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26.  O-Phospho-L-Serine, Multi-functional Excipient for B Domain Deleted Recombinant Factor VIII 
The AAPS journal  2007;9(2):E251-E259.
Factor VIII (FVIII) is an important cofactor in the blood coagulation cascade. A deficiency or dysfunction of FVIII causes hemophilia A, a life-threatening bleeding disorder. FVIII circulates in plasma as a heterodimer comprising 6 domains (heavy chain, A1-A2-B and light chain, A3-C1-C2). Replacement therapy using FVIII is the leading therapy in the management of hemophilia A. However, ∼15% to 30% of patients develop inhibitory antibodies that neutralize the activity of the protein. Neutralizing antibodies to epitopes in the lipid binding region of FVIII are commonly identified in patients’ plasma. In this report, we investigated the effect of O-phospho-L-serine (OPLS), which binds to the lipid binding region, on the immunogenicity of B domain deleted recombinant factor VIII (BDDrFVIII). Sandwich enzyme-linked immunosorbent assay (ELISA) studies showed that OPLS specifically bind to the lipid binding region, localized in the C2 domain of the coagulation factor. Size exclusion chromatography and fluorescence anisotropy studies showed that OPLS interfered with the aggregation of BDDrFVIII. Immunogenicity of free-vs BDDrFVIII-OPLS complex was evaluated in a murine model of hemophilia A. Animals administered subcutaneous (sc) injections of BDDrFVIII-OPLS had lower neutralizing titers compared with animals treated with BDDrFVIII alone. Based on these studies, we hypothesize that specific molecular interactions between OPLS and BDDrFVIII may improve the stability and reduce the immunogenicity of BDDrFVIII formulations.
doi:10.1208/aapsj0902028
PMCID: PMC2573386  PMID: 17907766
B domain deleted recombinant factor VIII; O-phospho-L-serine; protein formulation; excipient; physical stability; immunogenicity; inhibitor development
27.  O-phospho-L-serine, multi-functional excipient for B domain deleted recombinant factor VIII 
The AAPS Journal  2007;9(2):E251-E259.
Factor VIII (FVIII) is an important cofactor in the blood coagulation cascade. A deficiency or dysfunction of FVIII causes hemophilia A, a life-threatening bleeding disorder. FVIII circulates in plasma as a heterodimer comprising 6 domains (heavy chain, A1-A2-B and light chain A3-C1-C2). Replacement therapy using FVIII is the leading therapy in the management of hemophilia A. However, ∼15% to 30% of patients develop inhibitory antibodies that neutralize the activity of the protein. Neutralizing antibodies to epitopes in the lipid binding region of FVIII are commonly identified in patients' plasma. In this report, we investigated the effect of O-phospho-L-serine (OPLS), which binds to the lipid bindinding region, on the immunogenicity of B domain deleted recombinant factor VIII (BDDrFVIII). Sandwich enzyme-linked immunosorbent assay (ELISA) studies showed that OPLS specifically bind to the lipid binding region, localized in the C2 domain of the coagulation factor. Size exclusion chromatography and fluorescence anisotropy studies showed that OPLS interfered with the aggregation of BDDrFVIII. Immunogenicity of free-vs BDDrFVIII-OPLS complex was evaluated in a murine model of hemophilia A. Animals administered subcutaneous (sc) injections of BDDrFVIII-OPLS had lower neutralizing titers compared with animals treated with BDDRFVIII alone. Based on these studies, we hypothesize that specific molecular interactions between OPLS and BDDrFVIII may improve the stability and reduce the immunogenicity of BDDrFVIII formulations.
doi:10.1208/aapsj0902028
PMCID: PMC2573386  PMID: 17907766
B domain deleted recombinant factor VIII; O-phospho-L-serine; protein formulation; excipient; physical stability; immunogenicity; inhibitor development
28.  New Paradigms and Tools in Drug Design for Pain and Addiction 
The AAPS journal  2006;8(3):E450-E460.
