Sushama Talegaonkar

Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in Cancer Chemotherapy

Chemotherapy forms the mainstay of cancer treatment particularly for patients who do not respond to local excision or radiation treatment. However, cancer treatment by drugs is seriously limited by P-glycoprotein (P-gp) associated multi-drug resistance (MDR) in various tumor cells. On the other hand, it is now widely recognized that P-gp also influences drug transport across various biological membranes. P-gp transporter is widely present in the luminal surface of enterocytes, biliary canalicular surface of hepatocytes, apical surface of proximal tubular cells of kidney, endothelial cells of blood brain barrier, etc. thus affecting absorption, distribution, metabolism and excretion of xenobiotics. Clinical significance of above mentioned carrier is appreciated from the fact that more than fifty percent of existing anti-cancer drugs undergo inhibitable and saturable P-gp mediated efflux. Consequently, there is an increasing trend to optimize pharmacokinetics, enhance antitumour activity and reduce systemic toxicity of existing anti-cancer drugs by inhibiting P-gp mediated transport. Although a wide variety of P-gp inhibitors have been discovered, research efforts are underway to identify the most appropriate one. Flavonoids (polyphenolic herbal constituents) form the third generation, non-pharmaceutical category of P-gp inhibitors. The effects produced by some of these components are found to be comparable to those of well-known P-gp inhibitors verapamil and cyclosporine. Identification of effective P-gp modulator among herbal compounds have an added advantage of being safe, thereby making them ideal candidates for bioavailability enhancement, tissue-penetration (e.g. blood brain barrier (BBB)), decreasing biliary excretion and multi-drug resistance modulating agents. The dual effects, i.e. P-gp modulation and antitumor activity, of these herbal derivatives may synergistically act in cancer chemotherapy. This paper presents an overview of the investigations on the feasibility and application of flavonoids as P-gp modulators for improved efficacy of anti-cancer drugs like taxanes, anthracyclines, epipodophyllotoxins, camptothecins and vinca alkaloids. The review also focuses on flavonoid-drug interactions as well as the reversal activity of flavonoids useful against MDR. In addition, the experimental models which could be used for investigation on P-gp mediated efflux are also discussed.

Microemulsions: a novel approach to enhanced drug delivery.

Microemulsions are isotropic, thermodynamically stable transparent (or translucent) systems of oil, water and surfactant, frequently in combination with a cosurfactant with a droplet size usually in the range of 20-200 nm. They can be classified as oil-in-water (o/w), water-in-oil (w/o) or bicontinuous systems depending on their structure and are characterized by ultra low interfacial tension between oil and water phases. These versatile systems are currently of great technological and scientific interest to the researchers because of their potential to incorporate a wide range of drug molecules (hydrophilic and hydrophobic) due to the presence of both lipophilic and hydrophilic domains. These adaptable delivery systems provide protection against oxidation, enzymatic hydrolysis and improve the solubilization of lipophilic drugs and hence enhance their bioavailability. In addition to oral and intravenous delivery, they are amenable for sustained and targeted delivery through ophthalmic, dental, pulmonary, vaginal and topical routes. Microemulsions are experiencing a very active development as reflected by the numerous publications and patents being granted on these systems. They have been used to improve the oral bioavailability of various poorly soluble drugs including cyclosporine and paclitaxel as professed by Hauer et al., US patent 7235248, and Gao et al., US patent 7115565, respectively. Furthermore, they can be employed for challenging tasks such as carrying chemotherapeutic agents to neoplastic cells and oral delivery of insulin as diligently described by Maranhao, US patent 5578583 and Burnside et al., US patent 5824638 respectively. The recent commercial success of Sandimmune Neoral (Cyclosporine A), Fortovase (Saquinavir), Norvir (Ritonavir), etc. also reflects the tremendous potential of these newer drug therapeutic systems. A critical evaluation of recent patents claiming different approaches to improve the drug delivery is the focus of the current review.

Vesicular systems: An overview

There has been keen interest in the development of a novel drug delivery system. Novel drug delivery system aims to deliver the drug at a rate directed by the needs of the body during the period of treatment, and channel the active entity to the site of action. At present, no available drug delivery system behaves ideally achieving all the lofty goals, but sincere attempts have been made to achieve them through novel approaches in drug delivery. A number of novel drug delivery systems have emerged encompassing various routes of administration, to achieve controlled and targeted drug delivery. Encapsulation of the drug in vesicular structures is one such system, which can be predicted to prolong the existence of the drug in systemic circulation, and reduce the toxicity, if selective uptake can be achieved. Consequently a number of vesicular drug delivery systems such as liposomes, niosomes, transfersomes, and pharmacosomes were developed. Advances have since been made in the area of vesicular drug delivery, leading to the development of systems that allow drug targeting, and the sustained or controlled release of conventional medicines. The focus of this review is to bring out the application, advantages, and drawbacks of vesicular systems.

