scholarly journals A Biophysical Insight of Camptothecin Biodistribution: Towards a Molecular Understanding of Its Pharmacokinetic Issues

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 869
Author(s):  
Andreia Almeida ◽  
Eduarda Fernandes ◽  
Bruno Sarmento ◽  
Marlene Lúcio
Keyword(s):  
Oral Administration ◽  
Plasma Proteins ◽  
Drug Delivery Systems ◽  
Phospholipid Composition ◽  
Free Drug ◽  
Membrane Interaction ◽  
Biophysical Analysis ◽  
Ordered Phases ◽  
Membrane Models ◽  
Large Distribution

Camptothecin (CPT) is a potent anticancer drug, and its putative oral administration is envisioned although difficult due to physiological barriers that must be overcome. A comprehensive biophysical analysis of CPT interaction with biointerface models can be used to predict some pharmacokinetic issues after oral administration of this or other drugs. To that end, different models were used to mimic the phospholipid composition of normal, cancer, and blood–brain barrier endothelial cell membranes. The logD values obtained indicate that the drug is well distributed across membranes. CPT-membrane interaction studies also confirm the drug’s location at the membrane cooperative and interfacial regions. The drug can also permeate membranes at more ordered phases by altering phospholipid packing. The similar logD values obtained in membrane models mimicking cancer or normal cells imply that CPT has limited selectivity to its target. Furthermore, CPT binds strongly to serum albumin, leaving only 8.05% of free drug available to be distributed to the tissues. The strong interaction with plasma proteins, allied to the large distribution (VDSS = 5.75 ± 0.932 L·Kg−1) and tendency to bioaccumulate in off-target tissues, were predicted to be pharmacokinetic issues of CPT, implying the need to develop drug delivery systems to improve its biodistribution.

scholarly journals A Biophysical Insight of Camptothecin Biodistribution: Towards a Molecular Understanding of Its Pharmacokinetic Issues

2021 ◽  
Author(s):  
Andreia Almeida ◽  
Eduarda Fernandes ◽  
Bruno Sarmento ◽  
Marlene Lúcio
Keyword(s):  
Oral Administration ◽  
Plasma Proteins ◽  
Drug Delivery Systems ◽  
Phospholipid Composition ◽  
Free Drug ◽  
Membrane Interaction ◽  
Biophysical Analysis ◽  
Ordered Phases ◽  
Membrane Models ◽  
Large Distribution

Camptothecin (CPT) is a potent anticancer drug, and its putative oral administration is envisioned although difficult due to physiological barriers that must be overcome. A comprehensive biophysical analysis of CPT interaction with biointerface models can be used to predict some pharmacokinetic issues after oral administration of this or other drugs. To that end, different models were used to mimic the phospholipid composition of normal, cancer, and blood-brain barrier endothelial cell membranes. The logD values obtained indicate that the drug is well distributed across membranes. CPT-membrane interaction studies also confirm the drug’s location at the membrane cooperative and interfacial regions. The drug can also permeate membranes at more ordered phases by altering phospholipid packing. The similar logD values obtained in membrane models mimicking cancer or normal cells imply that CPT has limited selectivity to its target. Furthermore, CPT binds strongly to serum albumin, leaving only 8.05% of free drug available to be distributed to the tissues. The strong interaction with plasma proteins, allied to the large distribution (VDSS=5.75 ± 0.932 L·Kg-1) and tendency to bioaccumulate in off-target tissues, were predicted to be pharmacokinetic issues of CPT, implying the need to develop drug delivery systems to improve its biodistribution.

scholarly journals The Use of Sonophoresis in the Administration of Drugs Throughout the Skin

2009 ◽  
Vol 12 (1) ◽  
pp. 88 ◽  
Author(s):  
Jose Juan Escobar-Chavez ◽  
Dalia Bonilla-Martínez ◽  
Martha Angélica Villegas-González ◽  
Isabel Marlen Rodríguez-Cruz ◽  
Clara Luisa Domínguez-Delgado
Keyword(s):  
Drug Delivery ◽  
Drug Release ◽  
Oral Administration ◽  
Transdermal Delivery ◽  
Transdermal Drug Delivery ◽  
Drug Delivery Systems ◽  
Medical Diagnostics ◽  
Attractive Alternative ◽  
Delivery Methods ◽  
Conventional Drug