New modalities providing safe and effective treatment of pain, especially prolonged pathological pain, have not appeared despite much effort. In this mini-review/overview we suggest that new paradigms of drug design are required to counter the underlying changes that occur in the nervous system that may elicit chronic pain states. We illustrate this approach with the example of designing, in a single ligand, molecules that have agonist activity at μ and δ opioid receptors and antagonist activities at cholecystokinin (CCK) receptors. Our findings thus far provide evidence in support of this new approach to drug design. We also report on a new biophysical method, plasmon waveguide resonance (PWR) spectroscopy, which can provide new insights into information transduction in G-protein coupled receptors (GPCRs) as illustrated by the δ opioid receptor.
doi:10.1208/aapsj080353
PMCID: PMC1764851  PMID: 17025262
drug design; neuropathic pain; bifunctional ligands; plasmon waveguide resonance spectroscopy; GPCRs; opioid receptors; cholecystokinin receptors
29.  Modulation of microglial pro-inflammatory and neurotoxic activity for the treatment of Parkinson’s disease 
The AAPS Journal  2006;8(3):E606-E621.
Parkinson’s disease (PD) is a debilitating movement disorder resulting from a progressive degeneration of the nigrostriatal dopaminergic pathway and depletion of neurotransmitter dopamine in the striatum. Molecular cloning studies have identified nearly a dozen genes or loci that are associated with small clusters of mostly early onset and genetic forms of PD. The etiology of the vast majority of PD cases remains unknown, and the precise molecular and biochemical processes governing the selective and progressive degeneration of the nigrostriatal dopaminergic pathway are poorly understood. Current drug therapies for PD are symptomatic and appear to bear little effect on the progressive neurodegenerative process. Studies of postmortem PD brains and various cellular and animal models of PD in the last 2 decades strongly suggest that the generation of proinflammatory and neurotoxic factors by the resident brain immune cells, microglia, plays a prominent role in mediating the progressive neurodegenerative process. This review discusses literature supporting the possibility of modulating the activity of microglia as a neuroprotective strategy for the treatment of PD.
doi:10.1208/aapsj080369
PMCID: PMC2668934  PMID: 17025278
Dopamine neuron; Parkinson’s disease; movement disorder; microglia; neuroprotection; free radical
30.  New paradigms and tools in drug design for pain and addiction 
The AAPS Journal  2006;8(3):E450-E460.
New modalities providing safe and effective treatment of pain, especially prolonged pathological pain, have not appeared despite much effort. In this mini-review/overview we suggest that new paradigms of drug design are required to counter the underlying changes that occur in the nervous system that may elicit chronic pain states. We illustrate this approach with the example of designing, in a single ligand, molecules that have agonist activity at μ and σ opioid receptors and antagonist activities at cholecystokinin (CCK) receptors. Our findings thus far provide evidence in support of this new approach to drug design. We also report on a new biophysical method, plasmon waveguide resonance (PWR) spectroscopy, which can provide new insights into information transduction in g-protein coupled receptors (GPCRs) as illustrated by the δ opioid receptor.
doi:10.1208/aapsj080353
PMCID: PMC1764851  PMID: 17025262
drug design; neuropathic pain; bifunctional ligands; plasmon waveguide resonance spectroscopy; GPCRs; opioid receptors; cholecystokinin receptors
31.  Pharmacogenomic responses of rat liver to methylprednisolone: An approach to mining a rich microarray time series 
The AAPS Journal  2005;7(1):E156-E194.
A data set was generated to examine global changes in gene expression in rat liver over time in response to a single bolus dose of methylprednisolone. Four control animals and 43 drug-treated animals were humanely killed at 16 different time points following drug administration. Total RNA preparation from the livers of these animals were hybridized to 47 individual Affymetrix RU34A gene chips, generating data for 8799 different probe sets for each chip. Data mining techniques that are applicable to gene array time series data sets in order to identify drug-regulated changes in gene expression were applied to this data set. A series of 4 sequentially applied filters were developed that were designed to eliminate probe sets that were not expressed in the tissue, were not regulated by the drug treatment, or did not meet defined quality control standards. These filters eliminated 7287 probe sets of the 8799 total (82%) from further consideration. Application of judiciously chosen filters is an effective tool for data mining of time series data sets. The remaining data can then be further analyzed by clustering and mathematical modeling techniques.
