Other Pharmacy and Pharmaceutical Sciences Commons^™

Tolfenamic Acid Derivatives: A New Class Of Transcriptional Modulators With Potential Therapeutic Applications For Alzheimer’S Disease And Related Disorders, Juanetta Hill, Karim E. Shalaby, Syed W. Bihaqi, Bothaina H. Alansi, Benjamin Barlock, Keykavous Parang, Richard Thompson, Khalid Ourarhni, Nasser H. Zawia

Pharmacy Faculty Articles and Research

The field of Alzheimer’s disease (AD) has witnessed recent breakthroughs in the development of disease-modifying biologics and diagnostic markers. While immunotherapeutic interventions have provided much-awaited solutions, nucleic acid-based tools represent other avenues of intervention; however, these approaches are costly and invasive, and they have serious side effects. Previously, we have shown in AD animal models that tolfenamic acid (TA) can lower the expression of AD-related genes and their products and subsequently reduce pathological burden and improve cognition. Using TA as a scaffold and the zinc finger domain of SP1 as a pharmacophore, we developed safer and more potent brain-penetrating analogs …

Sirna Drug Delivery Across The Blood–Brain Barrier In Alzheimer's Disease, Muhammad Imran Sajid, Fahad Sultan Sheikh, Faiza Anis, Nourina Nasim, Rachita K. Sumbria, Surya M. Nauli, Rakesh K. Tiwari

Pharmacy Faculty Articles and Research

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a few FDA-approved drugs that provide modest symptomatic benefits and only two FDA-approved disease-modifying treatments for AD. The advancements in understanding the causative genes and non-coding sequences at the molecular level of the pathophysiology of AD have resulted in several exciting research papers that employed small interfering RNA (siRNA)-based therapy. Although siRNA is being sought by academia and biopharma industries, several challenges still need to be addressed. We comprehensively report the latest advances in AD pathophysiology, druggable targets, ongoing clinical trials, and the siRNA-based approaches across the blood–brain barrier for addressing …

Alcohol As A Modifiable Risk Factor For Alzheimer’S Disease—Evidence From Experimental Studies, Devaraj V. Chandrashekar, Ross A. Steinberg, Derick Han, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by cognitive impairment and memory loss. Epidemiological evidence suggests that heavy alcohol consumption aggravates AD pathology, whereas low alcohol intake may be protective. However, these observations have been inconsistent, and because of methodological discrepancies, the findings remain controversial. Alcohol-feeding studies in AD mice support the notion that high alcohol intake promotes AD, while also hinting that low alcohol doses may be protective against AD. Chronic alcohol feeding to AD mice that delivers alcohol doses sufficient to cause liver injury largely promotes and accelerates AD pathology. The mechanisms by which alcohol can …

Development And Validation Of An Ultrahigh-Performance Liquid Chromatography–Tandem Mass Spectrometry Method To Investigate The Plasma Pharmacokinetics Of A KCa2.2/KCa2.3 Positive Allosteric Modulator In Mice, Mohammad Asikur Rahman, Devaraj Venkatapura Chandrashekar, Young-Woo Nam, Basir Syed, David Salehi, Hamidreza Montazeri Aliabadi, Miao Zhang, Reza Mehvar

Pharmacy Faculty Articles and Research

Rationale

There is currently no treatment for spinocerebellar ataxias (SCAs), which are a group of genetic disorders that often cause a lack of coordination, difficulty walking, slurred speech, tremors, and eventually death. Activation of K_Ca2.2/K_Ca2.3 channels reportedly exerts beneficial effects in SCAs. Here, we report the development and validation of an analytical method for quantitating a recently developed positive allosteric modulator of K_Ca2.2/K_Ca2.3 channels (compound 2q) in mouse plasma.

Methods

Mouse plasma samples (10 μL) containing various concentrations of 2q were subjected to protein precipitation in the presence of a structurally similar …

Antibody-Drug Conjugates For Multiple Myeloma: Just The Beginning, Or The Beginning Of The End?, Upasana Ray, Robert Z Orlowski

Faculty, Staff and Student Publications

Multiple myeloma is a malignancy of immunoglobulin-secreting plasma cells that is now often treated in the newly diagnosed and relapsed and/or refractory settings with monoclonal antibodies targeting lineage-specific markers used either alone or in rationally designed combination regimens. Among these are the anti-CD38 antibodies daratumumab and isatuximab, and the anti-Signaling lymphocytic activation molecule family member 7 antibody elotuzumab, all of which are used in their unconjugated formats. Single-chain variable fragments from antibodies also form a key element of the chimeric antigen receptors (CARs) in the B-cell maturation antigen (BCMA)-targeted CAR T-cell products idecabtagene vicleucel and ciltacabtagene autoleucel, which are approved …

The Science Of Oral Carbapenems, Landon Olsen, Daniel J. Yang, Aiyi Chen, Thahn-Liem Vu, H. Stephen Lee

Annual Research Symposium

No abstract provided.

