Poor Pharmacokinetic Parameters Research Articles

A structure-based pharmacophore modelling approach to identify and design new neprilysin (NEP) inhibitors: An in silico-based investigation

Neutral endopeptidase or neprilysin (NEP) cleaves the natriuretic peptides, bradykinin, endothelin, angiotensin II, amyloid β protein, substance P, etc., thus modulating their effects on heart, kidney, and other organs. NEP has a proven role in hypertension, heart disease, renal disease, Alzheimer's, diabetes, and some cancers. NEP inhibitor development has been in focus since the US FDA approved a combination therapy of angiotensin II type 1 receptor inhibitor (valsartan) and NEP inhibitor (sacubitril) for use in heart failure. Considering the importance of NEP inhibitors the present work focuses on the designing of a potential lead for NEP inhibition. A structure-based pharmacophore modelling approach was employed to identify NEP inhibitors from the pool of 1140 chemical entities obtained from the ZINC database. Based on the docking score and pivotal interactions, ten molecules were selected and subjected to binding free energy calculations and ADMET predictions. The top two compounds were studied further by molecular dynamics simulations to determine the stability of the ligand-receptor complex. ZINC0000004684268, a phenylalanine derivative, showed affinity and complex stability comparable to sacubitril. However, in silico studies indicated that it may have poor pharmacokinetic parameters. Therefore, the molecule was optimized using bioisosteric replacements, keeping the phenylalanine moiety intact, to obtain five potential lead molecules with an acceptable pharmacokinetic profile. The works thus open up the scope to further corroborate the present in silico findings with the biological analysis.

In Vivo Sustained Release of the Retrograde Transport Inhibitor Retro-2.1 Formulated in a Thermosensitive Hydrogel

A recently developed inhibitor of retrograde transport, namely Retro-2.1, proved to be a potent and broad-spectrum lead in vitro against intracellular pathogens, such as toxins, parasites, intracellular bacteria and viruses. To circumvent its low aqueous solubility, a formulation in poly(ethylene glycol)-block-poly(D,L)lactide micelle nanoparticles was developed. This formulation enabled the study of the pharmacokinetic parameters of Retro-2.1 in mice following intravenous and intraperitoneal injections, revealing a short blood circulation time, with an elimination half-life of 5 and 6.7 h, respectively. To explain the poor pharmacokinetic parameters, the metabolic stability of Retro-2.1 was studied in vitro and in vivo, revealing fast cytochrome-P-450-mediated metabolism into a less potent hydroxylated analogue. Subcutaneous injection of Retro-2.1 formulated in a biocompatible and bioresorbable polymer-based thermosensitive hydrogel allowed for sustained release of the drug, with an elimination half-life of 19 h, and better control of its metabolism. This study provides a guideline on how to administer this promising lead in vivo in order to study its efficacy.

In vivo therapeutic effects of small molecule-drug conjugates enhanced by Fc grafting

Small molecule-drug conjugate (SMDC) shows great potential as a new class of targeted chemotherapeutic agents to tackle cancer. However, its in vivo therapeutic effect is compromised by its poor pharmacokinetic parameters. Herein we describe an approach that enables the precise conjugation of SMDC on N-terminus of the Fc protein to produce a SMDC-Fc bioconjugate (Fc1070) with superior specificity, affinity and potency to tumor cells. In vivo, Fc1070 exhibited an antibody-like pharmacokinetic profile with a long circulation half-life (t1/2 = 79 h) and pro-liver clearance pathway, that is distinct from the parent SMDC (t1/2 = 0.5 h and renal clearance). Intravenous injection of Fc1070 can eliminate the tumor with a single dosing of 7 mg/kg. Coupled with a predefined ligand toolbox, this approach allows the fast generation of other SMDC bioconjugates on demand, thus extending the format easily to other tumor targets. This may provide a general approach for the development of SMDC with enhanced therapeutic properties.

Cyclodextrin nanoparticles for diagnosis and potential cancer therapy: A systematic review.