doi:10.1208/aapsj070117
PMCID: PMC2607485  PMID: 16146338
Data mining; gene arrays; glucocorticoids; mathematical modeling; pharmacogenomics
33.  Commentary: Current Perspectives on the Aggregation of Protein Drugs 
The AAPS Journal  2014;16(3):413-414.
doi:10.1208/s12248-014-9580-0
PMCID: PMC4012046  PMID: 24563118
aggregation; analytical methods; protein drugs; symposium
34.  Screening of Bioactive Peptides Using an Embryonic Stem Cell-Based Neurodifferentiation Assay 
The AAPS Journal  2014;16(3):400-412.
Differentiation of pluripotent stem cells, PSCs, towards neural lineages has attracted significant attention, given the potential use of such cells for in vitro studies and for regenerative medicine. The present experiments were designed to identify bioactive peptides which direct PSC differentiation towards neural cells. Fifteen peptides were designed based on NCAM, FGFR, and growth factors sequences. The effect of peptides was screened using a mouse embryonic stem cell line expressing luciferase dual reporter construct driven by promoters for neural tubulin and for elongation factor 1. Cell number was estimated by measuring total cellular DNA. We identified five peptides which enhanced activities of both promoters without relevant changes in cell number. We selected the two most potent peptides for further analysis: the NCAM-derived mimetic FGLL and the synthetic NCAM ligand, Plannexin. Both compounds induced phenotypic neuronal differentiation, as evidenced by increased neurite outgrowth. In summary, we used a simple, but sensitive screening approach to identify the neurogenic peptides. These peptides will not only provide new clues concerning pathways of neurogenesis, but they may also be interesting biotechnology tools for in vitro generation of neurons.
doi:10.1208/s12248-014-9578-7
PMCID: PMC4012039  PMID: 24557747
bioactive peptides; embryonic stem cells; neural differentiation
35.  Stability: Recommendation for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Team 
The AAPS Journal  2014;16(3):392-399.
This paper provides a comprehensive overview of stability-related aspects of quantitative bioanalysis and recommends science-based best practices, covering small and large molecules as well as chromatographic and ligand-binding assays. It addresses general aspects, such as the use of reference values, transferability and treatment of failing stability results, and also focuses on specific types of stability assessment: bench-top, freeze/thaw and long-term frozen stability, stock stability, extract stability, stability in whole blood, tissue and urine, and stability of endogenous analytes, in special matrix types and in incurred samples.
doi:10.1208/s12248-014-9573-z
PMCID: PMC4012051  PMID: 24550081
GBC; regulated bioanalysis; stability assessment
36.  Sequential Bioequivalence Approaches for Parallel Designs 
The AAPS Journal  2014;16(3):373-378.
Regulators in EU, USA and Canada allow the use of two-stage approaches for evaluation of bioequivalence. The purpose of this paper is to evaluate such designs for parallel groups using trial simulations. The methods developed by Diane Potvin and co-workers were adapted to parallel designs. Trials were simulated and evaluated on basis of either equal or unequal variances between treatment groups. Methods B and C of Potvin et al., when adapted for parallel designs, protected well against type I error rate inflation under all of the simulated scenarios. Performance characteristics of the new parallel design methods showed little dependence on the assumption of equality of the test and reference variances. This is the first paper to describe the performance of two-stage approaches for parallel designs used to evaluate bioequivalence. The results may prove useful to sponsors developing formulations where crossover designs for bioequivalence evaluation are undesirable.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-014-9571-1) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-014-9571-1
PMCID: PMC4012040  PMID: 24526610
bioequivalence; parallel; power; sequential designs; type I errors
37.  Determination of the Most Influential Sources of Variability in Tacrolimus Trough Blood Concentrations in Adult Liver Transplant Recipients: A Bottom-Up Approach 
The AAPS Journal  2014;16(3):379-391.
