scholarly journals Effects of Experimental Hyperlipidemia on the Pharmacokinetics of Tadalafil in Rats

2012 ◽  
Vol 15 (4) ◽  
pp. 528 ◽  
Author(s):  
Joo Hyun Lee ◽  
Ju-Hee Oh ◽  
Young-Joo Lee
Keyword(s):  
Erectile Dysfunction ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Poloxamer 407 ◽  
Time Curve ◽  
Unbound Fraction ◽  
Therapeutic Implications ◽  
Experimental Hyperlipidemia ◽  
Increased Risk

Purpose. Hyperlipidemia is associated with an increased risk of erectile dysfunction. In this study, we investigated the effects of hyperlipidemia on the pharmacokinetics of tadalafil, a novel therapeutic agent for erectile dysfunction, in rats with experimental hyperlipidemia. Methods. Tadalafil (1 mg/kg) was administered to control rats and rats with poloxamer-407-induced hyperlipidemia (1 g/kg, i.p.). In addition, we performed in vitro studies to determine the hepatic metabolism in S9 fractions, intestinal absorption, and plasma protein binding. Results. Hyperlipidemia dramatically increased tadalafil’s the total area under the plasma concentration-time curve from time 0 to infinity after intravenous (2.09-fold) and oral (11.9-fold) administration, and decreased total body clearance (0.537-fold) and apparent volume of distribution at the steady state (0.438-fold) after intravenous administration of tadalafil. Further, we observed decreased in vitro hepatic S9 metabolism, intestinal first-pass metabolism, and unbound fraction of tadalafil. Conclusions. The alterations in the pharmacokinetics of tadalafil observed in rats with poloxamer 407-induced hyperlipidemia may be attributable to a decrease in hepatic and intestinal metabolism and unbound fraction of tadalafil in the plasma. These findings have potential therapeutic implications for predicting the pharmacokinetic responses of humans to hyperlipidemia. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Pharmacokinetics of a Cytochrome P450 2E1 Probe, Chlorzoxazone, and its 6-Hydroxy Metabolite in Poloxamer 407-Induced Hyperlipidemic Rats

2013 ◽  
Vol 16 (4) ◽  
pp. 648 ◽  
Author(s):  
Mi Hye Kwon ◽  
Cheol Jung Lee ◽  
Yong Yeon Cho ◽  
Hee Eun Kang
Keyword(s):  
Intravenous Administration ◽  
Poloxamer 407 ◽  
Time Curve ◽  
Therapeutic Implications ◽  
Concentration Time ◽  
Probe Drug ◽  
Cyp2e1 Expression ◽  
Expression And Activity ◽  
Hydroxy Metabolite

Purpose. To evaluate the possible changes in CYP2E1 expression and activity in hyperlipidemia (HL), we evaluated the pharmacokinetics of chlorzoxazone (CZX) as a CYP2E1 probe in rats with HL induced by poloxamer 407 (HL rats). Methods. The pharmacokinetics of CZX and its 6-hydroxy metabolite (OH-CZX) were evaluated after intravenous administration of 20 mg/kg CZX to both control and HL rats. We also examined changes in the expression of CYP2E1 and its in vitro metabolic activity in hepatic microsomal fractions from HL rats. Results. The total area under the plasma concentration–time curve (AUC) of CZX in the HL rats after its intravenous administration was comparable with that in the controls due to unchanged non-renal clearance (CLNR). The AUC of OH-CZX and AUCOH-CZX/AUCCZX ratios in HL rats also remained unchanged. This was primarily due to the comparable hepatic CLint for metabolism of CZX to OH-CZX via CYP2E1 between the control and HL rats as a result of unchanged expression of CYP2E1 in HL rats. Conclusions. This is the first study to evaluate CYP2E1 expression and activity in HL rats and their effects on the pharmacokinetics of a CYP2E1 probe drug. These findings have potential therapeutic implications assuming that the HL rat model qualitatively reflects similar changes in patients with HL.

scholarly journals New In Vitro Methodology for Kinetics Distribution Prediction in the Brain. An Additional Step towards an Animal-Free Approach

Animals ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 3521
Author(s):  
Bárbara Sánchez-Dengra ◽  
Isabel González-Álvarez ◽  
Marta González-Álvarez ◽  
Marival Bermejo
Keyword(s):  
Brain Homogenate ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
New Drugs ◽  
In Vitro Tests ◽  
Unbound Fraction ◽  
Standard Tool ◽  
New Formulation ◽  
The Brain