Cancer is still one of the world’s deadliest health concerns. As per latest statistics, lung, breast, liver, prostate, and cervical cancers are reported topmost worldwide. Although chemotherapy is most widely used methodology to treat cancer, poor pharmacokinetic parameters of anticancer drugs render them less effective. Novel nano-drug delivery systems have the caliber to improve the solubility and biocompatibility of various such chemical compounds. In this regard, cyclodextrins (CD), a group of natural nano-oligosaccharide possessing unique physicochemical characteristics has been highly exploited for drug delivery and other pharmaceutical purposes. Their cup-like structure and amphiphilic nature allows better accumulation of drugs, improved solubility, and stability, whereas CDs supramolecular chemical compatibility renders it to be highly receptive to various kinds of functionalization. Therefore combining physical, chemical, and bio-engineering approaches at nanoscale to specifically target the tumor cells can help in maximizing the tumor damage without harming non-malignant cells. Numerous combinations of CD nanocomposites were developed over the years, which employed photodynamic, photothermal therapy, chemotherapy, and hyperthermia methods, particularly targeting cancer cells. In this review, we discuss the vivid roles of cyclodextrin nanocomposites developed for the treatment and theranostics of most important cancers to highlight its clinical significance and potential as a medical tool.

Tumor Biology; Usefulness of Thermosensitive and pH Sensitive Polymeric Nanoparticles for Tumor Targeting: A Review

Polymeric nanoparticles (PNPs) have attracted the interest of many scientists and have been utilized in an increasing number of fields during the last two decades. The conventional chemotherapeutic agents have poor pharmacokinetic parameters such as non-specific distribution of drugs, the lack of drug specific affinity towards a pathological site, and thus necessitating large dose of a drug to achieve high local concentration in the body leading to systemic toxicity associated with serious side effects. A thorough and precise understanding of tumor microenvironment such as angiogenesis, tumor pH, enhanced permeation and retention (EPR) effect, abnormal lymphatics, multidrug resistance (MDR) and high interstitial fluid pressure, allows designing drug delivery systems that specifically target anti-cancer drugs to tumors. An attempt has been made in this article to highlight the temperature and pH sensitive PNPs, and PNPs with dual and double response to both temperature and pH that have a distinct capacity to target tumors with limited effect on healthy tissues. The stimuli responsive nanoparticles are classified based on their mechanism of response to temperature and pH. Structure of the polymer, methods of drug loading, and characterization of PNPs are elucidated.
 Keywords: Polymeric nanoparticles; pH sensitive polymers; Thermosensitive polymers; Tumor microenvironment; Multidrug resistance; Drug loading.

Investigation of benzimidazole anthelmintics as oral anticancer agents

AbstractRecently, there has been social controversy regarding whether benzimidazole anthelmintic drugs can be used as anticancer drugs. On this note, we wish to address the use of current benzimidazole anthelmintic drugs for the treatment of cancer patients. We explored the anticancer efficacy of benzimidazole anthelmintic drugs in vitro and their mechanism of action. We also conducted pharmacokinetic studies of two benzimidazole anthelmintics and assessed the predictive systemic efficacy. Finally, we present the anticancer efficacy of benzimidazole anthelmintics' putative metabolites from hydrolysis. Our data suggest that benzimidazole anthelmintic drugs are not expected to show systemic anticancer efficacy in vivo due to poor pharmacokinetic parameters. Therefore, patients should not consider oxibendazole or fenbendazole as cancer treatment option.

Nose to brain delivery of tailored clozapine nanosuspension stabilized using (+)-alpha-tocopherol polyethylene glycol 1000 succinate: Optimization and in vivo pharmacokinetic studies