Tacrolimus, an immunosuppressant drug, presents a narrow therapeutic window and a large pharmacokinetic variability with poor correlation between drug dosing regimen and blood concentration. The objective was to identify predictive factors influencing tacrolimus trough concentrations (C0) using a bottom-up approach. A physiologically based pharmacokinetic (PBPK) model of tacrolimus was proposed, taking into account the body weight, the proportion of fat (Pfat), hematocrit, lipid fraction of organs, typical intrinsic clearance (CLityp), CYP3A5 genotype of liver donor, plasma unbound fraction of tacrolimus (fup), and concomitant drugs (CYP3A4 inhibitors). For the evaluation of the PBPK model, mean C0 and concentrations 2 h after oral dose of tacrolimus were compared with those from 66 liver transplant recipients included in a multicentric pharmacokinetic study and were found very close. Tacrolimus concentration profiles were simulated in a virtual population defined by a set of covariate values similar to those from the real population. The sensitivity of tacrolimus C0 with respect to each covariate has been tested to identify the most influential ones. With the range of covariate values tested, the impact of each covariate on tacrolimus C0 may be ranked as follows: fup, CLityp, bioavailability, body weight, hematocrit, CYP3A5 polymorphism, Pfat, and CYP3A4 inhibitory drug–drug interactions. Values for initial dosing regimen of tacrolimus in order to reach a C0 of 10 ng/ml at day 5 (assuming a constant dosing schedule) as a function of CYP3A5 donor genotype and patient’s hematocrit and body weight are proposed.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-014-9577-8) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-014-9577-8
PMCID: PMC4012056  PMID: 24526611
bottom-up approach; liver transplantation; tacrolimus; therapeutic drug monitoring
38.  Novel Lansoprazole-Loaded Nanoparticles for the Treatment of Gastric Acid Secretion-Related Ulcers: In Vitro and In Vivo Pharmacokinetic Pharmacodynamic Evaluation 
The AAPS Journal  2014;16(3):361-372.
The objective of this study is to combine nanoparticle design and enteric coating technique to sustain the delivery of an acid-labile drug, lansoprazole (LPZ), in the treatment of acid reflux disorders. Lansoprazole-loaded Eudragit® RS100 nanoparticles (ERSNP-LPZ) as well as poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PLGANP-LPZ) were prepared using a solvent evaporation/extraction method. The effects of nanoparticle charge and permeation enhancers on lansoprazole uptake was assessed in Caco-2 cells. The confocal microscopic images revealed the successful localization of nanoparticles in the cytoplasm of Caco-2 cells. The cellular uptake of positively charged Eudragit nanoparticles was significantly higher than that of negatively charged PLGA nanoparticles, which were enhanced by sodium caprate via the transcellular pathway. Both types of nanoparticles exhibited sustained drug release behavior in vitro. The oral administration of enteric-coated capsules filled with nanoparticles sustained and prolonged the LPZ concentration up to 24 h in ulcer-induced Wistar rats, and 92.4% and 89.2% of gastric ulcers healed after a 7-day treatment with either EC-ERSNP1010-Na caprate or EC-PLGANP1005-Na caprate, respectively.
doi:10.1208/s12248-014-9564-0
PMCID: PMC4012042  PMID: 24519468
Caco-2 cell; lansoprazole; nanoparticles; pharmacodynamic study; pharmacokinetic study
39.  Recommendations and Best Practices for Reference Standards and Reagents Used in Bioanalytical Method Validation 
The AAPS Journal  2014;16(2):352-356.
The continued globalization of pharmaceutics has increased the demand for companies to know and understand the regulations that exist across the globe. One hurdle facing pharmaceutical and biotechnology companies developing new drug candidates is interpreting the current regulatory guidance documents and industry publications associated with bioanalytical method validation (BMV) from each of the different agencies throughout the world. The objective of this commentary is to provide our opinions on the best practices for reference standards and key reagents, such as metabolites and internal standards used in the support of regulated bioanalysis based on a review of current regulatory guidance documents and industry white papers for BMV.
doi:10.1208/s12248-014-9566-y
PMCID: PMC3933579  PMID: 24500277
bioanalytical method validation; internal standards; metabolites; reference standards; stock solutions
40.  New Frontiers—Accelerator Mass Spectrometry (AMS): Recommendation for Best Practices and Harmonization from Global Bioanalysis Consortium Harmonization Team 
The AAPS Journal  2014;16(2):357-359.
