Pharmacokinetics of anticancer drugs, plasmid DNA, and their delivery systems in tissue-isolated perfused tumors

To achieve an optimal chemotherapy or gene therapy against tumors or to realize rational design of delivery systems for cancer therapy, pharmacokinetic information in tumor should be obtained. A tissue-isolated tumor preparation is a useful experimental system to investigate the intratumoral disposition of drugs, carriers, and their complexes. The disposition of drugs in the solid tumor was analyzed in this system after intraarterial infusion (systemic route) or by intratumoral injection (topical route). Here the results of low-molecular weight drugs, their macromolecular prodrugs, lipid carriers like fat emulsions and liposomes, and plasmid DNA and its complexes, are addressed. Pharmacokinetic analyses in the tumor clearly indicate that the intratumoral fate of drugs and delivery systems are determined by (i) the anatomical and physiological properties of the tissue and (ii) the physicochemical characteristics of drugs and delivery systems such as molecular weight, size, lipophilicity, and electrical charge. These approaches are useful for designing and developing optimized drug delivery systems.     

Influence of physicochemical properties on pharmacokinetics of non-viral vectors for gene delivery

The influence of physicochemical properties on the in vivo pharmacokinetics of gene delivery vectors after systemic administration is reviewed based on our studies. We have been studying the development of DNA delivery systems, such as plasmid DNA complexed with cationic polymers (polyplexes) and cationic liposomes (lipoplexes). Even if target-recognizable ligand is incorporated into the system, the overall physicochemical properties, notably size and charge, are predominant factors influencing in vivo disposition characteristics of the vector. Based on this consideration, liver cell-specific carrier systems via receptor-mediated endocytosis were successfully developed by optimizing physicochemical characteristics. In conclusion, rational design of gene delivery vectors requires an understanding of their pharmacokinetics in relation to the physicochemical properties. Optimization of the physicochemical properties is important for successful in vivo gene delivery by non-viral vectors.     

Influence of Physicochemical Properties on Pharmacokinetics of Non-viral Vectors for Gene Delivery

The influence of physicochemical properties on the in vivo pharmacokinetics of gene delivery vectors after systemic administration is reviewed based on our studies. We have been studying the development of DNA delivery systems, such as plasmid DNA complexed with cationic polymers (polyplexes) and cationic liposomes (lipoplexes). Even if target-recognizable ligand is incorporated into the system, the overall physicochemical properties, notably size and charge, are predominant factors influencing in vivo disposition characteristics of the vector. Based on this consideration, liver cell-specific carrier systems via receptor-mediated endocytosis were successfully developed by optimizing physicochemical characteristics. In conclusion, rational design of gene delivery vectors requires an understanding of their pharmacokinetics in relation to the physicochemical properties. Optimization of the physicochemical properties is important for successful in vivo gene delivery by non-viral vectors.     

Disposition characteristics of emulsions and incorporated drugs after systemic or local injection

Lipid emulsions are useful tools for controlling the in vivo disposition of drugs and plasmid DNA. The dispositions of lipid emulsions are determined by their tissue interaction depending on the anatomical and physiological characteristics of each tissue and the physicochemical and biological properties of lipid emulsions. In addition, the retention of drugs is another issue, as too rapid a release of the drug would lead to failure of exerting its therapeutic potency. This review presents an overview about the disposition profiles and various physicochemical properties of lipid emulsions and incorporated drugs after systemic or local injection. Controlled biodistribution of lipid emulsions and incorporated drugs are also discussed.     

Factors affecting drug and gene delivery: effects of interaction with blood components

Targeted drug delivery systems have been used extensively to improve the pharmacological and therapeutic activities of a wide variety of drugs and genes. In this article, we summarize the factors determining the tissue disposition of delivery systems: the physicochemical and biological characteristics of the delivery system and the anatomic and physiological characteristics of the tissues. There are several modes of drug and gene targeting, ranging from passive to active targeting, and each of these can be achieved by optimizing the design of the delivery system to suit a specific aim. After entering the systemic circulation, either by an intravascular injection or through absorption from an administration site, however, a delivery system encounters a variety of blood components, including blood cells and a range of serum proteins.These components are by no means inert as far as interaction with the delivery system is concerned, and they can sometimes markedly effect its tissue disposition. The interaction with blood components is known to occur with particulate delivery systems, such as liposomes, or with cationic charge-mediated delivery systems for genes. In addition to these rather nonspecific ones, interactions via the targeting ligand of the delivery system can occur. We recently found that mannosylated carriers interact with serum mannan binding protein, greatly altering their tissue disposition in a number of ways that depend on the properties of the carriers involved.     