Evaluation Of Antifungal Efficacy In The Treatment Of Candida Auris Bloodstream Infections, Monique Busacay, Kaylee Putney, Rebecca Jayakumar

Annual Research Symposium

No abstract provided.

Adverse Infusion-Related Event Severity In Oncology Patients Receiving Chemotherapy Agents Vs. Immunotherapy Agents, Tayler Hutto

Annual Research Symposium

In recent years, immunotherapy investigational drugs in cancer research has been underway in treating multiple forms of cancer due to a lower side effect profile and decreased severe infusion-reaction risk compared to conventional chemotherapy agents. The purpose of this study was to determine the infusion reaction severity among patients receiving either chemotherapy treatment or immunotherapy agents based on the CTCAE (Common Terminology Criteria for Adverse Events) scale to improve patient care outcomes.

In this intent-to-treat, retrospective observational study, a survey of patients throughout 10 Intermountain Healthcare infusion clinics was conducted to obtain documentation on patients who had received chemotherapy and/or …

Characterization, Antibacterial, Antioxidant, Antidiabetic, And Anti-Inflammatory Activities Of Green Synthesized Silver Nanoparticles Using Phragmanthera Austroarabica A. G. Mill And J. A. Nyberg Extract, Shady Swidan, Dina Khodeer, Sarah Shabayek, Ali Nasr, Roaa Khinkar, Mohammed Aldurdunji, Maryam Ramadan, Jihan Badr

Pharmacy

Introduction: Diabetes mellitus is a chronic metabolic disorder that exhibited great expansion all over the world. It is becoming an epidemic disease adding a major burden to the health care system, particularly in developing countries.

Methods: The plant under investigation in the current study Phragmanthera austroarabica A. G. Mill and J. A. Nyberg is traditionally used in Saudi Arabia for the treatment of diabetes mellitus. The methanolic extract (200 mg/kg) of the plant and pure gallic acid (40 mg/kg), a major metabolite of the plant, as well as their silver nanoparticle formulae (AgNPs) were evaluated for their antidiabetic activity.

Results …

Physiologically-Based Pharmacokinetic (Pbpk) Modeling For The Preclinical Development Of Spectinamide Antibiotics, Keyur R. Parmar

Theses and Dissertations (ETD)

Despite being an ancient disease caused by Mycobacterium tuberculosis (Mtb) and after decades of research, tuberculosis (TB) still affects millions of people every year worldwide. In 2018, the World Health Organization (WHO) reported that 10 million people developed tuberculosis and 1.5 million died of the disease. With the increase in the multidrug-resistant (MDR) and extensively drug-resistant (XDR) cases, the treatment for TB with the standard first and second-line therapy is becoming increasingly difficult. Therefore, there is an urgent need to find new anti-TB drugs as combination partners of existing and experimental classes of antimicrobial agents to shorten and simplify the …

Il-21 Signaling Promotes The Establishment Of Kshv Infection In Human Tonsil Lymphocytes By Increasing Differentiation And Targeting Of Plasma Cells, Nedaa Alomari, Jennifer Totonchy

Pharmacy Faculty Articles and Research

Introduction: Factors influencing Kaposi’s sarcoma-associated herpesvirus (KSHV) transmission and the early stages of KSHV infection in the human immune system remain poorly characterized. KSHV is known to extensively manipulate the host immune system and the cytokine milieu, and cytokines are known to influence the progression of KSHV-associated diseases. Our previous work identified the early targeting of plasma cells for KSHV infection. In this study, we examine whether IL-21, a cytokine known to profoundly influence plasma cell fate, influences the early stages of KSHV infection in B lymphocytes.