The technique of accelerator mass spectrometry (AMS) is applicable to the analysis of a wide range of trace elemental isotopes. However, in the context of the pharmaceutical industry, it is invariably used to measure radiocarbon (14C). There are two broad modes of application: analysis of total 14C sometimes termed “direct AMS” and analysis of specific 14C-labelled analytes in a variety of matrices following some method of isolation. It is the latter application which is within the remit of the GBC team, and the team has made efforts to propose harmonized recommendations for the validation of AMS when used in a regulatory bioanalytical mode, i.e. the quantification of specific analyte(s) using liquid chromatography with off-line detection by AMS now known as “LC + AMS”. The GBC team has reached a position where they have agreed to many aspects, but also differ on some aspects of what constitutes a bioanalytical assay validation in support of clinical studies using this technology. The detail of most of this will be covered under separate publication(s), but for the purposes of this paper, we have outlined the points of consensus. The purpose of this article is not to provide a roadmap for validation of LC + AMS assays, but to highlight agreements amongst the industry representative experts and the practitioners, as well as identifying specific areas essential for establishing assay quality but where additional discussion is required to reach agreement.
doi:10.1208/s12248-014-9568-9
PMCID: PMC3933583  PMID: 24500278
accelerator mass spectrometry; bioanalysis; LC + AMS
41.  [No title available] 
PMCID: PMC3933585  PMID: 24493374
42.  [No title available] 
PMCID: PMC3933571  PMID: 24482005
43.  [No title available] 
PMCID: PMC3933587  PMID: 24477942
44.  [No title available] 
PMCID: PMC3933589  PMID: 24477941
45.  Ethinyl Estradiol and Other Human Pharmaceutical Estrogens in the Aquatic Environment: A Review of Recent Risk Assessment Data 
The AAPS Journal  2014;16(2):299-310.
Interest in pharmaceuticals in the environment has increased substantially in recent years. Several studies in particular have assessed human and ecological risks from human pharmaceutical estrogens, such as 17α-ethinyl estradiol (EE2). Regulatory action also has increased, with the USA and other countries developing rules to address estrogens and other pharmaceuticals in the environment. Accordingly, the Center for Drug Evaluation and Research at the US Food and Drug Administration has conducted a review and analysis of current data on the long-term ecological exposure and effects of EE2 and other estrogens. The results indicate that mean-flow long-term predicted environmental concentrations (PECs) of EE2 in approximately 99% or more of US surface water segments downstream of wastewater treatment plants are lower than a predicted no-effect concentration (PNEC) for aquatic chronic toxicity of 0.1 ng/L. Exceedances are expected to be primarily in localized, effluent-dominated water segments. The median mean-flow PEC is more than two orders of magnitude lower than this PNEC. Similar results exist for other pharmaceutical estrogens. Data also suggest that the contribution of EE2 more broadly to total estrogenic load in the environment from all sources (including other human pharmaceutical estrogens, endogenous estrogens, natural environmental estrogens, and industrial chemicals), while highly uncertain and variable, appears to be relatively low overall. Additional data and a more comprehensive approach for data collection and analysis for estrogenic substances in the environment, especially in effluent-dominated water segments in sensitive environments, would more fully characterize the risks.
doi:10.1208/s12248-014-9561-3
PMCID: PMC3933577  PMID: 24470211
aquatic ecology; environmental impact; estrogens; regulatory science; toxicity
46.  Novel Endogenous Glycan Therapy for Retinal Diseases: Safety, In Vitro Stability, Ocular Pharmacokinetic Modeling, and Biodistribution 
The AAPS Journal  2014;16(2):311-323.
