PKMS Knowledge Center | UM College of Pharmacy (2024)

Pharmaco*kinetics (PK)is the study of the time course of drug’s absorption, distribution, metabolism, and excretion (ADME), what the body interact with a drug, related to the movement of drug into, pass, and out of the body. In order for a drug to be effective in the body, enough of the active form must reach the target to elicit the desired effect. The compound with the best activity against the target enzyme or receptor may have very poor ADME characteristics such as metabolic instability or poor intestinal absorption. When choosing a lead candidate from multiple compounds, the activity of the drug in the efficacy screen must be balanced with acceptable ADME and stability characteristics. Pharmaco*kinetic studies with mass spectrometry bioanalysis can provide the quantitative information about the half-life of the administrated compound from in vitro and in vivo test, and more useful information of how quickly it can be metabolized or excreted by enzymatically or nonenzymatically. To track the drug accumulation and distribution in organism from in vivo PK study, the mass spectrometry imaging and quantification can come up with innovative solutions to quantify dynamic drug exposures in all targeted tissues, or using artificial intelligence modeling to predict the drug exposure in disease or normal organs.

Capture PK.JPG

PKMS Knowledge Center | UM College of Pharmacy (1)

Representaive Case Study from PKMS Core:

1.Borkin D, He SH, Miao HZ, Kempinska K, Pollock J, Chase J, Purohit T, Malik B, Zhao T, Wang JY, Wen B, Zong HL, Jones M, Danet-Desnoyers G, Guzman ML, Talpaz M, Bixby DL, Sun DX, Hess JL, Muntean AG, Maillard I, Cierpicki T, Grembecka J.Pharmacologic Inhibition of the Menin-MLL Interaction Blocks Progression of MLL Leukemia In Vivo. Cancer Cell. 2015;27(4):589-602. PMCID:PMC4415852

2.Li W, Tanikawa T, Kryczek I, Xia H, Li G, Wu K, Wei S, Zhao L, Vatan L, Wen B, Shu P, Sun D, Kleer C, Wicha M, Sabel M, Tao K, Wang G, Zou W. Aerobic Glycolysis Controls Myeloid-Derived Suppressor Cells and Tumor Immunity via a Specific CEBPB Isoform in Triple-Negative Breast Cancer. Cell Metab. 2018 Jul 3;28(1):87-103.e6. doi: 10.1016/j.cmet.2018.04.022. Epub 2018 May 24. PubMed PMID: 29805099.

3.Kahl, D.J., Hutchings, K.M., Lisabeth, E.M., Haak, A.J., Leipprandt, J.R., Dexheimer, T., Khanna, D., Tsou, P.S., Campbell, P.L., Fox, D.A., Wen, B., Sun, D., Bailie, M., Neubig, R.R. & Larsen, S.D. 5-Aryl-1,3,4-oxadiazol-2-ylthioalkanoic Acids: A Highly Potent New Class of Inhibitors of Rho/Myocardin-Related Transcription Factor (MRTF)/Serum Response Factor (SRF)-Mediated Gene Transcription as Potential Antifibrotic Agents for Scleroderma. J Med Chem 62, 4350-4369 (2019) PMC6590913.

4.Madak, J.T., Cuthbertson, C.R., Miyata, Y., Tamura, S., Petrunak, E.M., Stuckey, J.A., Han, Y., He, M.,Sun, D., Showalter, H.D. & Neamati, N. Design, Synthesis, and Biological Evaluation of 4-Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase.J Med Chem61, 5162-5186 (2018)

5.Zhao Y, Bai L, Liu L, McEachern D, Stuckety JA, Meagher JL, Yang CY, Ran X, Zhou B, Hu Y, Li X, Wen B, Zhao T, Li S, Sun D, Wang S.Structure-based discovery of 4-(6-methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (CD161) as a potent and orally bioavailable BET bromodomain inhibitor. J Med Chem. 2017 May 11;60(9):3887-3901. PMID: 28463487

6.Zhao Y, Liu L, Sun W, Lu J, McEachern D, Li X, Yu S, Bernard D, Ochsenbein P, Ferey V, Carry JC, Deschamps JR, Sun D, Wang S.Diastereomeric spirooxindoles as highly potent and efficacious MDM2 inhibitors. JAm Chem Soc. 2013;135(19):7223-34. PMCID: PMC3806051


PKMS Knowledge Center | UM College of Pharmacy (2)

Instruments application notes from different company to describe the capability of the each instrument. (UM PKMS core own those cutting-edge technology and instrument to perform similar studies.)