Methods: Using our unique model of ex vivo KSHV infection in tonsil lymphocytes, …

Novel Drugs Approved In 2021-2022, Michael Do, Bona Shin, Elaina Lioudis, Emaleigh Munn

Transformative Medicine

This article provides an abbreviated overview of the newly Federal Drug Administration (FDA)approved novel drugs of 2021-2022 with their respective approved indication(s). The FDA serves as the governing body that regularly evaluates and approves medications that will eventually be introduced to the market for routine use. These medications include both drugs that are the same or related to previously approved products (e.g., Extended indications of priorly approved medications) and novel drugs. By definition, a novel drug is an innovative product which serves to improve quality care in patient populations with unmet or advanced medical needs to overall advance patient care …

Identifying A Glucocorticoid-Activated Gpcr That Rapidly And Non-Genomically Increases Camp Levels In Mammalian Cells, Francisco Nunez

Pharmaceutical Sciences (PhD) Dissertations

Glucocorticoids (GCs) are steroid hormones that regulate diverse physiological processes. Synthetic versions of GCs are commonly used to treat inflammatory diseases such as asthma by modulating gene expression to suppressing several inflammatory activities. However, it is estimated that 5-10% of asthmatics are unresponsive to GCs, which may be explained by receptor desensitization and/or the presence of a neutrophilic endotype. One understudied phenomenon of GCs is their ability to induce rapid, non-genomic actions. For example, GCs can acutely modulate calcium concentrations levels, induce smooth muscle relaxation and modulate nitric oxide synthase activity, within minutes and sometimes seconds, which is too rapid …

Channelopathy Of Small- And Intermediate-Conductance Ca2+-Activated K+ Channels, Young-Woo Nam, Miles Downey, Mohammad Asikur Rahman, Meng Cui, Miao Zhang

Pharmacy Faculty Articles and Research

Small- and intermediate-conductance Ca²⁺-activated K⁺ (K_Ca2.x/K_Ca3.1 also called SK/IK) channels are gated exclusively by intracellular Ca²⁺. The Ca²⁺ binding protein calmodulin confers sub-micromolar Ca²⁺ sensitivity to the channel-calmodulin complex. The calmodulin C-lobe is constitutively associated with the proximal C-terminus of the channel. Interactions between calmodulin N-lobe and the channel S4-S5 linker are Ca²⁺-dependent, which subsequently trigger conformational changes in the channel pore and open the gate. KCNN genes encode four subtypes, including KCNN1 for K_Ca2.1 (SK1), KCNN2 for K_Ca2.2 (SK2), KCNN3 for K …

Ciliogenesis Mechanisms Mediated By Pak2-Arl13b Signaling In Brain Endothelial Cells Is Responsible For Vascular Stability, Karthikeyan Thirugnanam, Shubhangi Prabhudesai, Emma Van Why, Amy Pan, Ankan Gupta, Koji Foreman, Rahima Zennadi, Kevin R. Rarick, Surya M. Nauli, Sean P. Palacek, Ramani Ramchandran

Pharmacy Faculty Articles and Research

In the developing vasculature, cilia, microtubule-based organelles that project from the apical surface of endothelial cells (ECs), have been identified to function cell autonomously to promote vascular integrity and prevent hemorrhage. To date, the underlying mechanisms of endothelial cilia formation (ciliogenesis) are not fully understood. Understanding these mechanisms is likely to open new avenues for targeting EC-cilia to promote vascular stability. Here, we hypothesized that brain ECs ciliogenesis and the underlying mechanisms that control this process are critical for brain vascular stability. To investigate this hypothesis, we utilized multiple approaches including developmental zebrafish model system and primary cell culture systems. …

Investigating The Efficacy Of Tazemetosttat For In Vitro Treatment Of Human Triple Negative Breast Cancer Cells, Harshita Indukuri

Honors Scholars Collaborative Projects

Cancer is a formidable, genetic disease that affects many people, either directly or indirectly. Breast cancer is the most commonly diagnosed cancer worldwide (31). Triple-negative breast cancer (TNBC) is a type of breast cancer that has a higher lethality compared to other breast cancers and has a poor prognosis due to its highly invasive nature and limited treatment options. Finding safe, effective, and accessible treatment for TNBC is integral to treating TNBC patients. Tazemetostat is an EZH2-inhibitor that has recently been approved for use in epithelioid sarcoma (23). EZH2 is an overexpressed protein in many cancers, including TNBC (11). However, …

Late-Stage Chemoenzymatic Installation Of Hydroxy-Bearing Allyl Moiety On The Indole Ring Of Tryptophan-Containing Peptides, Nagaraju Mupparapu, Lauren Brewster, Katrina F. Ostrom, Sherif I. Elshahawi

Pharmacy Faculty Articles and Research

The late-stage functionalization of indole- and tryptophan-containing compounds with reactive moieties facilitates downstream diversification and leads to changes in their biological properties. Here, the synthesis of two hydroxy-bearing allyl pyrophosphates is described. A chemoenzymatic method is demonstrated which uses a promiscuous indole prenyltransferase enzyme to install a dual reactive hydroxy-bearing allyl moiety directly on the indole ring of tryptophan-containing peptides. This is the first report of late-stage indole modifications with this reactive group.

