Adsorption and Release Performance

2021 ◽  
Vol 22 ◽  
Author(s):  
Cuiyan Liu ◽  
Yun Zhu ◽  
Yanfei He ◽  
Guangtai Fan ◽  
Jingang Gu ◽  
...  
Keyword(s):  
Herbal Medicine ◽  
Active Pharmaceutical Ingredients ◽  
Active Components ◽  
Time Curve ◽  
Pharmaceutical Ingredients ◽  
Concentration Time ◽  
Adsorption And Release ◽  
Adsorption Rates

Background: Carbonized herbal medicine has been used clinically for centuries in China; however, its influence on the bioavailability of compatible medicinal herbs is still unknown. Objective: To explore the effect of a carbonized herbal medicine on the in vivo adsorption and release and absorption of other active pharmaceutical ingredients in a compound prescription. Methods: The bioavailability of carbonized Herba schizonepetae (CHS) to eight active components (epiberberine, coptisine, palmatine, berberine, phellodendrine, aesculin, aesculetin, and anemoside B4) in the aqueous extract of Pulsatillae Decoction (PDAE) was evaluated by the in vitro adsorption and release and in vivo pharmacokinetics tests. Activated carbon (AC) was used as the control. Results: In vitro experiment showed that the cumulative adsorption rates of CHS to the eight active components were 33.17%, 54.32%, 21.48%, 42.01%, 39.1%, 25.11%, 32.11%, and 23.08% which was characterized by copsitine > berberine > phellodendrine > epiperberine > aesculetin > anemoside B4 > palmatine., and they were significantly lower than those of AC. The stable release concentration in sequence was 3.23, 3.04, 3.32, 7.29, 3.17, 2.80, 1.45, and 3.81 µg/mL, which was characterized by berberine > anemoside B4 > palmatine > epiberberine > phellodendrine > coptisine > aesculin > aesculetin, and they were significantly higher than those of AC. The animal experiment indicated that the areas under the concentration-time curve (AUC0-∞) of epiberberine, berberine, aesculetin, and anemoside B4 in PDAE+CHS group were significantly higher than those in the PDAE and PDAE+AC groups, and the other four components in the PDAE+CHS group were lower than those in PDAE group but higher than those in PDAE+AC group. Conclusion: CHS could significantly improve the bioavailability of epiberberine, berberine, aesculetin, and anemoside B4 in Pulsatillae Decoction and has a sustained-release effect on berberine, aesculin, aesculetin, and anemoside B4.

scholarly journals An Optimized Mouse Thigh Infection Model for Enterococci and Its Impact on Antimicrobial Pharmacodynamics

2014 ◽  
Vol 59 (1) ◽  
pp. 233-238 ◽  
Author(s):  
Carlos A. Rodriguez ◽  
Maria Agudelo ◽  
Javier M. Gonzalez ◽  
Omar Vesga ◽  
Andres F. Zuluaga
Keyword(s):  
Drug Exposure ◽  
Culture Conditions ◽  
Infection Model ◽  
Time Curve ◽  
Unbound Fraction ◽  
Concentration Time ◽  
Inoculum Preparation ◽  
High Level

ABSTRACTNegligiblein vivogrowth of enterococci and high-level dispersion of data have led to inaccurate estimations of antibiotic pharmacodynamics (PD). Here we improved anin vivomodel apt for PD studies by optimizing thein vitroculture conditions for enterococci. The PD of vancomycin (VAN), ampicillin-sulbactam (SAM), and piperacillin-tazobactam (TZP) against enterococci were determinedin vivo, comparing the following different conditions of inoculum preparation: aerobiosis, aerobiosis plus mucin, and anaerobiosis plus mucin. Drug exposure was expressed as the ratio of the area under the concentration-time curve for the free, unbound fraction of the drug to the MIC (fAUC/MIC) (VAN) or the time in a 24-h period that the drug concentration for the free, unbound fraction exceeded the MIC under steady-state pharmacokinetic conditions (fT>MIC) (SAM and TZP) and linked to the change in log10CFU/thigh. Only anaerobiosis plus mucin enhanced thein vivogrowth, yielding significant PD parameters with all antibiotics. In conclusion, robustin vivogrowth of enterococci was crucial for better determining the PD of tested antibacterial agents, and this was achieved by optimizing the procedure for preparing the inoculum.

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