Role of nanotechnology in pharmaceutical product development

A number of new molecular entities (NMEs) selected for full-scale development based on their safety and pharmacological data suffer from undesirable physicochemical and biopharmaceutical properties, which lead to poor pharmacokinetics and distribution after in vivo administration. An optimization of the preformulation studies to develop a dosage form with proper drug delivery system to achieve desirable pharmacokinetic and toxicological properties can aid in the accelerated development of these NMEs into therapies. Nanoparticulate drug delivery systems show a promising approach to obtain desirable druglike properties by altering the biopharmaceutics and pharmacokinetics properties of the molecule. Apart from the advantages of enhancing potential for systemic administration, nanoparticulate drug delivery systems can also be used for site-specific delivery, thus alleviating unwanted toxicity due to nonspecific distribution, improve patient compliance, and provide favorable clinical outcomes. This review summarizes some of the parameters and approaches that can be used to evaluate nanoparticulate drug delivery systems in early stages of formulation development.     

Absorption, pharmacokinetics and disposition properties of solid lipid nanoparticles (SLNs)

In recent years, many researchers have paid more and more attentions on the use of Nanotechnology. Solid lipid nanoparticles (SLNs) are emerged as a promising alternation herein to emulsions, liposomes, microparticles and polymeric nanoparticles for their advantages. As promising drug carrier systems, SLNs are valuable for nanomedicine and have been widely used as delivery systems mostly for drugs and macromolecules like proteins, oligonucleotides and DNA by various application routes, such as intravenous, oral, duodenalous, intramuscular, pulmonary, intranasal, ocular, rectal and intraperitoneal administrations. It has been shown that SLNs can increase bioavailability, alter pharmacokinetic parameters and tissue distribution of the drug loaded. In this review, we will primarily focus on the absorption, pharmacokinetics and disposition properties of SLNs for their possible applications in drug delivery.     

The effects of pharmaceutical excipients on drug disposition

Many new chemical entities are poorly soluble, requiring the use of co-solvents or excipients to produce suitable intravenous formulations for early pre-clinical development studies. There is some evidence in the literature that these formulation components can have significant physiological and physicochemical effects which may alter the distribution and elimination of co-administered drugs. Such effects have the potential to influence the results of pre-clinical pharmacokinetic studies, giving a false impression of a compound's intrinsic pharmacokinetics and frustrating attempts to predict the drug's ultimate clinical pharmacokinetics. This review describes the reported effects of commonly used co-solvents and excipients on drug pharmacokinetics and on physiological systems which are likely to influence drug disposition. Such information will be useful in study design and evaluating data from pharmacokinetic experiments, so that the potential influence of formulation components can be minimised.     

Retina-Choroid-Sclera Permeability for Ophthalmic Drugs in the Vitreous to Blood Direction: Quantitative Assessment

Purpose

To determine the outward permeability of retina-choroid-sclera (RCS) layer for different ophthalmic drugs and to develop correlations between drug physicochemical properties and RCS permeability.

Methods

A finite volume model was developed to simulate pharmacokinetics in the eye following drug administration by intravitreal injection. The RCS permeability was determined for 32 compounds by best fitting the drug concentration-time profile obtained by simulation with previously reported experimental data. Multiple linear regression was then used to develop correlations between best fit RCS permeability and drugs physicochemical properties.

Results

The RCS drug permeabilities had values that ranged over 3?×?10^?6?m/s. Regression analysis for hydrophilic compounds showed that more than 92% of the variation in permeability values can be explained by correlative models of drug properties that include logarithm of the octanol-water partition coefficient (LogP), protein binding (PB), number of hydrogen bond acceptors (HBA), hydrogen bond donors (HBD), polar surface area (PSA) and dissociation constant (pKa) as independent variables. Regression analysis for lipophilic compounds showed that no significant correlation can be found between just physicochemical properties and RCS permeability.

Conclusion

Using the RCS permeability obtained from this study for different drugs, one can predict pharmacokinetics of intravitreal drug delivery systems such as solid implants or colloidal systems. Furthermore, the developed correlations between RCS permeability and physicochemical properties of drugs are useful in early drug development by predicting RCS permeability and drug concentration in the vitreous without experimental data.     