Clozapine is widely used to treat schizophrenia as an atypical antipsychotic. Low solubility, poor dissolution rate, degradation in the gastrointestinal tract, high hepatic first-pass metabolism, and eventually less drug transfer in the brain are all issues with oral clozapine administration. On account of this poor pharmacokinetic parameters, the authors aimed to develop clozapine nanosuspension using (+)-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS) and polyvinylpyrrolidone K-30 (PVP K-30) and deliver it through the intranasal route. The nanosuspension was prepared by the high-speed homogenization method with 32 full factorial design for optimization of the product. Quality Target Product Profile (QTPP) was enlisted before the product development. The amount of TPGS and speed of homogenizer were selected as independent variables whereas, particle size and drug permeation profile after 24 h (Y2, %) were selected as dependent variables. As per the results of optimization, amount of TPGS and speed of homogenizer were chosen as 0.1% and 7000 rpm, respectively. The particle size of the optimized nanosuspension of clozapine was found to be 281 nm. The conversion of clozapine crystals to an amorphous form was verified by characterization studies (XRD and DSC). The drug permeability study showed 96.15% and 41.12% clozapine release after 24 h from nanosuspension and conventional suspension, respectively. The study of nasal cilio-toxicity (histopathological studies) demonstrated the appropriateness of nanosuspension for intranasal purposes. The single-dose in vivo pharmacokinetic analysis in the rat model showed a substantial increase in the therapeutic concentration of clozapine in the brain tissue in the case of intranasal nanosuspension (dose = 0.05 mg drug/0.1 mL, Cmax = 8.62 ± 0.45 μg/g, tmax = 1 h) compared to conventional oral clozapine suspension (dose = 26.43 mg drug/0.158 mL, Cmax = 1.14 ± 0.12 μg/g, tmax = 1 h).Ultimately, in the case of an intranasal route, a 3.56-fold increase in brain drug concentration was observed with a 528-fold lower drug dose compared with oral administration. The results suggest that clozapine nanosuspension may be used for successful nose-to-brain delivery.

Food-Effect on (-) - Hydroxycitric Acid Absorption After Oral Administration of Garcinia cambogia Extract Formulation: a Phase I, Randomized, Cross-Over Study.

Garcinia cambogia extract (GCE)/(-) - hydroxycitric acid (HCA) has been identified as a potential antiobesity agent. However, controversial clinical trial results have been published on its biological effect and poor pharmacokinetic (PK) information increases its dubious efficacy. The aim of this study was to determine the main PK parameters of GCE/HCA in healthy women, and to evaluate food effects on HCA absorption. Healthy women ages 21-41 years with body mass index (BMI; kg/m2) 20.29-25.82 participated in a phase I, open-label, randomized, single-dose, cross-over study. In the fasted- and fed-conditions subjects received 1500/750mg of GCE/HCA under 8h of fasting. In the fed-period was given a high calorie breakfast (~600 calories) after dosing. Plasma HCA concentrations were substantially reduced in fed-state. Peak plasma concentration (Cmax) and area under the curve of time-concentration (AUC0-10h) were 3-fold and 2-fold lower (p<0.001, 0.01) in fed-condition, respectively. Higher volume of distribution (Vd/F) and clearance (Cl/F) were achieved in fed state, probably due to the lower fraction (F) of HCA absorbed induced by food effect. Large inter-individual variations were observed for the main pharmacokinetics parameters in both periods. These findings suggest that HCA might suffer an active absorption uptake and intense adsorption on food.

Long Circulating liposomes: Challenges and Opportunities

The poor pharmacokinetic parameters and low solubility of many anticancer therapeutics have warranted the use of drug-delivery systems such as liposomes. Overcoming some drawbacks of the conventional liposomes, targeted liposomal delivery by longer circulation time by addition of poly(ethylene glycol) to the liposomal surface and further adding specific ligands to achieve ligand selective retention and uptake has been introduced. PEGylated liposomes are the only second-generation liposomal formulations in clinical use and are now being challenged with the allergenic response they pose even in the treatment of naive patients. This article will review the challenges and hindrances in the use of long circulating liposomes and explore the opportunities to overcome this issue.

Enhanced Both in vitro and in vivo Kinetics by SLNs Induced Transdermal System of Furosemide: A Novel Approach

