Slow drug delivery decreased total body clearance and altered bioavailability of immediate‐ and controlled‐release oxycodone formulations

Oxycodone is a commonly used analgesic with a large body of pharmacokinetic data from various immediate‐release or controlled‐release formulations, under different administration routes, and in diverse populations. Longer terminal half‐lives from extravascular administration as compared to IV administration have been attributed to flip‐flop pharmacokinetics with the rate constant of absorption slower than elimination. However, PK parameters from the extravascular studies showed faster absorption than elimination. Sustained release formulations guided by the flip‐flop concept produced mixed outcomes in formulation development and clinical studies. This research aims to develop a mechanistic knowledge of oxycodone ADME, and provide a consistent interpretation of diverging results and insight to guide further extended release development and optimize the clinical use of oxycodone. PK data of oxycodone in human studies were collected from literature and digitized. The PK data were analyzed using a new PK model with Weibull function to describe time‐varying drug releases/ oral absorption, and elimination dependent upon drug input to the portal vein. The new and traditional PK models were coded in NONMEM. Sensitivity analyses were conducted to address the relationship between rates of drug release/absorption and PK profiles plus terminal half‐lives. Traditional PK model could not be applied consistently to describe drug absorption and elimination of oxycodone. Errors were forced on absorption, elimination, or both parameters when IV and PO profiles were fitted separately. The new mechanistic PK model with Weibull function on absorption and slower total body clearance caused by slower absorption adequately describes the complex interplay between oxycodone absorption and elimination in vivo. Terminal phase of oxycodone PK profile was shown to reflect slower total body drug clearance due to slower drug release/absorption from oral formulations. Mechanistic PK models with Weibull absorption functions, and release rate‐dependent saturable total body clearance well described the diverging oxycodone absorption and elimination kinetics in the literature. It showed no actual drug absorption during the terminal phase, but slower drug clearance caused by slower release/absorption producing the appearance of flip‐flop and offered new insight for the development of modified release formulations and clinical use of oxycodone.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/116943/1/prp2210_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/116943/2/prp2210.pd

Metabolomics revealed the toxicity of cationic liposomes in HepG2 cells using UHPLC‐Q‐TOF/MS and multivariate data analysis

Cationic liposomes (CLs) are novel nonviral vectors widely used for delivering drugs or genes. However, applications of CLs are largely hampered by their cytotoxicity, partly because the potential mechanism underlying the cytotoxicity of CLs remains unclear. The aim of the present study was to explore the underlying mechanism of cytotoxicity induced by CLs on HepG2 cells. Differential metabolites were identified and quantified using ultra‐liquid chromatography quadrupole time‐of‐flight mass spectrometry (UHPLC‐Q‐TOF/MS). The toxicity of CLs on HepG2 cells was evaluated by multivariate data analysis and statistics. Additionally, CCK‐8 assay, heatmap, pathway and co‐expression network were carried out to explore the relations between the metabolites and the pathways. The results showed a dose‐dependent toxic effect of CLs on HepG2 cells, with an IC50 value of 119.9 μg/mL. Multivariate statistical analysis identified 42 potential metabolites between CLs exposure and control groups. Pathway analysis showed significant changes in pathways involving amino acid metabolism, energy metabolism, lipid metabolism and oxidative stress in the CLs exposure group vs the control group. Metabolites related to the above‐mentioned pathways included phenylalanine, methionine, creatine, oxalacetic acid, glutathione, oxidized glutathione, choline phosphate and several unsaturated fatty acids, indicating that cells were disturbed in amino acid metabolism, energy and lipid supply when CLs exposure‐induced injury occurred. It is concluded that CLs may induce cytotoxicity by enhancing reactive oxygen species in vitro, affect the normal process of energy metabolism, disturb several vital signaling pathways and finally induce cell death.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139913/1/bmc4036.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139913/2/bmc4036_am.pd

Trimodal Therapy: A Tumor Vascularâ Targeted Interlocking Trimodal Nanosystem That Induces and Exploits Hypoxia (Adv. Sci. 8/2018)