Disposition of Drugs in Block Copolymer Micelle Delivery Systems

Since their discovery in the early 1980s, polymeric micelles have been the subject of several studies as delivery systems that can potentially improve the therapeutic performance and modify the toxicity profile of encapsulated drugs by changing their pharmacokinetic characteristics. The efforts in this area have led in recent years to the advancement of several polymeric micellar formulations to clinical trials, some of which have shown promise in changing the biodistribution of the incorporated drug after intravenous administration as a means of tumour-targeted drug delivery. Recently, the possible benefit of polymeric micellar delivery in enhancing the absorption and bioavailability of incorporated drugs from alternative routes of drug administration has attracted interest. This article provides an overview of the effect of polymeric micellar delivery on absorption, distribution, metabolism and excretion of incorporated therapeutic agents. It also aims to assess the current information on the performance of polymeric micellar delivery systems in modifying the pharmacokinetics/pharmacodynamics of the incorporated drugs in clinical trials, and to re-examine the important structural factors required for successful design of polymeric micellar delivery systems capable of inducing favourable changes in the pharmacokinetics of the encapsulated drug.     

Macromolecular Carrier Systems for Targeted Drug Delivery: Pharmacokinetic Considerations on Biodistribution

This review article describes the current status and future perspectives of site-specific drug delivery by means of macromolecular carrier systems. Basic aspects and recent advances of targeted delivery of 1) conventional drugs, 2) protein drugs, and 3) gene medicines including antisense oligonucleotides and plasmid DNA, are reviewed from a pharmacokintic perspective. Successful in vivo application of macromolecular carrier systems requires pharmacokinetic considerations at whole body, organ, cellular and subcellular levels. The integration of simultaneous research progress in the multidisciplinary fields such as biochemistry, cell and molecular biology, pharmacology, and pharmacokinetics will accelerate the emergence of marketed drugs with macromolecular carrier systems.     

Disposition and gene expression characteristics in solid tumors and skeletal muscle after direct injection of naked plasmid DNA in mice

Previous studies have suggested that direct injection of naked plasmid DNA (pDNA) into solid tumors can be a useful method for in vivo gene transfer into tumor cells. To gain more insight into this approach, we studied the disposition and gene expression characteristics of naked pDNA after intratumoral injection by direct comparison with those after intramuscular injection in mice. pDNA encoding reporter genes were directly injected into subcutaneous solid tumor models and skeletal muscles. Biodistribution studies using radiolabeled pDNA showed that the elimination of pDNA from the injection site was relatively fast and a part of the pDNA was absorbed from the lymphatic system after both local injections. Confocal microscopic studies using fluorescein-labeled pDNA demonstrated that pDNA distributed efficiently throughout the muscle tissue whereas pDNA localization in the tumor tissue was restricted. Characterization of gene expression clarified the variation in expression level between tumor preparations and some factors affecting the expression level in the tumor. Reporter gene expression was significantly inhibited by simultaneous administration of some polyanions in both cases, suggesting that a specific mechanism may be involved in the naked pDNA uptake by muscle and tumor cells. These findings provide useful information for direct naked pDNA delivery into solid tumors.     

Molecular design for enhancement of ocular penetration

Over the past two decades, many oral drugs have been designed in consideration of physicochemical properties to attain optimal pharmacokinetic properties. This strategy significantly reduced attrition in drug development owing to inadequate pharmacokinetics during the last decade. On the other hand, most ophthalmic drugs are generated from reformulation of other therapeutic dosage forms. Therefore, the modification of formulations has been used mainly as the approach to improve ocular pharmacokinetics. However, to maximize ocular pharmacokinetic properties, a specific molecular design for ocular drug is preferable. Passive diffusion of drugs across the cornea membranes requires appropriate lipophilicity and aqueous solubility. Improvement of such physicochemical properties has been achieved by structure optimization or prodrug approaches. This review discusses the current knowledge about ophthalmic drugs adapted from systemic drugs and molecular design for ocular drugs. I propose the approaches for molecular design to obtain the optimal ocular penetration into anterior segment based on published studies to date.     

