Current Drug Metabolism - Volume 15, Issue 6, 2014

Nanomaterials have made a significant impact on cancer therapeutics and an emergence of polymeric nanoparticle provides a unique platform for delivery of drug molecules of diverse nature. Nanoparticles can be targeted at the tumor cells due to enhanced permeability and retention effect. Moreover, nanoparticles can be grafted by various ligands on their surface to target the specific receptors overexpressed by cancer cells or angiogenic endothelial cells. These approaches ultimately result in longer circulation half-lives, improved drug pharmacokinetics, reduced side effects of therapeutically active substances and overcoming cancer chemo-resistance thereby enhancing the therapeutic efficacy of the treatment. This review article summarizes the recent efforts in cancer nanochemotherapeutics using polymeric nanoparticles with a special reference to their pharmacokinetic and biodistribution profiles, their role in reversing multidrug resistance in cancer and strategies of tumor targeting with them, along with the challenges in the field.

Drug bioavailability may vary greatly amongst individuals, affecting both efficacy and toxicity: in humans, genetic variations account for a relevant proportion of such variability. In the last decade the use of pharmacogenetics in clinical practice, as a tool to individualize treatment, has shown a different degree of diffusion in various clinical fields. In the field of infectious diseases, several studies identified a great number of associations between host genetic polymorphisms and responses to antiretroviral therapy. For example, in patients treated with abacavir the screening for HLA-B*5701 before starting treatment is routine clinical practice and standard of care for all patients; efavirenz plasma levels are influenced by single nucleotide polymorphism (SNP) CYP2B6-516G>T (rs3745274). Regarding antibiotics, many studies investigated drug transporters involved in antibiotic bioavailability, especially for fluoroquinolones, cephalosporins, and antituberculars. To date, few data are available about pharmacogenetics of recently developed antibiotics such as tigecycline, daptomycin or linezolid. Considering the effect of SNPs in gene coding for proteins involved in antibiotics bioavailability, few data have been published. Increasing knowledge in the field of antibiotic pharmacogenetics could be useful to explain the high drug inter-patients variability and to individualize therapy. In this paper we reported an overview of pharmacokinetics, pharmacodynamics, and pharmacogenetics of antibiotics to underline the importance of an integrated approach in choosing the right dosage in clinical practice.

The cytochrome P450 family of enzymes play an important role in the metabolism of drugs and other xenobiotics. While genotypic variation can contribute to the inter-individual variability in drug metabolism, individuals sharing the same genotype for an enzyme can still show considerable variability in drug metabolising capacity by that enzyme. It is well recognised that in some disease states (e.g. inflammation, infection, diabetes) or other physiological conditions (e.g. pregnancy), the clearance of drugs may significantly alter, possibly via modulation of drug metabolising enzymes by varying levels of endogenous substances. This review investigates the current knowledge on the modulating effects of various endogenous substances on DMEs in vitro and possible utility of available in vitro data for quantitative prediction of clinical outcome. It is postulated that understanding and estimating the inter-individual variability in DMEs within each population might be possible by application of in vitro in vivo extrapolation linked physiologically-based pharmacokinetic modelling. However, in vitro information for building such quantitative relationships is currently not abundant.

Gold nanoparticles (AuNPs) have demonstrated increasingly wide applications in drug delivery due to their unique physicochemical and optical properties as well as low toxicity. Compared to the organic nanocarriers for therapeutic agents, AuNPs have shown superior performance as drug delivery vectors, including the inert nature, well-developed synthesis strategies, tunable size, and flexible and easy surface modification with various chemical and biological molecules. In this review, we emphasize on the applications of AuNPs in the aspect of improving pharmaceutical property and therapeutic efficacy of drugs, especially those covalently and noncovalently connected to the surface of AuNPs. Acting as a solid core to link drugs and their derivatives, AuNPs provide the nano-prodrug system with compressed size, high loading efficiency, three-dimension structure, and enhanced cellular uptake capability. With the intensive and systematical investigation of the drug-connected AuNPs, several important issues will become the hot but emergent topics for future research in this field, such as the toxicity in live human subjects, ultimate destination, and possible pathways and mechanisms for their absorption, circulation, distribution, metabolism, and excretion.

Cancer is still considered to be one of the most severe diseases so far. Multidrug resistance (MDR) is a major obstacle against curative cancer chemotherapy. The over-expression of drug efflux pumps in cellular membrane plays a critical role in preventing cancer cells from conventional chemotherapy. Nanotechnology is emerging as a class of therapeutics for MDR. This review mainly focuses on some pivotal strategies to combat MDR, including the enhanced permeability and retention (EPR) effect, stealth nanoparticles to prolong circulation time, endosomal escape, active drug delivery, stimuli sensitive drug release, and targeted co-delivery of different compounds. While convinced challenges need combatting, large numbers of preclinical studies strongly suggest that nanomedicine formations have potential application for improving the treatment of MDR.