Channelopathy-Causing Mutations In The S45A/S45B And Ha/Hb Helices Of KCa2.3 And KCa3.1 Channels Alter Their Apparent Ca2+ Sensitivity, Razan Orfali, Young-Woo Nam, Hai Minh Nguyen, Mohammad Asikur Rahman, Grace Yang, Meng Cui, Heike Wulff, Miao Zhang

Pharmacy Faculty Articles and Research

Small- and intermediate-conductance Ca²⁺-activated potassium (K_Ca2.x and K_Ca3.1, also called SK and IK) channels are activated exclusively by a Ca²⁺-calmodulin gating mechanism. Wild-type K_Ca2.3 channels have a Ca²⁺ EC₅₀ value of ∼0.3 μM, while the apparent Ca²⁺ sensitivity of wild-type K_Ca3.1 channels is ∼0.27 μM. Heterozygous genetic mutations of K_Ca2.3 channels have been associated with Zimmermann-Laband syndrome and idiopathic noncirrhotic portal hypertension, while K_Ca3.1 channel mutations were reported in hereditary xerocytosis patients. K_Ca2.3_S436C and K_Ca2.3_V450L channels with …

Investigating The Mitochondrial Protein Mitoneet In C. Elegans Models Of Aging And Alzheimer's Disease, Jacob Ryan Boos

Graduate Theses, Dissertations, and Problem Reports (ETD)

Oxidative stress is an imbalance between reactive oxygen species production and elimination, favoring the former. Reactive oxygen species serve as important signaling molecules for physiological homeostasis. However, when produced in excess, these once important signaling molecules become detrimental, disrupting cellular functions, and ultimately leading to cell death. In aging, reactive oxygen species production is increased, accompanied with reductions in oxidative stress resistance, increasing the risk for developing age-related diseases including cardiovascular disease, cancer, stroke, and neurodegenerative diseases. The outer mitochondrial membrane iron-sulfur cluster containing protein mitoNEET (CISD1; gene CISD1) has shown to be a mediator of mitochondrial function and …

The Benefits Of Astaxanthin To Improve Pain Relief In Patients With Painful Diabetic Neuropathy: An Open-Label, Randomized Controlled Trial, Rizaldy Taslim Pinzon, Mary Rose Angelina Budi Harsana

Pharmaceutical Sciences and Research

Treatment of diabetic neuropathy is still carried out by providing symptomatic therapy, which only improves ± 50% of the total symptoms felt by patients, but does not tackle the underlying causes of the disease. Astaxanthin is a potent antioxidant, anti-inflammatory, and anti-diabetic carotenoid that could be an additional treatment option. We aimed to measure the effectiveness of administering astaxanthin as an additional therapy to improve the impact of pain and discomfort experienced daily by diabetes mellitus patients with painful diabetic neuropathy. We conducted a randomized experimental study with an open label design of 36 patients who had been diagnosed with …

The Effect Of Heparinoid As Systemic Prophylactic Anticoagulants On Covid-19 Patient Mortality And Its Safety Profiles: A Systematic Review And Meta-Analysis, Ariska Deffy Anggarany, Rani Sauriasari, Muhammad Alkaff, Famila Takhwifa, Hayatun Nufus, Diana Paramita

Pharmaceutical Sciences and Research

Coagulopathy is one of the complications of COVID-19 and is associated with a higher risk of mortality. However, evidence regarding the effectiveness and safety of anticoagulant therapy in various doses among COVID-19 patients is limited. This systematic review and meta-analysis aims to review and explore the effect of using heparinoids as a systemic anticoagulant at prophylactic doses on mortality in COVID-19 patients. Systematic searches were conducted of various databases (Pubmed, ScienceDirect, SpringerLink, Scopus, and ProQuest) covering the period 2019-2021. We assessed the quality of the articles using the STROBE checklist. Studies with a high risk of bias were excluded before …