Asialo, tri-antennary oligosaccharide (NA3 glycan) is an endogenous compound, which supports proper folding of outer segment membranes, promotes normal ultrastructure, and maintains protein expression patterns of photoreceptors and Müller cells in the absence of retinal pigment epithelium support. It is a potential new therapeutic for atrophic age-related macular degeneration (AMD) and other retinal degenerative disorders. Herein, we evaluate the safety, in vitro stability, ocular pharmacokinetics and biodistribution of NA3. NA3 was injected into the vitreous of New Zealand white rabbits at two concentrations viz. 1 nM (minimum effective concentration (MEC)) and 100 nM (100XMEC) at three time points. Safety was evaluated using routine clinical and laboratory tests. Ocular pharmacokinetics and biodistribution of [3H]NA3 were estimated using scintillation counting in various parts of the eye, multiple peripheral organs, and plasma. Pharmacokinetic parameters were estimated by non-compartmental modeling. A 2-aminobenzamide labeling and hydrophilic interaction liquid interaction chromatography were used to assess plasma and vitreous stability. NA3 was well tolerated by the eye. The concentration of NA3 in eye tissues was in the order: vitreous > retina > sclera/choroid > aqueous humor > cornea > lens. Area under the curve (0 to infinity) (AUC∞) was the highest in the vitreous thereby providing a positive concentration gradient for NA3 to reach the retina. Half-lives in critical eye tissues ranged between 40 and 60 h. NA3 concentrations were negligible in peripheral organs. Radioactivity from [3H]NA3 was excreted via urine and feces. NA3 was stable at 37°C in vitreous over a minimum of 6 days, while it degraded rapidly in plasma. Collectively, these results document that NA3 shows a good safety profile and favorable ocular pharmacokinetics.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-014-9563-1) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-014-9563-1
PMCID: PMC3933590  PMID: 24470212
age-related macular degeneration (AMD); NA3 glycan; pharmacokinetics; safety
47.  Synthesis, Spectral Characterization, and In Vitro Cellular Activities of Metapristone, a Potential Cancer Metastatic Chemopreventive Agent Derived from Mifepristone (RU486) 
The AAPS Journal  2014;16(2):289-298.
Mifepristone (RU486) is marketed and used widely by women as an abortifacient, and experimentally for psychotic depression and anticancer treatments. After administration, metapristone is found to be the most predominant metabolite of mifepristone. We hypothesized that adhesion of circulating tumor cells (CTCs) to vascular endothelial bed is a crucial starting point in metastatic cascade, and that metapristone can serve as a cancer metastatic chemopreventive agent that can interrupt adhesion and invasion of CTCs to the intima of microvasculature. In the present study, we modified the synthesis procedure to produce grams of metapristone, fully characterized its spectral properties and in vitro cellular activities, including its cytostatic effects, cell cycle arrest, mitochondrial membrane potential, and apoptosis on human colorectal cancer HT-29 cells. Metapristone concentration dependently interrupted adhesion of HT-29 cells to endothelial cells. Metapristone may potentially be a useful agent to interrupt metastatic initiation.
doi:10.1208/s12248-013-9559-2
PMCID: PMC3933578  PMID: 24442753
cancer metastasis chemoprevention; in vitro cellular activities; metapristone; mifepristone; spectral properties
48.  Combined Inhaled Salbutamol and Mannitol Therapy for Mucus Hyper-secretion in Pulmonary Diseases 
The AAPS Journal  2014;16(2):269-280.
This study focuses on the co-engineering of salbutamol sulphate (SS), a common bronchodilator, and mannitol (MA), a mucolytic, as a potential combination therapy for mucus hypersecretion. This combination was chosen to have a synergic effect on the airways: the SS will act on the β2-receptor for relaxation of smooth muscle and enhancement of ciliary beat frequency, whilst mannitol will improve the fluidity of mucus, consequently enhancing its clearance from the lung. A series of co-spray-dried samples, containing therapeutically relevant doses of SS and MA, were prepared. The physico-chemical characteristics of the formulations were evaluated in terms of size distribution, morphology, thermal and moisture response and aerosol performance. Additionally, the formulations were evaluated for their effects on cell viability and transport across air interface Calu-3 bronchial epithelial cells, contractibility effects on bronchial smooth muscle cells and cilia beat activity using ciliated nasal epithelial cells in vitro. The formulations demonstrated size distributions and aerosol performance suitable for inhalation therapy. Transport studies revealed that the MA component of the formulation enhanced penetration of SS across the complex mucus layer and the lung epithelia cells. Furthermore, the formulation in the ratios of SS 10−6 and MA 10−3 M gave a significant increase in cilia beat frequency whilst simultaneously preventing smooth muscle contraction associated with mannitol administration. These studies have established that co-spray dried combination formulations of MA and SS can be successfully prepared with limited toxicity, good aerosol performance and the ability to increase ciliary beat frequency for improving the mucociliary clearance in patients suffering from hyper-secretory diseases, whilst simultaneously acting on the underlying smooth muscle.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-014-9560-4) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-014-9560-4
PMCID: PMC3933573  PMID: 24431080
cilia responce; epithelia transport; lung delivery; mannitol; salbutamol; smooth muscle responce
49.  Dietary Flavonoids Modulate CYP2C to Improve Drug Oral Bioavailability and Their Qualitative/Quantitative Structure–Activity Relationship 
The AAPS Journal  2014;16(2):258-268.
