Ala Nassar, PhD
Senior Research ScientistCards
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Research
Overview
Our research focuses on understanding how structure modification can improve the ADME-Tox profile for new chemical entities as they advance toward clinical candidacy. Our recent efforts use Mass Cytometry & MALDI-IHC as novel tools for Cancer Research. With their capacity for tremendous detail, these techniques produce enhanced investigative power for analyses involving simultaneous cellular profiling of multiple cell populations. Our latest endeavors are focused on an advance in single cell analysis using a hybrid mass spectrometry-flow cytometry instrument to identify and characterize rare cell types in clinical samples. Another emphasis is the development of mass spectrometric and proteomic methods for application in biological and clinical contexts to identify and quantify proteins with greater depth and coverage in a single cell.
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The activity-exposure-toxicity relationship, which can be described as "the rule of three", presents the single most difficult challenge in the design of drug candidates and their subsequent advancement to the development stage.
- Photo by Biotransformation and Metabolite Elucidation of Xenobiotics: Characterization and identification Edited by Ala F Nassar, Wiley & Sons, Inc., 2010
In general, orally active drugs that are well absorbed from the gut are lipophilic compounds (logD7.4 > 1) that require biotransformation (chemical modification) to facilitate their urinary and/or biliary elimination. The oxidative, reductive and hydrolytic drug-metabolizing enzymes that introduce or expose a functional group are often classified as Phase 1 enzymes (such as cytochrome P450). The drug-metabolizing enzymes that conjugate the metabolite with a water-soluble molecule (such as glucuronic acid or sulfonic acid) are often classified as Phase 2 enzymes. However, some drugs are conjugated directly such that Phase 2 metabolism occurs in the absence of Phase 1 metabolism, and some drug conjugates are metabolized by cytochrome P450, such that Phase 2 metabolism precedes Phase 1 metabolism. Conjugates formed by Phase 2 metabolism are transported out of the liver by canalicular or sinusoidal transporters for elimination in bile or urine, respectively.
- Photo by Biotransformation and Metabolite Elucidation of Xenobiotics: Characterization and identification Edited by Ala F Nassar, Wiley & Sons, Inc., 2010
Highly permeable drugs (drugs with high oral absorption) belong to Classes 1 and 2, which are distinguished based on their aqueous solubility (which is high for Class 1 drugs and low for Class 2). Class 3 and 4 drugs both have low permeability (poor oral absorption) but with different aqueous solubility (high for Class 3, low for Class 4).
As a general rule, biotransformation represents the predominant route of elimination of Class 1 and 2 drugs (i.e., the highly permeable drugs that show high oral absorption). Drugs in Classes 3 and 4 tend to be eliminated unchanged. Whereas metabolism plays an important role in the disposition of Class 1 and 2 drugs, transporters play an important role in the disposition of Class 3 and 4 drugs. Efflux transporters tend to play an important role in the disposition of drugs with low aqueous solubility (Classes 2 and 4).
Because they are well absorbed from the gastrointestinal tract, BCS Class 1 and 2 drugs contain a large number of orally active drugs. Their high permeability is largely due to their lipophilicity. This same property prevents their elimination in urine and feces because, even if eliminated, the unchanged drugs can readily be reabsorbed from the kidney and intestine. For this reason, biotransformation is the predominant route of elimination of lipophilic, high permeable drugs (those in BCS Class 1 and 2) because their conversion to water-soluble metabolites permits their excretion in urine and feces.
- Photo by Biotransformation and Metabolite Elucidation of Xenobiotics: Characterization and identification Edited by Ala F Nassar, Wiley & Sons, Inc., 2010
Drugs that are metabolized by CYP2D6, a genetically polymorphic drug-metabolizing enzyme. When the parent drug is pharmacologically active (as in the case of the antihypertensive drug debrisoquine and various antidepressants) UMs are at risk of deriving no therapeutic benefit whereas PMs are at risk of exaggerated or prolonged pharmacological effects. The converse occurs when the pharmacological effects of a drug are mediated by a metabolite; in this case PMs are at risk from deriving little or no therapeutic benefit, which is why, for example, CYP2D6 PMs are at increased risk for breast cancer recurrence following tamoxifen adjuvant therapy because these individuals cannot convert tamoxifen to endoxifen, which is 30- to 100-fold more potent than tamoxifen in suppressing estrogen-dependent cell proliferation.
When an adverse effect is due to the parent drug (such as the hepatotoxic effects of the perhexilline), PMs are at increased risk. Conversely, when an adverse effect is due to a metabolite, UMs are at increased risk. For example, in the case of codeine, which is converted by CYPD6 to morphine (an effective analgesic that causes respiratory depression), CYP2D6 UMs are at increased risk of morphine toxicity. The death of an elderly man administered a recommended dose of codeine and the death of a baby who was breast-fed by a woman on codeine have been attributed to the CYP2D6 UM genotype that causes rapid conversion of codeine to morphine causes respiratory depression.
- Photo by Bendall SC, et al. Trends Immunol. 2012;33:323–332.
A liquid sample containing cells labeled with heavy metal isotope-conjugated probes (ICPs) (a) is introduced into the nebulizer (b), where it is aerosolized. The aerosol droplets are directed into the ICP torch (c),
where the cells are vaporized, atomized, and ionized. Low-mass ions are
removed in the radiofrequency (RF) quadrupole ion guide (d), resulting in a cloud of ions enriched for the probe isotopes. The ion cloud then enters the time-of-flight (TOF) chamber (e),
where the ions are separated on the basis of their mass:charge ratio as
they accelerate toward the detector. Thus, the time-resolved detector
measures a mass spectrum (f) that represents the identity and quantity of each isotope on a per cell basis. Data are generated in .fcs format (g) and analyzed using the cloud-based Cytobank platform (h).
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