The development of new drugs or formulations for central nervous system (CNS) diseases is a complex pharmacologic and pharmacokinetic process; it is important to evaluate their access to the CNS through the blood−brain barrier (BBB) and their distribution once they have acceded to the brain. The gold standard tool for obtaining this information is the animal microdialysis technique; however, according to 3Rs principles, it would be better to have an “animal-free” alternative technique. Because of that, the purpose of this work was to develop a new formulation to substitute the brain homogenate in the in vitro tests used for the prediction of a drug’s distribution in the brain. Fresh eggs have been used to prepare an emulsion with the same proportion in proteins and lipids as a human brain; this emulsion has proved to be able to predict both the unbound fraction of drug in the brain (fu,brain) and the apparent volume of distribution in the brain (Vu,brain) when tested in in vitro permeability tests. The new formulation could be used as a screening tool; only the drugs with a proper in vitro distribution would pass to microdialysis studies, contributing to the refinement, reduction and replacement of animals in research.

scholarly journals Evaluation of Accessory Gene Regulator (agr) Group and Function in the Proclivity towards Vancomycin Intermediate Resistance in Staphylococcus aureus

2006 ◽  
Vol 51 (3) ◽  
pp. 1089-1091 ◽  
Author(s):  
Brian T. Tsuji ◽  
Michael J. Rybak ◽  
Kerry L. Lau ◽  
George Sakoulas
Keyword(s):  
Staphylococcus Aureus ◽  
Wild Type ◽  
Accessory Gene ◽  
Time Curve ◽  
Unbound Fraction ◽  
Accessory Gene Regulator ◽  
Intermediate Resistance ◽  
And Function ◽  
Type Strains

ABSTRACT Simulated therapeutic vancomycin exposures were evaluated against agr wild-type and knockout Staphylococcus aureus groups I, II, III, and IV using an in vitro pharmacodynamic model. All agr groups developed intermediate resistance to vancomycin after subtherapeutic exposure. The free unbound fraction of the area under the concentration-time curve (fAUC/MIC) required to suppress resistance was fourfold higher (P < 0.001) in agr dysfunctional strains (112 to 169) than that in parent wild-type strains (28).

scholarly journals Comparative Efficacies of Human Simulated Exposures of Telavancin and Vancomycin against Methicillin-Resistant Staphylococcus aureus with a Range of Vancomycin MICs in a Murine Pneumonia Model

2010 ◽  
Vol 54 (12) ◽  
pp. 5115-5119 ◽  
Author(s):  
Jared L. Crandon ◽  
Joseph L. Kuti ◽  
David P. Nicolau
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Load ◽  
Infection Model ◽  
Time Curve ◽  
Unbound Fraction ◽  
Methicillin Resistant ◽  
Vancomycin Mics ◽  
Mrsa Strains

ABSTRACT Telavancin displays potent in vitro and in vivo activity against methicillin-resistant Staphylococcus aureus (MRSA), including strains with reduced susceptibility to vancomycin. We compared the efficacies of telavancin and vancomycin against MRSA strains with vancomycin MICs of ≥1 μg/ml in a neutropenic murine lung infection model. Thirteen clinical MRSA isolates (7 vancomycin-susceptible, 2 vancomycin-heteroresistant [hVISA], and 4 vancomycin-intermediate [VISA] isolates) were tested after 24 h, and 7 isolates (1 hVISA and 4 VISA isolates) were tested after 48 h of exposure. Mice were administered subcutaneous doses of telavancin at 40 mg/kg of body weight every 12 h (q12h) or of vancomycin at 110 mg/kg q12h; doses were designed to simulate the area under the concentration-time curve for the free, unbound fraction of drug (fAUC) observed for humans given telavancin at 10 mg/kg q24h or vancomycin at 1 g q12h. Efficacy was expressed as the 24- or 48-h change in lung bacterial density from pretreatment counts. At dose initiation, the mean bacterial load was 6.16 ± 0.26 log10 CFU/ml, which increased by averages of 1.26 ± 0.55 and 1.74 ± 0.68 log in untreated mice after 24 and 48 h, respectively. At both time points, similar CFU reductions were noted for telavancin and vancomycin against MRSA, with vancomycin MICs of ≤2 μg/ml. Both drugs were similarly efficacious after 24 and 48 h of treatment against the hVISA strains tested. Against VISA isolates, telavancin reduced bacterial burdens significantly more than vancomycin for 1 of 4 isolates after 24 h and for 3 of 4 isolates after 48 h. These data support the potential utility of telavancin for the treatment of MRSA pneumonia caused by pathogens with reduced susceptibility to vancomycin.