This study aims to improve the drug oral bioavailability by co-administration with flavonoid inhibitors of the CYP2C isozyme and to establish qualitative and quantitative (QSAR) structure–activity relationships (SAR) between flavonoids and CYP2C. A total of 40 naturally occurring flavonoids were screened in vitro for CYP2C inhibition. Enzyme activity was determined by measuring conversion of tolbutamide to 4-hydroxytolbutamide by rat liver microsomes. The percent inhibition and IC50 of each flavonoid were calculated and used to develop SAR and QSAR. The most effective flavonoid was orally co-administered in vivo with a cholesterol-reducing drug, fluvastatin, which is normally metabolized by CYP2C. The most potent CYP2C inhibitor identified in vitro was tamarixetin (IC50 = 1.4 μM). This flavonoid enhanced the oral bioavailability of fluvastatin in vivo, producing a >2-fold increase in the area under the concentration–time curve and in the peak plasma concentration. SAR analysis indicated that the presence of a 2,3-double bond in the C ring, hydroxylation at positions 5, 6, and 7, and glycosylation had important effects on flavonoid–CYP2C interactions. These findings should prove useful for predicting the inhibition of CYP2C activity by other untested flavonoid-like compounds. In the present study, tamarixetin significantly inhibited CYP2C activity in vitro and in vivo. Thus, the use of tamarixetin could improve the therapeutic efficacy of drugs with low bioavailability.
doi:10.1208/s12248-013-9549-4
PMCID: PMC3933575  PMID: 24431079
bioavailability; CYP2C; flavonoid; structure–activity relationship; tamarixetin
50.  Headway and Hurdles in the Clinical Development of Dietary Phytochemicals for Cancer Therapy and Prevention: Lessons Learned from Vitamin A Derivatives 
The AAPS Journal  2014;16(2):281-288.
Accumulating epidemiologic and preclinical evidence support the pharmacologic use of a variety of dietary chemicals for the prevention and treatment of cancer. However, it will be challenging to translate these findings into routine clinical practice since phytochemicals have pleiotropic biological activities that have to be balanced for optimal efficacy without unacceptable and potentially unanticipated toxicities. Correctly matching patient populations and settings with optimal, natural product-based phytochemical therapies will require a greater understanding of the specific mechanisms underlying the efficacy, toxicity, and resistance of each agent in a variety of normal, premalignant, and malignant settings. This, in turn, necessitates continued commitment from the basic research community to guide carefully designed and informed clinical trials. The most developed class of anticancer phytochemicals consists of the derivatives of vitamin A called retinoids. Unlike other natural product chemicals currently under study, the retinoids have been extensively tested in humans. Over 30 years of clinical investigation has resulted in several disappointments, but there were some spectacular successes where certain retinoid-based protocols are now FDA-approved standard of care therapies to treat specific malignancies. Furthermore, retinoids are one of the most evaluated pharmacologic agents in the ultra-challenging setting of interventional cancer prevention. This review will summarize the development of retinoids in cancer therapy and prevention with an emphasis on currently proposed mechanisms mediating their efficacy, toxicity, and resistance.
doi:10.1208/s12248-014-9562-2
PMCID: PMC3933572  PMID: 24431081
chemoprevention; clinical trials; differentiation therapy; retinoids

Results 26-50 (854)