Retraction: Pharmacokinetic Interaction of Paeoniflorin and Sinomenine: Pharmacokinetic Parameters and Tissue Distribution Characteristics in Rats and Protein Binding Ability In Vitro  Retraction: Erratum to J Pharmacol Sci 99, 381-391 (2005)

ABSTRACTOne of the most frequent comorbidities of HIV infection is depression, with a lifetime prevalence of 22 to 45%. Therefore, it was decided to study a potential pharmacokinetic interaction between the nonnucleoside reverse transcriptase inhibitor nevirapine (NVP) and the tricyclic antidepressant nortriptyline (NT). NVP and NT were administered to rats either orally, intraduodenally, or intravenously, and the changes in plasma levels and pharmacokinetic parameters were analyzed. Experiments with rat and human hepatic microsomes were carried out to evaluate the inhibitory effects of NT on NVP metabolism. NVP plasma concentrations were significantly higher when this drug was coadministered with NT. The maximum plasma concentrations of NVP were increased 2 to 5 times and the total plasma clearance was decreased 7-fold in the presence of NT. However, statistically significant differences in the pharmacokinetic parameters of NT in the absence and presence of NVP were not found.In vitrostudies with rat and human hepatic microsomes confirmed the inhibition of NVP hepatic metabolism by NT in a concentration-dependent way, with the inhibition being more intense in the case of rat microsomes. In conclusion, a pharmacokinetic interaction between NVP and NT was detected. This interaction was a consequence of the inhibition of hepatic metabolism of NVP by NT.In vivohuman studies are required to evaluate the effects of this interaction on the pharmacokinetics of NVP before it can be taken into account for patients receiving NVP.

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Pharmacokinetic Modeling and Simulations of Interaction of Amprenavir and Ritonavir

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.3.746-754.2002 ◽

2002 ◽

Vol 46 (3) ◽

pp. 746-754 ◽

Cited By ~ 39

Author(s):

Mark Sale ◽

Brian M. Sadler ◽

Daniel S. Stein

Keyword(s):

Protein Binding ◽

Interaction Model ◽

Pharmacokinetic Interaction ◽

Wild Type Virus ◽

Maximum Effect ◽

Pharmacokinetic Parameters ◽

Wild Type ◽

Mixed Effect ◽

Once Daily ◽

Dosing Regimens

ABSTRACT Data from three pharmacokinetic drug interaction studies of amprenavir and ritonavir were used to develop a pharmacokinetic interaction model using NONMEM (nonlinear mixed-effect model). A two-compartment linear model with first-order absorption best fit the amprenavir data, while a one-compartment model was used to describe the ritonavir data. The inhibition of elimination of amprenavir by ritonavir was modeled with a maximum effect (E max) inhibition model and the observed ritonavir concentration. Monte Carlo simulation was then used to predict amprenavir concentrations for various combinations of amprenavir and ritonavir in twice-daily and once-daily dosing regimens. Simulated minimum amprenavir concentrations in plasma (C min) in twice-daily and once-daily dosing regimens were compared with protein binding-adjusted 50% inhibitory concentrations (IC50s) for clinical human immunodeficiency virus isolates with different susceptibilities to protease inhibitors (central tendency ratios). The model based on the first two studies predicted the results of the third study. Data from all three studies were then combined to refine the final model. The observed and simulated noncompartmental pharmacokinetic parameters agreed well. From this model, several candidate drug regimens were simulated. These simulations suggest that, in patients who have clinically failed a traditional amprenavir regimen, a regimen of 600 mg of amprenavir with 100 mg of ritonavir twice daily would result in C min-to-IC50 ratios similar to that of 1,200 mg of amprenavir twice daily alone for wild-type viruses. In addition, once-daily regimens that result in C mins above the protein binding-corrected IC50s for wild-type virus are clearly feasible.