scholarly journals Toward Harmonization of Voriconazole CLSI and EUCAST Breakpoints for Candida albicans Using a Validated In Vitro Pharmacokinetic/Pharmacodynamic Model

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Maria-Ioanna Beredaki ◽  
Panagiota-Christina Georgiou ◽  
Maria Siopi ◽  
Lamprini Kanioura ◽  
David Andes ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Simulation Analysis ◽  
Maximal Activity ◽  
Wild Type ◽  
Time Curve ◽  
Unbound Fraction ◽  
Content Type ◽  
Interval Probability

ABSTRACT CLSI and EUCAST susceptibility breakpoints for voriconazole and Candida albicans differ by one dilution (≤0.125 and ≤0.06 mg/liter, respectively) whereas the epidemiological cutoff values for EUCAST (ECOFF) and CLSI (ECV) are the same (0.03 mg/liter). We therefore determined the pharmacokinetic/pharmacodynamic (PK/PD) breakpoints of voriconazole against C. albicans for both methodologies with an in vitro PK/PD model, which was validated using existing animal PK/PD data. Four clinical wild-type and non-wild-type C. albicans isolates (voriconazole MICs, 0.008 to 0.125 mg/liter) were tested in an in vitro PK/PD model. For validation purposes, mouse PK were simulated and in vitro PD were compared with in vivo outcomes. Human PK were simulated, and the exposure-effect relationship area under the concentration-time curve for the free, unbound fraction of a drug from 0 to 24 h (fAUC0–24)/MIC was described for EUCAST and CLSI 24/48-h methods. PK/PD breakpoints were determined using the fAUC0–24/MIC associated with half-maximal activity (EI50) and Monte Carlo simulation analysis. The in vitro 24-h PD EI50 values of voriconazole against C. albicans were 2.5 to 5 (1.5 to 17) fAUC/MIC. However, the 72-h PD were higher at 133 (51 to 347) fAUC/MIC for EUCAST and 94 (35 to 252) fAUC/MIC for CLSI. The mean (95% confidence interval) probability of target attainment (PTA) was 100% (95 to 100%), 97% (72 to 100%), 83% (35 to 99%), and 49% (8 to 91%) for EUCAST and 100% (97 to 100%), 99% (85 to 100%), 91% (52 to 100%), and 68% (17 to 96%) for CLSI for MICs of 0.03, 0.06, 0.125, and 0.25 mg/liter, respectively. Significantly, >95% PTA values were found for EUCAST/CLSI MICs of ≤0.03 mg/liter. For MICs of 0.06 to 0.125 mg/liter, trough levels 1 to 4 mg/liter would be required to attain the PK/PD target. A PK/PD breakpoint of C. albicans voriconazole at the ECOFF/ECV of 0.03 mg/liter was determined for both the EUCAST and CLSI methods, indicating the need for breakpoint harmonization for the reference methodologies.

Molecular Modeling Approaches for the Prediction of Selected Pharmacokinetic Properties

2019 ◽  
Vol 18 (26) ◽  
pp. 2230-2238 ◽  
Author(s):  
Emilio S. Petito ◽  
David J.R. Foster ◽  
Michael B. Ward ◽  
Matthew J. Sykes
Keyword(s):  
Molecular Modeling ◽  
In Silico ◽  
Volume Of Distribution ◽  
Future Directions ◽  
Unbound Fraction ◽  
Drug Candidates ◽  
New Methods ◽  
Pharmacokinetic Properties

Poor profiles of potential drug candidates, including pharmacokinetic properties, have been acknowledged as a significant hindrance to the development of modern therapeutics. Contemporary drug discovery and development would be incomplete without the aid of molecular modeling (in-silico) techniques, allowing the prediction of pharmacokinetic properties such as clearance, unbound fraction, volume of distribution and bioavailability. As with all models, in-silico approaches are subject to their interpretability, a trait that must be balanced with accuracy when considering the development of new methods. The best models will always require reliable data to inform them, presenting significant challenges, particularly when appropriate in-vitro or in-vivo data may be difficult or time-consuming to obtain. This article seeks to review some of the key in-silico techniques used to predict key pharmacokinetic properties and give commentary on the current and future directions of the field.