Recombinant Human Proteoglycan 4 Regulates Phagocytic Activation Of Monocytes And Reduces Il-1Β Secretion By Urate Crystal Stimulated Gout Pbmcs, Sandy Elsayed, Gregory D. Jay, Ralph Cabezas, Marwa Qadri, Tannin A. Schmidt, Khaled A. Elsaid

Pharmacy Faculty Articles and Research

Objectives

To compare phagocytic activities of monocytes in peripheral blood mononuclear cells (PBMCs) from acute gout patients and normal subjects, examine monosodium urate monohydrate (MSU) crystal-induced IL-1β secretion ± recombinant human proteoglycan 4 (rhPRG4) or interleukin-1 receptor antagonist (IL-1RA), and study the anti-inflammatory mechanism of rhPRG4 in MSU stimulated monocytes.

Methods

Acute gout PBMCs were collected from patients in the Emergency Department and normal PBMCs were obtained from a commercial source. Monocytes in PBMCs were identified by flow cytometry. PBMCs were primed with Pam3CSK4 (1μg/mL) for 24h and phagocytic activation of monocytes was determined using fluorescently labeled latex beads. MSU …

Modulating The Tumor Microenvironment To Improve Immunotherapy Treatments, Lleayem Nazario-Johnson, David Rowley

Senior Honors Projects

Advances in immunotherapy are revolutionizing the treatments of certain cancers, especially those in the blood. However, wider applications for eradicating solid tumors have been slow to emerge. A likely reason is the presence of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment that secrete immunosuppressive molecules which attenuate the attack of immune cells. We hypothesize that small molecule Wnt/Beta- Catenin inhibitors can be used to modulate the immunosuppressive actions of MDSCs and increase the effectiveness of immunotherapy treatments, such as with chimeric antigen receptor (CAR) T-cells. The Wnt/Beta-Catenin Pathway has been shown to be a crucial driving force behind the …

Comparative Metabolism Of Aflatoxin B1 In Two Quail Genera Coturnix Japonica And Callipepla Californica, Sean Moody

All Graduate Plan B and other Reports, Spring 1920 to Spring 2023

Avian species are highly susceptible to the hepatotoxic mycotoxin aflatoxin B₁ (AFB₁). Domesticated turkeys are exquisitely sensitive, due to a combination of highly-efficient hepatic cytochrome P450 (CYP)-mediated bioactivation, and to dysfunctional alpha-class glutathione S-transferases (GSTAs) which typically detoxify the bioactivated electrophilic metabolite exo-AFB₁-8,9-epoxide (AFBO). Wild turkeys are relatively resistant to AFB₁ in large part due to expression of functional GSTAs. Quail, a related Galliforme, are slightly less sensitive in vivo to AFB₁, but whether this is related to the hepatic metabolic profiles of these two critical enzymes has not been rigorously evaluated. …

Physiological Roles Of Mammalian Transmembrane Adenylyl Cyclase Isoforms, Katrina F. Ostrom, Justin E. Lavigne, Tarsis F. Brust, Roland Seifert, Carmen Dessauer, Val J. Watts, Rennolds S. Ostrom

Pharmacy Faculty Articles and Research

Adenylyl cyclases (ACs) catalyze the conversion of ATP to the ubiquitous second messenger cAMP. Mammals possess nine isoforms of transmembrane ACs, dubbed AC1-9, that serve as major effector enzymes of G protein-coupled receptors. The transmembrane ACs display varying expression patterns across tissues, giving potential for them having a wide array of physiologic roles. Cells express multiple AC isoforms, implying that ACs have redundant functions. Furthermore, all transmembrane ACs are activated by Gα_s so it was long assumed that all ACs are activated by Gα_s-coupled GPCRs. AC isoforms partition to different microdomains of the plasma membrane and form …

Local Renin-Angiotensin System Activation And Myofibroblast Formation In Graft Versus Host Disease–Associated Conjunctival Fibrosis, Kiumars Shamloo, Judy Weng, Christopher Ross, Jenni Lee, Saleh Alfuraih, Jennifer Totonchy, Ajay Sharma

Pharmacy Faculty Articles and Research

Purpose: The present study was designed to investigate the role of myofibroblast transdifferentiation and the conjunctival renin–angiotensin system (RAS) in the pathogenesis of graft-versus-host disease (GVHD)–associated conjunctival fibrosis.