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Identification of an MIP-1α–binding heparan sulfate oligosaccharide that supports long-term in vitro maintenance of human LTC-ICs

Blood ◽

10.1182/blood-2002-08-2588 ◽

2003 ◽

Vol 101 (6) ◽

pp. 2243-2245 ◽

Cited By ~ 9

Author(s):

Sally E. Stringer ◽

Matthew S. Nelson ◽

Pankaj Gupta

Keyword(s):

Protein Binding ◽

Heparan Sulfate ◽

Size Structure ◽

Structural Features ◽

Minimum Size ◽

Binding Ability ◽

Inflammatory Protein ◽

Wide Range

We previously showed that heparan sulfate (HS) is required for in vitro cytokine + chemokine-mediated maintenance of primitive human hematopoietic progenitors. However, HS preparations are mixtures of polysaccharide chains of varying size, structure, and protein-binding abilities. Therefore, we examined whether the long-term culture-initiating cells (LTC-IC) supportive capability of HS is attributable to an oligosaccharide of defined length and protein-binding ability. Oligosaccharides of a wide range of sizes were prepared, and their capability to support human marrow LTC-IC maintenance in the presence of low-dose cytokines and a single chemokine, macrophage inflammatory protein-1α (MIP-1α), was examined. LTC-IC supportive capability of HS oligosaccharides correlated directly with size and MIP-1α binding ability. A specific MIP-1α-binding HS oligosaccharide preparation of Mr 10 kDa that optimally supported LTC-IC maintenance was identified. This oligosaccharide had the structure required for MIP-1α binding, which we have recently described. The present study defines the minimum size and structural features of LTC-IC supportive HS.

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Pharmacokinetic interactions: from mechanisms to clinical relevance

Batna Journal of Medical Sciences (BJMS) ◽

10.48087/bjmstf.2014.1209 ◽

2014 ◽

Vol 1 (2) ◽

pp. 85-95

Author(s):

Amel Ahmane ◽

◽

Hocine Gacem ◽

Karim Boulesbiaat ◽

Meriem Boullelli

Keyword(s):

Protein Binding ◽

Drug Interactions ◽

Tissue Distribution ◽

Nuclear Receptors ◽

Clinical Relevance ◽

Pharmacokinetic Interaction ◽

Current Data ◽

Pharmacological Properties ◽

Drug Concentrations ◽

Pharmacokinetic Properties

Among the various types of known drug interactions, those involving pharmacokinetic processes are more complex and dangerous. From digestive pH changes to plasma protein binding and induction or inhibition phenomena; current data used to define, with precision, the sites of interaction. The enzymes involved in metabolism, the transporters involved in tissue distribution and excretion of drugs, and nuclear receptors that regulate the expression of these enzymes and transporters are keys determinants that should be defined for each drug. The clinical relevance of a pharmacokinetic interaction is related to the magnitude of changes in drug concentrations and pharmacological properties of these. Good knowledge of the pharmacokinetic properties of drugs and the mechanisms involved in the genesis of these interactions is, then, needed to prevent and avoid theme.

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In Vitro ADME, Preclinical Pharmacokinetics and Prediction of Human Pharmacokinetics of RBx14255, a Novel Ketolide with Pharmacodynamics Against Multidrug-Resistant Bacterial Pathogens

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/jpps30942 ◽

2020 ◽

Vol 23 ◽

pp. 206-219

Author(s):

SAMUEL RAJ VETHAKKANI ◽

Trdib Chaira ◽

Tarani Barman

Keyword(s):

Protein Binding ◽

Plasma Protein Binding ◽

Plasma Protein ◽

Oral Dosage ◽

Absolute Bioavailability ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Studies ◽