Abstract Transdermal drug delivery offers an attractive alternative to the conventional drug delivery methods of oral administration and injection. However, the stratum corneum acts as a barrier that limits the penetration of substances through the skin. Application of ultrasound to the skin increases its permeability (sonophoresis) and enables the delivery of various substances into and through the skin. Ultrasound has been used extensively for medical diagnostics and to a certain extent in medical therapy (physiotherapy, ultrasonic surgery, hyperthermia). Nevertheless, it has only recently become popular as a technique to enhance drug release from drug delivery systems. A number of studies suggest the use of ultrasound as an external mean of delivering drugs at increased rates and at desired times. This review presents the main findings in the field of sonophoresis, namely transdermal drug delivery and transdermal monitoring. Particular attention is paid to proposed enhancement mechanisms and trends in the field of topical and transdermal delivery.

Kinetics of protein binding determine rates of uptake of drugs by brain

1986 ◽  
Vol 251 (6) ◽  
pp. R1212-R1220 ◽  
Author(s):  
P. J. Robinson ◽  
S. I. Rapoport
Keyword(s):  
Protein Binding ◽  
Rate Constants ◽  
Plasma Proteins ◽  
Numerical Solutions ◽  
Free Drug ◽  
Arterial Blood ◽  
Drug Concentrations ◽  
Analytical Expressions ◽  
Kinetics Of ◽  
The Brain

A mathematical model describing the kinetics of binding and release of substances by plasma proteins is presented. The effects of protein binding on the uptake of substances such as drugs from the capillary network of the brain are discussed. The model assumes equilibration between bound and free forms of drug in arterial blood and incorporates the on-off rate constants for the drug-protein complex and rate constants for passage of free drug across the blood-brain barrier and for drug metabolism in the brain. Regional cerebral blood flow and the related capillary transit time are important parameters in the model. Analytical expressions for bound and free drug concentrations and for the net extraction of drug are derived where practicable, and numerical solutions also are presented. Effects of changes in the total drug and protein concentrations in the plasma are discussed with special reference to the uptake of bilirubin by the brain.

scholarly journals Poly(d,l-Lactide-Coglycolide) Particles Containing Gentamicin: Pharmacokinetics and Pharmacodynamics in Brucella melitensis- Infected Mice

2007 ◽  
Vol 51 (4) ◽  
pp. 1185-1190 ◽  
Author(s):  
M. C. Lecaroz ◽  
M. J. Blanco-Prieto ◽  
M. A. Campanero ◽  
H. Salman ◽  
C. Gamazo
Keyword(s):  
Drug Delivery Systems ◽  
Brucella Melitensis ◽  
Free Drug ◽  
Intravenous Dose ◽  
Pharmacokinetic Parameters ◽  
Single Intravenous Dose ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Phagocytic Cells ◽  
Target Organs ◽  
Parameter Values

ABSTRACT Drug delivery systems containing gentamicin were studied as a treatment against experimental brucellosis in mice. Micro- and nanoparticles prepared by using poly(d,l-lactide-coglycolide) (PLGA) 502H and microparticles made of PLGA 75:25H were successfully delivered to the liver and the spleen, the target organs for Brucella melitensis. Both polymers have the same molecular weight but have different lactic acid/glycolic acid ratios. Microparticles of PLGA 502H and 75:25H released their contents in a sustained manner, in contrast to PLGA 502H nanoparticles, which were degraded almost completely during the first week postadministration. The values of the pharmacokinetic parameters after administration of a single intravenous dose of 1.5 mg/kg of body weight of loaded gentamicin revealed higher areas under the curve (AUCs) for the liver and the spleen and increased mean retention times (MRTs) compared to those for the free drug, indicating the successful uptake by phagocytic cells in both organs and the controlled release of the antibiotic. Both gentamicin-loaded PLGA 502H and 75:25H microparticles presented similar pharmacokinetic parameter values for the liver, but those made of PLGA 75:25 H were more effective in targeting the antibiotic to the spleen (higher AUCs and MRTs). The administration of three doses of 1.5 mg/kg significantly reduced the load associated with the splenic B. melitensis infection. Thus, the formulation made with the 75:25H polymer was more effective than that made with 502H microspheres (1.45-log and 0.45-log reductions, respectively, at 3 weeks posttreatment). Therefore, both, pharmacokinetic and pharmacodynamic parameters showed the suitability of 75:25H microspheres to reduce the infection of experimentally infected mice with B. melitensis.