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145503/1/advs201870048.pd

A Tumor Vascularâ Targeted Interlocking Trimodal Nanosystem That Induces and Exploits Hypoxia

Vascularâ targeted photodynamic therapy (VTP) is a recently approved strategy for treating solid tumors. However, the exacerbated hypoxic stress makes tumor eradication challenging with such a single modality approach. Here, a new graphene oxide (GO)â based nanosystem for rationally designed, interlocking trimodal cancer therapy that enables VTP using photosensitizer verteporfin (VP) (1) with codelivery of banoxantrone dihydrochloride (AQ4N) (2), a hypoxiaâ activated prodrug (HAP), and HIFâ 1α siRNA (siHIFâ 1α) (3) is reported. The VTPâ induced aggravated hypoxia is highly favorable for AQ4N activation into AQ4 (a topoisomerase II inhibitor) for chemotherapy. However, the hypoxiaâ induced HIFâ 1α acts as a â hidden brake,â through downregulating CYP450 (the dominant HAPâ activating reductases), to substantially hinder AQ4N activation. siHIFâ 1α is rationally adopted to suppress the HIFâ 1α expression upon hypoxia and further enhance AQ4N activation. This trimodal nanosystem significantly delays the growth of PCâ 3 tumors in vivo compared to the control nanoparticles carrying VP, AQ4N, or siHIFâ 1α alone or their pairwise combinations. This multimodal nanoparticle design presents, the first example exploiting VTP to actively induce hypoxia for enhanced HAP activation. It is also revealed that HAP activation is still insufficient under hypoxia due to the hidden downregulation of the HAPâ activating reductases (CYP450), and this can be well overcome by GO nanoparticleâ mediated siHIFâ 1α intervention.Vascularâ targeted photodynamic therapy (VTP) is integrated with hypoxiaâ activated prodrug (AQ4N) and HIFâ 1α siRNA (siHIFâ 1α) for interlocking trimodal therapy. The VTPâ induced aggravated hypoxia is exploited for efficient AQ4N activation for chemotherapy. HIFâ 1α induced by hypoxia acts as a â hidden brake,â through downregulating CYP450 reductases, to hinder AQ4N activation. siHIFâ 1α is rationally adopted to suppress HIFâ 1α expression upon VTP to enhance AQ4N activation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145505/1/advs661-sup-0001-S1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145505/2/advs661.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145505/3/advs661_am.pd

DEFENS - Drug Exposure Feedback and Education for Nurses’ Safety: study protocol for a randomized controlled trial

Abstract Background Three decades of research findings have documented the health effects of handling hazardous drugs. Oncology nurses are vulnerable due to frequent administration of antineoplastics, low adherence to equipment use, reported barriers to use, and perceived low risk of health effects. No interventions have been tested in a controlled, multi-site trial to increase nurses’ use of protective equipment when handling hazardous drugs. The Drug Exposure Feedback and Education for Nurses’ Safety (DEFENS) study will compare the efficacy of education (control) versus an audit and feedback intervention (treatment) on nurses’ self-reported use of personal protective equipment when handling hazardous drugs. The treatment intervention will include tailored messages based on nurses’ reported barriers to protective equipment use. Methods/Design The DEFENS Study is a cluster randomized controlled trial. We are enrolling cancer centers and will recruit nurse participants in April 2015. Eligible cancer centers employ at least 20 eligible registered nurses in the chemotherapy infusion setting and have on-site phlebotomy resources. Eligible participants are nurses who work at least 0.40 full-time equivalent hours in the chemotherapy infusion setting and have not received an antineoplastic drug for a health problem in the past year. An encrypted, user-authenticated website will administer surveys and deliver control and treatment interventions. The primary endpoint is the change in score on nurses’ reports of the Revised Hazardous Drug Handling Questionnaire between baseline and approximately 18 months later. A baseline survey is completed after informed consent and is repeated 18 months later. Nurses in all sites who experience a drug spill will also report incidents as they occur; these reports inform the treatment intervention. Plasma will be obtained at baseline, approximately 18 months later (the primary endpoint), and with drug spill occurrences to measure hazardous drugs levels and to inform the treatment intervention. Potential mediators include knowledge of hazardous drug handling and perceived risk of drug exposure. We will examine whether personal factors and organizational factors moderate the intervention effects. Trial registration Clinicaltrials.gov NCT02283164 , registered 31 October 2014.http://deepblue.lib.umich.edu/bitstream/2027.42/111045/1/13063_2015_Article_674.pd