Human Pharmacokinetics ◽

Infection Models

Purpose: The preclinical pharmacokinetic and pharmacodynamic properties of a potent fluoroketolide RBx14255 against Streptococcus pneumoniae and Haemophilus influenzae was compared with telithromycin and human clinical dose was predicted for preclinical development. Methods: The in vitro pharmacokinetic characterization was performed for solubility, Caco-2 permeability, microsomal stability, CYP inhibition and plasma protein binding. In vivo pharmacokinetic studies were performed in Swiss albino mice, Sprague Dawley rats and Beagle dogs. The pharmacodynamic studies were carried out in mouse against S. pneumoniae in systemic infection and against S. pneumoniae and H. influenzae in rat lung infection models. Results: RBx14255 showed superior potency and efficacy in mouse and rat infection models. RBx14255 showed pH dependent solubility (0.41 mg/mL at pH 6.8 and >1 mg/mL at pH 1.2), moderate Caco-2 permeability (A to B: 12 nm/s) with high efflux ratio. It showed high plasma protein binding (>97%) in mouse and low binding (45-70%) in rat, dog and human. The compound is mainly metabolized through CYP3A4. Pharmacokinetic parameters and absolute bioavailability of both, RBx14255 and telithromycin are similar in mouse. Both the ketolides showed low plasma clearance (18% of the normal hepatic blood flow rate) in mouse, moderate to high clearance in rat and dog. Mean oral bioavailability was high in mouse (≥85%), moderate in rat (RBx14255: 15% and telithromycin: 51%) and high to moderate in dog (RBx14255: 98% and telithromycin: 56%). The predicted efficacious dose for a 70 kg man ranges from 124 mg BID to 226 mg BID. Conclusion: RBx14255 displayed significantly better pharmacodynamics which correlates with the pharmacokinetic properties against S. pneumoniae and H. influenzae as compared to telithromycin. The predicted human efficacious doses are in the range of 124-226 mg, making it amenable to oral dosage form drug in human. This could be a promising clinical candidate for future studies.

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Development of 11-DGA-3-O-Gal-Modified Cantharidin Liposomes for Treatment of Hepatocellular Carcinoma

Molecules ◽

10.3390/molecules24173080 ◽

2019 ◽

Vol 24 (17) ◽

pp. 3080

Author(s):

Lili Zhou ◽

Manshu Zou ◽

Kun Zhu ◽

Shuangcheng Ning ◽

Xinhua Xia

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle ◽

Cell Migration ◽

Tissue Distribution ◽

Targeted Delivery ◽

Inhibition Mechanism ◽

Pharmacokinetic Parameters ◽

Distribution Analysis ◽

Targeting Efficiency

Background: Liver cancer is a common malignant tumor worldwide, and its morbidity and mortality increase each year. The disease has a short course and high mortality, making it a serious threat to human health. Purpose: The objective of this study was to create novel liver-targeting nanoliposomes to encapsulate cantharidin (CTD) as a potential treatment for hepatic carcinoma. Methods: 3-Galactosidase-30-stearyl deoxyglycyrrhetinic acid (11-DGA-3-O-Gal)-modified liposomes (11-DGA-3-O-Gal-CTD-lip) for the liver-targeted delivery of CTD were prepared via the film-dispersion method and characterized. In vitro analyses of the effects on cellular cytotoxicity, cell migration, cell cycle, and cell apoptosis were carried out and an in vivo pharmacokinetics study and tissue distribution analysis were performed. Results: Compared with unmodified liposomes (CTD-lip), 11-DGA-3-O-Gal-CTD-lip showed higher cytotoxicity and increased the inhibition of HepG2 cell migration, but they did not increase the apoptotic rate of cells. The inhibition mechanism of 11-DGA-3-O-Gal-CTD-lip on hepatocellular carcinoma was partly through cell cycle arrest at the S phase. Analysis of pharmacokinetic parameters indicated that 11-DGA-3-O-Gal-CTD-lip were eliminated more rapidly than CTD-lip. Regarding tissue distribution, the targeting efficiency of 11-DGA-3-O-Gal-CTD-lip to the liver was (41.15 ± 3.28)%, relative targeting efficiency was (1.53 ± 0.31)%, relative uptake rate was( 1.69 ± 0.37)%, and peak concentration ratio was (2.68 ± 0.12)%. Conclusion: 11-DGA-3-O-Gal-CTD-lip represent a promising nanocarrier for the liver-targeted delivery of antitumor drugs to treat hepatocellular carcinoma.

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