The Øie-Tozer model of drug distribution and its suitability for drugs with different pharmacokinetic behavior

INTRODUCTION: Drug distribution is a major pharmacokinetic process that affects the time course of drug concentrations in tissues, biological fluids and the resulting pharmacological activities. Drug distribution may follow different pathways and patterns, and is governed by the drug's physicochemical properties and the body's physiology. The classical ?ie-Tozer model is frequently used for predicting volume of drug distribution and for pharmacokinetic calculations. AREAS COVERED: In this review, the suitability of the ?ie-Tozer model for drugs that exhibit different distribution patterns is critically analyzed and illustrated. The method used is a pharmacokinetic modeling and simulation approach. It is demonstrated that the major limitation of the ?ie-Tozer model stems from its focus on the total drug concentrations and not on the active (unbound) concentrations. Moreover, the ?ie-Tozer model may be inappropriate for drugs with nonlinear or complex pharmacokinetic behavior, such as biopharmaceuticals, drug conjugates or for drugs incorporated into drug delivery systems. Distribution mechanisms and alternative distribution models for these drugs are discussed. EXPERT OPINION: The ?ie-Tozer model can serve for predicting unbound volume of drug distribution for 'classical' small molecular mass drugs with linear pharmacokinetics. However, more detailed mechanism-based distribution models should be used in preclinical and clinical settings for drugs that exhibit more complex pharmacokinetic behavior.     

Physicochemical and pharmacokinetic characteristics of cationic liposomes

After intravenous administration of plasmid DNA (pDNA)/cationic liposome complexes, the gene expression is predominantly observed in the lung due to the physicochemical properties of the liposome complexes and the physiology of the lung. To determine the physicochemical properties and distribution behavior of cationic liposomes for lung-selective drug and/or gene delivery systems, N-[1-(2,3-dioleyloxy)propyl]-n,n,n-trimethylammonium chloride (DOTMA)/cholesterol and 1,2-dioleoyl-3-trimethyl-ammoniopropane (DOTAP)/cholesterol liposomes were studied. The particle sizes of DOTMA/cholesterol and DOTAP/cholesterol liposomes were very similar: 126 and 128 nm, respectively. Furthermore, the zeta potentials of these two liposomes were 51 and 66 mV, respectively. After intravenous injection into mice, both cationic liposomes were rapidly eliminated from the blood circulation and preferentially recovered in the lung. Interestingly, the highest lung accumulation was observed at 1 min, and then, decreased gradually. The distribution characteristics of DOTMA/cholesterol and DOTAP/cholesterol liposomes were almost identical due to the similarities in their physicochemical properties. These results demonstrated that DOTMA/cholesterol and DOTAP/cholesterol liposomes, which possess a positive charge, are promising carriers for lung-selective drug and/or gene delivery systems.     

Pharmacokinetic Analysis of Drug Disposition After Intratumoral Injection in a Tissue-Isolated Tumor Perfusion System

Purpose. The purpose of this study was to establish an experimental system for evaluation of the intratumoral behavior of drugs after intratumoral injection using perfused tissue-isolated tumor preparations of Walker 256 carcinoma (3.46–9.73g, n = 16). Methods. We quantified the recovery of Phenol Red (model drug) in the tumor, leakage from the tumor surface and the venous outflow after intratumoral injection using perfused tissue-isolated tumors, and analyzed venous appearance curves based on a pharmacokinetic model in which the tumor tissue was assumed to be divided into two compartments, i.e., well- and poorly-perfused regions. Results. In small tumors (Type 1, 5.42 ± 0.39 g), the drug appeared immediately in the venous outflow, and the amount remaining in the tumor tissue at 2 hr after injection was small. In contrast, the venous appearance rate reached a significantly lower peak a few minutes after injection, and a large amount of injected drug remained in some large tumors (Type 2, 8.17 ± 0.51 g). Pharmacokinetic analysis revealed that there was a correlation between tumor weight and the rate constants of transfer from the poorly-perfused region to the well-perfused region, and between the rate constants of transfer from the well-perfused region to the venous outflow and dosing ratios into the well-perfused region. Conclusions. An experimental system and analytical method were established for the evaluation of the intratumoral behavior of drugs after intratumoral injection using a tissue-isolated tumor perfusion system. This experimental system will be useful in analyzing the antitumor drug disposition after intratumoral injection.     