Synthesis of deuterium‐labelled amlexanox and its metabolic stability against mouse, rat, and human microsomes

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149374/1/jlcr3716_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149374/2/jlcr3716.pd

Identification of non‐reported bupropion metabolites in human plasma

Bupropion and its three active metabolites exhibit clinical efficacy in the treatment of major depression, seasonal depression and smoking cessation. The pharmacokinetics of bupropion in humans is highly variable. It is not known if there are any non‐reported metabolites formed in humans in addition to the three known active metabolites. This paper reports newly identified and non‐reported metabolites of bupropion in human plasma samples. Human subjects were dosed with a single oral dose of 75 mg of an immediate release bupropion HCl tablet. Plasma samples were collected and analysed by LC–MS/MS at 0, 6 and 24 h. Two non‐reported metabolites (M1 and M3) were identified with mass‐to‐charge (m/z) ratios of 276 (M1, hydration of bupropion) and 258 (M3, hydroxylation of threo/erythrohydrobupropion) from human plasma in addition to the known hydroxybupropion, threo/erythrohydrobupropion and the glucuronidation products of the major metabolites (M2 and M4–M7). These new metabolites may provide new insight and broaden the understanding of bupropion’s variability in clinical pharmacokinetics. © 2016 The Authors Biopharmaceutics & Drug Disposition Published by John Wiley & Sons Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134787/1/bdd2046_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134787/2/bdd2046.pd

Structure-Based Optimization of a Novel Class of Aldehyde Dehydrogenase 1A (ALDH1A) Subfamily-Selective Inhibitors as Potential Adjuncts to Ovarian Cancer Chemotherapy

Aldehyde dehydrogenase (ALDH) activity is commonly used as a marker to identify cancer stem-like cells. The three ALDH1A isoforms have all been individually implicated in cancer stem-like cells and in chemoresistance; however, which isoform is preferentially expressed varies between cell lines. We sought to explore the structural determinants of ALDH1A isoform selectivity in a series of small-molecule inhibitors in support of research into the role of ALDH1A in cancer stem cells. An SAR campaign guided by a cocrystal structure of the HTS hit CM39 (7) with ALDH1A1 afforded first-in-class inhibitors of the ALDH1A subfamily with excellent selectivity over the homologous ALDH2 isoform. We also discovered the first reported modestly selective single isoform 1A2 and 1A3 inhibitors. Two compounds, 13g and 13h, depleted the CD133+ putative cancer stem cell pool, synergized with cisplatin, and achieved efficacious concentrations in vivo following IP administration. Compound 13h additionally synergized with cisplatin in a patient-derived ovarian cancer spheroid model

Synthesis and Biological Activities of a 3′-Azido Analogue of Doxorubicin Against Drug-Resistant Cancer Cells

Doxorubicin (DOX), an anthracycline antibiotic, is one of the most active anticancer chemotherapeutic agents. The clinical use of DOX, however, is limited by the dose-dependant P-glycoprotein (P-gp)-mediated resistance. Herein, a 3′-azido analogue of DOX (ADOX) was prepared from daunorubicin (DNR). ADOX exhibited potent antitumor activities in drug-sensitive (MCF-7 and K562) and drug-resistant cell lines (MCF-7/DNR, K562/DOX), respectively. The drug resistance index (DRI) values of ADOX were much lower than that of DOX. The cytotoxicity experiments of ADOX or DOX against K562/DOX, with or without P-gp inhibitor, indicated that ADOX circumvents resistance by abolishing the P-gp recognition. This conclusion was further supported by drug influx/efflux flow cytometry experiments, as well as by molecular docking of ADOX to P-gp. In vivo animal tests, ADOX exhibited higher activity and less toxicity than DOX. The current data warranted ADOX for additional pre-clinical evaluations for new drug development