Methods: A mouse model of major histocompatibility-matched allogeneic transplantation was used to induce GVHD, with male B10.D2 mice as donors and female BALB/c mice as recipients. Male BALB/c to female BALB/c syngeneic transplantation was used as control. Y chromosome staining in the spleen cells obtained from female recipient mice was used to confirm engraftment. The phenol red thread test and fluorescein staining were used to quantify tears and corneal keratopathy. …

A Comparison Of Calcium Aggregation And Ultracentrifugation Methods For The Preparation Of Rat Brain Microsomes For Drug Metabolism Studies, Barent N. Dubois, Farideh Amirrad, Reza Mehvar

Pharmacy Faculty Articles and Research

Preparation of brain microsomes by the calcium chloride aggregation method has been suggested as an alternative to the ultracentrifugation method. However, the effects of the calcium chloride concentration on the quality of the microsomal fractions are not known. Brain microsomes were prepared from the adult rat brains using the high-speed ultracentrifugation and low-speed calcium chloride (10–100 mM) aggregation methods (n = 5–6 per group). The microsomal protein yield (spectrometry), the cytochrome P450 reductase (CPR) activity (spectrometry), and the monooxygenase activities (UPLC-MS/MS) of CYP2D and CYP2E1 were determined in the obtained fractions. Increasing the concentrations of calcium chloride progressively increased …

Clinical Implications Of Combinatorial Pharmacogenomic Tests Based On Cytochrome P450 Variant Selection, Michael R. Sayer, Ashley Duche, Trang Jenny Tran Nguyen, Michelle Le, Kunj Patel, Jacqueline Vu, Danny Pham, Brianne Vernick, Richard Beuttler, Don Roosan, Moom R. Roosan

Pharmacy Faculty Articles and Research

Despite the potential to improve patient outcomes, the application of pharmacogenomics (PGx) is yet to be routine. A growing number of PGx implementers are leaning toward using combinatorial PGx (CPGx) tests (i.e., multigene tests) that are reusable over patients’ lifetimes. However, selecting a single best available CPGx test is challenging owing to many patient- and population-specific factors, including variant frequency differences across ethnic groups. The primary objective of this study was to evaluate the detection rate of currently available CPGx tests based on the cytochrome P450 (CYP) gene variants they target. The detection rate was defined as the percentage of …

Subtype-Selective Positive Modulation Of KCa 2 Channels Depends On The Ha/Hb Helices, Young-Woo Nam, Meng Cui, Naglaa Salem, Razan Orfali, Misa Nguyen, Grace Yang, Mohammad Asikur Rahman, Judy Lee, Miao Zhang

Pharmacy Faculty Articles and Research

Background and Purpose

In the activated state of small-conductance Ca2+-activated potassium (KCa 2) channels, calmodulin interacts with the HA/HB helices and the S4-S5 linker. CyPPA potentiates KCa 2.2a and KCa 2.3 channel activity but not the KCa 2.1 and KCa 3.1 subtypes.

Experimental Approach

Site-directed mutagenesis, patch-clamp recordings and in silico modeling were utilized to explore the structural determinants for the subtype-selective modulation of KCa 2 channels by CyPPA.

Key Results

Mutating residues in the HA (V420) and HB (K467) helices of KCa 2.2a channels to their equivalent residues in KCa 3.1 channels diminished the potency of CyPPA. CyPPA elicited …

Uplc-Ms/Ms Analysis Of The Michaelis-Menten Kinetics Of Cyp3a-Mediated Midazolam 1′- And 4-Hydroxylation In Rat Brain Microsomes, Devaraj Venkatapura Chandrashekar, Barent Dubois, Reza Mehvar

Pharmacy Faculty Articles and Research

Midazolam (MDZ) is a short-acting benzodiazepine with rapid onset of action, which is metabolized by CYP3A isoenzymes to two hydroxylated metabolites, 1′-hydroxymidazolam and 4-hydroxymidazolam. The drug is also commonly used as a marker of CYP3A activity in the liver microsomes. However, the kinetics of CYP3A-mediated hydroxylation of MDZ in the brain, which contains much lower CYP content than the liver, have not been reported. In this study, UPLC-MS/MS and metabolic incubation methods were developed and validated for simultaneous measurement of low concentrations of both hydroxylated metabolites of MDZ in brain microsomes. Different concentrations of MDZ (1–500 µM) were incubated with …