Cyclodextrin complexes: Perspective from drug delivery and formulation

Cyclodextrins (CDs) have been widely investigated as a unique pharmaceutical excipient for past few decades and is still explored for new applications. They are highly versatile oligosaccharides which possess multifunctional characteristics, and are mainly used to improve the physicochemical stability, solubility, dissolution rate, and bioavailability of drugs. Stability constant, factors affecting complexation, techniques to enhance complexation efficiency, the preparation methods for molecular inclusion complexes and release of guest molecules are discussed in brief. In addition, different CD derivatives and their pharmacokinetics are elaborated. Further, the significance of CD complex in aqueous solubility, dissolution and bioavailability, stability, and taste masking is explained. The recent advancement of CDs in developing various drug delivery systems is enlightened. Indeed, the potential of CDs by means of inclusion complex formation have widen the applicability of these materials in various drug delivery systems including ocular, osmotic, mucoadhesive, transdermal, nasal, and targeted delivery systems. Feasibility studies have been performed on the benefit of these cyclic oligomers as nanocarriers, a strategy that can modify the drugs with improved physicochemical properties. Studies also demonstrated the feasibility of CDs to self‐assemble in the form of stable nanoaggregates, which may extend the scope of CDs in drug delivery to the continually expanding list of new drug entities.     

From physical pharmacy to clinical pharmacology

Research works on molecular interactions in solutions were carried out at School of Pharmacy, the University of Wisconsin under the direction of Prof. T. Higuchi and at Faculty of Pharmaceutical Sciences, Kyoto University under the direction of Prof. H. Sezaki. Studies on permeation of drugs through polymer membranes were carried out at Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada and at Pharmaceutical Chemistry Research Laboratories at Food and Drug Directorate, Department of Health and Welfare, Canada. Studies on modification of delivery patterns by means of pharmaceutical approaches were carried out at Faculty of Pharmaceutical Sciences, Hokkaido University. Topics related to modification of drug delivery patterns include employment of amorphous forms such as ground mixture with micro-crystalline cellulose and coprecipitate with polyvinylpyrrolidone, use of biodegradable polymers such as polylactic acid and polycarbonates, gel-forming materials such as konjac, agar and hydroxypropylcellulose, and physicochemical systems such as complexation. Works related to drug delivery and disposition of drugs in humans were carried out at Department of Pharmacy, Kumamoto University Hospital. Topics related to drug delivery in humans include injections containing anticancer drugs for intra-arterial administration, lidocaine gels for dermal anesthesia, glucagon solution for nasal administration. Topics related to disposition of drugs in humans include clinical pharmacokinetic studies in infants and elderly and medical uses of adsorbents.     

The effect of food on the oral bioavailability of drugs: a review of current developments and pharmaceutical technologies for pharmacokinetic control

Here we review the mediation of the food effects on drugs by pharmaceutical technologies. The pharmacokinetics of drugs are affected by the interaction of drugs with food, which changes drug physicochemical and physiological properties (food effects). Several pharmaceutical technologies may be used to control food effects. Drugs exhibit different patterns of solubilization depending on release formulations. Formulations such as nanoparticle, solid dispersion and cyclodextrin systems, may control the solubility and release of insoluble drugs. Other controlled-release technologies, such as osmotic-controlled release or colon-specific delivery systems may also control food effects. As the structure of drug candidates becomes more complex, different methods of investigation, such as in vitro and in vivo correlation and in silico simulation will be required to predict drug characteristics and food effects.     

Pharmacokinetics and in vivo gene transfer of plasmid DNA complexed with mannosylated poly(L-lysine) in mice

To achieve mannose receptor-mediated, cell-specific, in vivo gene transfer by intravenous injection of plasmid DNA, mannosylated poly(L-lysine) (Man-PLL) was synthesized as a carrier molecule, and mixed with a plasmid DNA encoding chloramphenicol acetyltransferase (CAT) gene to form DNA/Man-PLL complex. The particle size and zeta potential of DNA/Man-PLL (prepared at 1:0.7 on a weight basis) were determined to be 220 nm and +12 mV, respectively. The pharmacokinetics of the DNA/Man-PLL complex was assessed in mice using 32P-labeled DNA ([32P]DNA). After intravenous injection of [32P]DNA/Man-PLL, the radioactivity in plasma fell rapidly and was recovered mainly in the liver nonparenchymal cells. The amount in the liver reached more than 80% of the dose. Radioactivity observed in kidney, lung, and spleen was very low compared to that in the liver. Then, the in vivo gene expression after intravenous injection of DNA/Man-PLL was examined by a CAT assay. Highest CAT activity was detected in the liver, but no activity was detected in the lung, kidney, and spleen. These results clearly indicate that a cell-specific gene delivery system can be developed by regulating the biodistribution of DNA/carrier complex through the control of its physicochemical properties.