scholarly journals Cell-derived plasma membrane vesicles are permeable to hydrophilic macromolecules

2019 ◽  
Author(s):  
AD Skinkle ◽  
I Levental
Keyword(s):  
Plasma Membrane ◽  
Membrane Vesicles ◽  
Permeability Barrier ◽  
Hydrophobic Core ◽  
Plasma Membrane Vesicles ◽  
Giant Vesicles ◽  
Membrane Asymmetry ◽  
Preparation Conditions ◽  
Biophysical Analysis ◽  
Membrane Models

ABSTRACTGiant Plasma Membrane Vesicles (GPMVs) are a widely used model system for biochemical and biophysical analysis of the isolated mammalian plasma membrane (PM). A core advantage of these vesicles is that they maintain the native lipid and protein diversity of the plasma membrane while affording the experimental flexibility of synthetic giant vesicles. In addition to fundamental investigations of PM structure and composition, GPMVs have been used to evaluate the binding of proteins and small molecules to cell-derived membranes, and the permeation of drug-like molecules through them. An important assumption of such experiments is that GPMVs are sealed; i.e. that permeation occurs by diffusion through the hydrophobic core rather than through hydrophilic pores. Here we demonstrate that this assumption is often incorrect. We find that most GPMVs isolated using standard preparations are passively permeable to various hydrophilic solutes as large as 40 kDa, in contrast to synthetic giant unilamellar vesicles (GUVs). We attribute this leakiness to relatively large and heterogeneous pores formed by rupture of vesicles from cells. These pores are stable and persist throughout experimentally relevant time scales. Finally, we identify preparation conditions that minimize poration and allow evaluation of sealed GPMVs. These unexpected observations of GPMV poration are of critical importance for interpreting experiments utilizing GPMVs as plasma membrane models, particularly for drug permeation and membrane asymmetry.STATEMENT OF SIGNIFICANCEA critical assumption in using Giant Plasma Membrane Vesicles to study membrane penetration and interactions is that these vesicles maintain the permeability barrier of the native membrane from which they form. Using large fluorescently-labeled hydrophilic probes, we demonstrate that this assumption is often incorrect and conclude that macromolecular solutes permeate GPMVs through stable pores formed during shear-induced rupture of vesicles from cells. Using these insights into the mechanisms of poration, we demonstrate an approach to isolate sealed GPMVs.

Liposomes as Vancomycin Hydrochloride Delivery System

2021 ◽  
Vol 903 ◽  
pp. 3-8
Author(s):  
Mārīte Skrinda ◽  
Arita Dubnika ◽  
Janis Locs
Keyword(s):  
Drug Delivery ◽  
Drug Administration ◽  
Delivery System ◽  
Drug Delivery Systems ◽  
Encapsulation Efficiency ◽  
Release Kinetics ◽  
Delivery Systems ◽  
Free Drug ◽  
Hydrophobic Drugs ◽  
Vancomycin Hydrochloride

Liposomes are being used as unique drug delivery systems due to their ability to encapsulate both hydrophilic and hydrophobic drugs, as well as for the fact that they improve the disadvantages of free drug administration. However, liposomes have a significant disadvantage - low encapsulation efficiency. In the research carried out, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol (Chol), in the ratio (n/n) of 2:1, 3:1 and 4:1 respectively, were used to prepare the liposomes. Blank liposomes (LIP) and vancomycin hydrochloride (VANKA) containing liposomes (VANKA-LIP) were prepared for each of the DSPC and Chol compositions. The aim of our study was to evaluate the effect of liposome composition on the VANKA encapsulation efficiency and release kinetics.

Sign in / Sign up

Export Citation Format

Share Document