Effect of P-glycoprotein inhibitor, verapamil, on oral bioavailability and pharmacokinetics of irinotecan in rats.

The objective of present investigation was to study the effect of verapamil on the pharmacokinetics of irinotecan in order to evaluate the role of P-glycoprotein (P-gp) in irinotecan disposition. An in vitro study using Caco-2 intestinal cell monolayer was first carried out to determine the effect of verapamil on the function of intestinal P-gp. Verapamil (25mg/kg) was administered orally 2h before irinotecan oral (80 mg/kg) or intravenous (20mg/kg) dosing in female Wistar rats. Plasma and biliary samples were collected at specified time points from control and treated animals to determine irinotecan and its metabolite, SN-38 concentrations. Bi-directional transport and inhibition studies in Caco-2 cells indicated irinotecan to be a P-gp substrate and the function of intestinal P-gp was significantly inhibited in presence of verapamil. After oral irinotecan dosing, the mean area under the plasma concentration-time curve (AUC) was found to be 14.03+/-2.18 microgh/ml which was increased significantly, i.e. 61.71+/-15.0 microgh/ml when verapamil was co-administered (P<0.05). Similarly, the mean maximum plasma concentration of irinotecan increased from 2.93+/-0.37 microg/ml (without verapamil) to 10.75+/-1.0 microg/ml (with verapamil) (P<0.05). There was approximately 4-5-folds increase in apparent bioavailability. On the other hand, the intravenous irinotecan administration with verapamil resulted in small but statistically significant effect on AUC (10.76+/-2.0 to 23.3+/-3.8 microgh/ml; P<0.05) and systemic clearance (1206.4+/-159.7 to 713.5+/-78.2 ml/(hkg)). In addition, SN-38 showed significant change in oral pharmacokinetic parameters and minor changes in intravenous pharmacokinetic profile. Biliary excretion curves of both irinotecan and SN-38 were lowered by verapamil. The mean percent of irinotecan excreted into bile over 5h following intravenous and oral administration was found to be 8% and 1%, respectively, which was further reduced to half when treated with verapamil. These results are quite stimulating for further development of a clinically useful oral formulation of irinotecan based on P-gp inhibition.

Recent approaches for the treatment of periodontitis.

Periodontal disease is a localised inflammatory response caused by the infection of a periodontal pocket arising from the accumulation of subgingival plaque. Periodontal disease has been considered as a possible risk factor for other systemic diseases such as cardiovascular diseases and pre-term low birth weight infants. Advances in understanding the aetiology, epidemiology and microbiology of periodontal pocket flora have revolutionised the therapeutic strategies for the management of periodontal disease progression. This review summarises the recent developments in the field of intra-pocket drug delivery systems and identifies areas where further research may lead to a clinically effective intra-pocket delivery system.

Microemulsions as a Surrogate Carrier for Dermal Drug Delivery

Microemulsions are isotropic, thermodynamically stable transparent (or translucent) systems of oil, water, and surfactant, frequently in combination with a cosurfactant with a droplet size usually in the range of 20–200 nm. Since their discovery, they have attained increasing significance both in basic research and in industry. Due to their distinct advantages such as enhanced drug solubility, thermodynamic stability, facile preparation, and low cost, uses and applications of microemulsions have been numerous. Recently, there is a surge in the exploration of microemulsion for transdermal drug delivery for their ability to incorporate both hydrophilic (5-fluorouracil, apomorphine hydrochloride, diphenhydramine hydrochloride, tetracaine hydrochloride, and methotrexate) and lipophilic drugs (estradiol, finasteride, ketoprofen, meloxicam, felodipine, and triptolide) and enhance their permeation. Very low surface tension in conjunction with enormous increase in the interfacial area due to nanosized droplets of the microemulsion influences the drug permeation across the skin. A large number of oils and surfactants are available, which can be used as components of microemulsion systems for transdermal delivery but their toxicity, irritation potential, and unclear mechanism of action limit their use. Besides surfactants, oils can also act as penetration enhancers (oleic acid, linoleic acid, isopropyl myristate, isopropyl palmitate, etc.). The transdermal drug delivery potential of microemulsions is dependent not only on the applied constituents of the vehicle but also drastically on the composition/internal structure of the phases which may promote or hamper the drug distribution in the vehicles. This article explores microemulsion as transdermal drug delivery vehicles with emphasis on components selection for enhanced drug permeation and skin tolerability of these systems and further future directions.