scholarly journals A Semimechanistic Pharmacokinetic-Enzyme Turnover Model for Rifampin Autoinduction in Adult Tuberculosis Patients

2012 ◽  
Vol 56 (4) ◽  
pp. 2091-2098 ◽  
Author(s):  
Wynand Smythe ◽  
Akash Khandelwal ◽  
Corinne Merle ◽  
Roxana Rustomjee ◽  
Martin Gninafon ◽  
...  
Keyword(s):  
Steady State ◽  
Hiv Infection ◽  
Selection Procedure ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Oral Clearance ◽  
Time Curve ◽  
Turnover Model ◽  
Enzyme Turnover ◽  
Apparent Volume Of Distribution

ABSTRACTThe currently recommended doses of rifampin are believed to be at the lower end of the dose-response curve. Rifampin induces its own metabolism, although the effect of dose on the extent of autoinduction is not known. This study aimed to investigate rifampin autoinduction using a semimechanistic pharmacokinetic-enzyme turnover model. Four different structural basic models were explored to assess whether different scaling methods affected the final covariate selection procedure. Covariates were selected by using a linearized approach. The final model included the allometric scaling of oral clearance and apparent volume of distribution. Although HIV infection was associated with a 30% increase in the apparent volume of distribution, simulations demonstrated that the effect of HIV on rifampin exposure was slight. Model-based simulations showed close-to-maximum induction achieved after 450-mg daily dosing, since negligible increases in oral clearance were observed following the 600-mg/day regimen. Thus, dosing above 600 mg/day is unlikely to result in higher magnitudes of autoinduction. In a typical 55-kg male without HIV infection, the oral clearance, which was 7.76 liters · h−1at the first dose, increased 1.82- and 1.85-fold at steady state after daily dosing with 450 and 600 mg, respectively. Corresponding reductions of 41 and 42%, respectively, in the area under the concentration-versus-time curve from 0 to 24 h were estimated. The turnover of the inducible process was estimated to have a half-life of approximately 8 days in a typical patient. Assuming 5 half-lives to steady state, this corresponds to a duration of approximately 40 days to reach the induced state for rifampin autoinduction.

scholarly journals Phase I Study To Evaluate the Pharmacokinetics, Safety, and Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Participants

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Eric Wenzler ◽  
Susan C. Bleasdale ◽  
Monica Sikka ◽  
Kristen L. Bunnell ◽  
Matthew Finnemeyer ◽  
...  
Keyword(s):  
Phase I ◽  
Healthy Adult ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Open Label ◽  
Time Curve ◽  
Elimination Half ◽  
Apparent Clearance ◽  
Dosing Regimens ◽  
Repeated Dosing

ABSTRACTThe pharmacokinetics (PK), safety, and tolerability of two repeated dosing regimens of oral fosfomycin tromethamine were evaluated in 18 healthy adult subjects. Subjects received 3 g every other day (QOD) for 3 doses and then every day (QD) for 7 doses, or vice versa, in a phase I, randomized, open-label, two-period-crossover study. Serial blood (n= 11) and urine (n= 4 collection intervals) samples were collected before and up to 24 h after dosing on days 1 and 5, along with predose concentrations on days 3 and 7. PK parameters were similar between days 1 and 5 within and between dosing regimens. The mean (± standard deviation [SD]) PK parameters for fosfomycin in plasma on day 5 during the respective QOD and QD dosing regimens were as follows: maximum concentration of drug in serum (Cmax) = 24.4 ± 6.2 versus 23.8 ± 5.6 μg/ml, time toCmax(Tmax) = 2.2 ± 0.7 versus 2.0 ± 0.4 h, apparent volume of distribution (V/F) = 141 ± 67.9 versus 147 ± 67.6 liters, apparent clearance (CL/F) = 21.4 ± 8.0 versus 20.4 ± 5.3 liters/h, renal clearance (CLR) = 7.5 ± 4.1 versus 7.3 ± 3.5 liters/h, area under the concentration-time curve from 0 to 24 h (AUC0–24) = 151.6 ± 35.6 versus 156.6 ± 42.5 μg · h/ml, and elimination half-life (t1/2) = 4.5 ± 1.1 versus 5.0 ± 1.7 h. Urine concentrations peaked at approximately 600 μg/ml through the 0- to 8-h urine collection intervals but displayed significant interindividual variability. Roughly 35 to 40% of the 3-g dose was excreted in the urine by 24 h postdose. No new safety concerns were identified during this study. The proportion of diarrhea-free days during the study was significantly lower with the QD regimen than with the QOD regimen (61% versus 77%;P< 0.0001). Further studies to establish the clinical benefit/risk ratio for repeated dosing regimens of oral fosfomycin tromethamine are warranted. (This trial is registered at ClinicalTrials.gov under registration no. NCT02570074.)