Furosemide is a potent diuretic agent used to treat pulmonary arterial hypertension. Variable dosage regimen and poor pharmacokinetic parameters have led to the development of transdermal drug delivery system. Patent on suitability of multi-lamellar structures for excellent transdermal delivery (US0367475A1) has encouraged us to formulate the solid lipid nanoparticles (SLNs) induced transdermal systems of furosemide to enhance the kinetic properties without incorporating any penetration enhancer and rate limiting polymers. SLNs were prepared by hot homogenization and ultra-sonication method; optimization was done based on entrapment efficiency and particle size. Optimized SLNs were incorporated in to transdermal patches by solvent casting method. In vitro and in vivo studies were carried out for characterization of transdermal patches. SLNs of F9 (GMS: Span 60: Pluronic F 68 in 6:2.5:0.2) were optimized for incorporating in to transdermal system (entrapment efficiency 96.5±0.045%, particle size 69.6±1.48nm and in vitro release 94.38±1.02%). Transdermal patches were formulated using combinations of hydrophilic and hydrophobic polymers to study the diffusion kinetics. Formulation FS1 (HPMC 4 parts) was optimized for further studies (in vitro release 98.11±1.21% with flux of 58.726±0.023µg/cm2/h) and no significant difference from ex vivo permeation studies was observed. Drug release followed mixed order diffusion kinetics and super case -II transport mechanism. In vivo pharmacokinetic data of SLNs induced transdermal system suggested a 3.6 times increase in AUC and 5.4 times increase in MRT when compared with oral route. The SLNs induced transdermal patch was found to beneficial in enhancing kinetic properties both in vitro and in vivo.

Pharmacokinetic parameters explain the therapeutic activity of antimicrobial agents in a silkworm infection model

Poor pharmacokinetic parameters are a major reason for the lack of therapeutic activity of some drug candidates. Determining the pharmacokinetic parameters of drug candidates at an early stage of development requires an inexpensive animal model with few associated ethical issues. In this study, we used the silkworm infection model to perform structure-activity relationship studies of an antimicrobial agent, GPI0039, a novel nitrofuran dichloro-benzyl ester, and successfully identified compound 5, a nitrothiophene dichloro-benzyl ester, as a potent antimicrobial agent with superior therapeutic activity in the silkworm infection model. Further, we compared the pharmacokinetic parameters of compound 5 with a nitrothiophene benzyl ester lacking chlorine, compound 7, that exerted similar antimicrobial activity but had less therapeutic activity in silkworms, and examined the metabolism of these antimicrobial agents in human liver fractions in vitro. Compound 5 had appropriate pharmacokinetic parameters, such as an adequate half-life, slow clearance, large area under the curve, low volume of distribution, and long mean residence time, compared with compound 7, and was slowly metabolized by human liver fractions. These findings suggest that the therapeutic effectiveness of an antimicrobial agent in the silkworms reflects appropriate pharmacokinetic properties.

Cathepsin B Degradable Star-Shaped Peptidic Macromolecules for Delivery of 2-Methoxyestradiol

2-Methoxyestradiol (2ME), a natural metabolite of estradiol, has antiproliferative and antiangiogenic activity. However, its clinical success is limited due to poor water solubility and poor pharmacokinetic parameters suggesting the need for a delivery vehicle. In this study we evaluated cathepsin B degradable star-shaped peptidic macromolecules (SPMs) that can potentially be used to create higher generation and high molecular weight peptidic polymer as delivery vehicle of 2ME. Two peptidic macromolecules having positively charged amine (ASPM) or negatively charged carboxyl surface groups (CSPM) were synthesized and evaluated for their degradation in the presence of cathepsin B and stability in the presence of neutral or acidic buffer and serum. Both ASPM and CSPM degraded rapidly in the presence of cathepsin B. Both were stable in neutral and acidic buffer whereas only CSPM exhibited substantial stability in the presence of serum. Both macromolecules were nontoxic toward breast cancer cells whereas 2ME-containing macromolecules exhibited antiproliferative activity in the micromolar range. Overall, results from the current study indicate that tetrapeptide GFLG can be used to create star-shaped macromolecules that are degraded in the presence of cathepsin B and have the potential to be developed as delivery vehicles of 2ME.

Naphthalene/quinoline amides and sulfonylureas as potent and selective antagonists of the EP4 receptor

Two new series of EP(4) antagonists based on naphthalene/quinoline scaffolds have been identified as part of our on-going efforts to develop treatments for inflammatory pain. One series contains an acidic sulfonylurea pharmacophore, whereas the other is a neutral amide. Both series show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. While the amide series generally displays poor pharmacokinetic parameters, the sulfonylureas exhibit greatly improved profile. MF-592, the optimal compound from the sulfonylurea series, has a desirable overall preclinical profile that suggests it is suitable for further development.