Multiple Emulsions: An Overview

Multiple emulsions are complex polydispersed systems where both oil in water and water in oil emulsion exists simultaneously which are stabilized by lipophillic and hydrophilic surfactants respectively. The ratio of these surfactants is important in achieving stable multiple emulsions. Among water-in-oil-in-water (w/o/w) and oil-in-water-in-oil (o/w/o) type multiple emulsions, the former has wider areas of application and hence are studied in great detail. Formulation, preparation techniques and in vitro characterization methods for multiple emulsions are reviewed. Various factors affecting the stability of multiple emulsions and the stabilization approaches with specific reference to w/o/w type multiple emulsions are discussed in detail. Favorable drug release mechanisms and/or rate along with in vivo fate of multiple emulsions make them a versatile carrier. It finds wide range of applications in controlled or sustained drug delivery, targeted delivery, taste masking, bioavailability enhancement, enzyme immobilization, etc. Multiple emulsions have also been employed as intermediate step in the microencapsulation process and are the systems of increasing interest for the oral delivery of hydrophilic drugs, which are unstable in gastrointestinal tract like proteins and peptides. With the advancement in techniques for preparation, stabilization and rheological characterization of multiple emulsions, it will be able to provide a novel carrier system for drugs, cosmetics and pharmaceutical agents. In this review, emphasis is laid down on formulation, stabilization techniques and potential applications of multiple emulsion system.

The emerging role of P-glycoprotein inhibitors in drug delivery: a patent review

Introduction: The ATP-binding cassette superfamily contains membrane transporter proteins that transport a wide range of diverse compounds across cellular membranes. The P-glycoprotein (P-gp) is an important member of this family and a multi-specific drug efflux transporter that plays a significant role in governing the bioavailability of many clinically active drugs. The inhibition of this efflux transporter by various P-gp inhibitors forms a distinctive approach in improving bioavailability and conquering drug resistance. Most P-gp inhibitors exhibit limitations associated with their safety and unwanted pharmacokinetic interactions, thereby restraining their clinical applicability. Areas covered: This review explores the investigations on the feasibility and applicability of various classes of P-gp inhibitors as described in recent patents for enhanced drug delivery. Expert opinion: Several candidates presently under development look promising as P-gp inhibitors, e.g., tariquidar and elacridar. Pharmaceutical excipients currently constitute the most promising class of P-gp inhibitors and are considered safe and pharmaceutically acceptable for use in formulations. In addition, lipid-based excipients and thiolated polymers play an active role in affecting P-gp-mediated transport not only by altering the membrane fluidity or ATPase activity but by down regulating P-gp expression. An additional overture such as the prodrug derivatization of P-gp substrates is a feasible approach to bypass P-gp-mediated efflux.

Role of CD44 in tumour progression and strategies for targeting

CD44 or hyaluronan receptor is a transmembrane receptor associated with aggressive tumour growth, proliferation, and metastasis. In normal physiology, this receptor has a crucial role in cell adhesion, inflammation, and repair processes. However, many tumour cells over-express this receptor and abuse it to become progressive and perpetual units. The article comments from common functioning of the CD44 receptor, to its diabolic multi-dimensional effects in promotion of malignant cells. It also illuminates the relations of CD44 endorsed processes with other biomolecular events in cancer progression. In an end, the review focuses comprehensively at ongoing researches to exploit the CD44 over-expression as a probable target in treatment, management, and diagnosis of malignancy.

Chemical penetration enhancers: a patent review

Background: Ever since transdermal drug delivery came into existence, it has offered great promises, although most of them are yet to be fulfilled owing to some intrinsic restrictions of the transdermal route. On the positive side, transdermal drug delivery systems present advantages including non-invasiveness, prolonged therapeutic effect, reduced side effects, improved bioavailability, better patient compliance and easy termination of drug therapy. The greatest hindrance in the percutaneous delivery is the obstruction property of the stratum corneum, the outermost layer of the skin, in addition to usual problems such as skin binding, skin metabolism, cutaneous toxicity and prolonged lag times. Objective: This paper reviews investigations on the feasibility and application of penetration enhancers as described in recent patents, which help in the selection of a suitable sorption promoter(s) for enhanced delivery of medicaments through the skin. Method: The patents granted under various categories of penetration enhancers have been discussed including fatty acids, terpenes, fatty alcohol, pyrrolidone, sulfoxides, laurocapram, surface active agents, amides, amines, lecithin, polyols, quaternary ammonium compounds, silicones, alkanoates and so on. Conclusion: Scores of promising chemicals have been harnessed for their skin permeation promoting capacity as mentioned earlier. In future, many more chemicals and putative enhancers are likely be documented and patented.