scholarly journals Decrease in Brain Distribution of Fluvoxamine in Experimental Hyperlipidemic Rats

2011 ◽  
Vol 14 (3) ◽  
pp. 414 ◽  
Author(s):  
Keizo Fukushima ◽  
Shinji Kobuchi ◽  
Masakazu Shibata ◽  
Kanji Takada ◽  
Nobuyuki Sugioka
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Protein Binding ◽  
Intravenous Administration ◽  
Intraperitoneal Administration ◽  
Plasma Lipoprotein ◽  
Plasma Lipoproteins ◽  
Poloxamer 407 ◽  
Time Curve

ABSTRACT: Purpose. Many clinical reports and trials have suggested that fluvoxamine (FLV) reduces plasma lipoprotein levels. However, few studies have reported the effect of plasma lipoproteins on FLV pharmacokinetics. The aim of the present study was to investigate the affinities of FLV to plasma lipoproteins and the effect of plasma lipoproteins on the biodistribution of FLV using an experimental hyperlipidemic (HL) rat model. Methods. HL rats were prepared by intraperitoneal administration of Poloxamer-407 solution (1.0 g/kg). In vitro protein binding and distribution of FLV in plasma lipoproteins were determined in control and HL rats. In vivo pharmacokinetic study (intravenous administration of FLV, 5.0 mg/kg) and biodistribution analysis for brain and liver at a steady state (infusion, 1.5 mg/kg/hr, 6 hrs) were also performed. Results. The plasma protein binding of FLV was around 83% and 95% in control and HL rats, respectively, whereas the FLV recoveries in triglyceride-rich lipoprotein fractions were increased in HL. Therefore, the elevation of lipoproteins was likely responsible for the increase in protein binding in HL. After intravenous administration, the area under the plasma concentration vs. time curve (AUC) in HL was 3.9-fold greater than that in control rats, whereas the distribution ratio of FLV plasma concentration to the brain at a steady state was decreased to approximately 20% of that of the control. Conclusions. FLV has an affinity to plasma lipoproteins, and their elevation might decrease the FLV biodistribution to brain; the plasma lipoprotein levels could not be found to correlate positively with the FLV pharmacokinetic effect in brain, but rather may attenuate it. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

CORTICOSTEROIDOGENESIS IN THE FRESH WATER AND SALINE-MAINTAINED DUCK (ANAS PLATYRHYNCHOS)

1965 ◽  
Vol 32 (3) ◽  
pp. 329-336 ◽  
Author(s):  
E. M. DONALDSON ◽  
W. N. HOLMES
Keyword(s):  
Fresh Water ◽  
Salt Solution ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Unit Weight ◽  
Secretory Rate ◽  
Corticosterone Secretion ◽  
Significant Difference

SUMMARY No differences were observed in the patterns of adrenal steroidogenesis in vitro by ducks maintained on fresh water or on a hypertonic salt solution. Determinations in vivo of the biological half-life of corticosterone showed no significant difference between ducks maintained on or loaded with saline and fresh water controls. An increase in the apparent volume of distribution of corticosterone was, however, observed in birds loaded with the salt solution after maintenance on fresh water or salt solution. Estimations were made of the secretory rate of corticosterone in vivo. In the ducks maintained on the salt solution an increased adrenal weight was responsible for the enhanced secretory rate but ducks maintained on fresh water and loaded with saline secreted corticosterone at a higher rate per unit weight of adrenal. The implications of the increased rate of corticosterone secretion are discussed in relation to the known dependence of nasal gland function in marine birds on a functional adrenal gland.

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