  1. SCIEX Triple Quad 5500 LC-MS/MS --- Highly Sensitive and Robust Quantification Method for Ethinyl Estradiol and Drospirenone in plasma
  2. SCIEX Triple Quad 5500 Qtrap system --- In Vivo Metabolic Profiling of Carbamazepine Using the QTRAP® 5500 System and LightSight® Software v2.2
  3. SCIEX X500R QTOF system --- Using MS/MSallwith SWATH Acquisition For Forensic Designer Drug Analysis with SCIEX X500R QTOF system and SCIEX OS Software
  4. SCIEX X500R QTOF system --- Rapid Metabolite Identification using MetabolitePilot™ Software and TripleTOF™ 5600 system
  5. SYNAPT G2-Si HDMS QTOF system --- Targeted High Resolution Quantification with Tof-MRM and HD-MRM
  6. Waters SYNAPT G2-Si HDMS QTOF system --- Qualitative and Quantitative Metabolite Identification for Verapamil in Rat Plasma Using a UPLC/SYNAPT G2 HDMS Strategy with MSE
  7. Waters SYNAPT G2-Si HDMS QTOF system --- Ion Mobility Separation Coupled With Desorption Electrospray Ionization Mass Spectrometry for High Specificity MS Imaging
  8. Waters SYNAPT G2-Si HDMS QTOF system --- Lipid Visualization and Identification Through Collisional Cross Section Aided Correlation of MS Imaging and Ex Situ MS Data for MS-MS Identification

Edited by Bo Wen, 05/2020

Mass spectrometry imaging (MSI)is an emerging technique that allows molecular visualization of the distribution of drugs, lipids, peptides, proteins and metabolites in a two-dimensional space directly in biological tissues. MSI allows unlabeled drug compounds and drug metabolites to be detected and identified and quantified according to their mass-to-charge ratios (m/z) at high resolution in complex tissue environments. This technique has better specificity and provides the possibility to combine histological data with MS ones and to visualize simultaneously the distribution drugs or biomarkers in relation to tumor heterogeneity, provide new understandings of the dynamic processes impacting drug uptake and metabolism at the local sites targeted by therapy.

UM PKMS MSI Workflow.png

PKMS Knowledge Center | UM College of Pharmacy (3)

We have a state of the art MALDI/DESI SYNAPT G2-Si High Definition Mass Spectrometry (Waters®) in our Pharmaco*kinetics and Mass Spectrometry Core Facility (PKMS). Using the MALDI and DESI ion source together with T-Wave ion mobility technology, our experienced team of mass spectrometry imagers can provide distribution profiling information for a wide range of sample types, such as tissue specimens, industrial and biological materials, horticultural specimens, and microbiological populations. We offer MSI sample preparation, including cryo-sectioning and microtome techniques, histological staining, and tissue microscopy. We can also combine imaging data with data acquired by different analytical techniques to deliver more comprehensive results. Our team works with you to identify MSI approaches to address your application requirements.

  • Drug development
  • Pharmaco*kinetics: Drug and Metabolite Distribution, 2D and 3D label free Imaging
  • Disease characterization and biomarker investigations
  • Carcinomas
  • Inter-and intra-tumor heterogeneity
  • Inflammatory diseases
  • Fibrosis
  • Bacterial infections and manifestations
  • Neurological diseases
PKMS Case study 1 : small molecular or lipids mass spectrometry imaging on mouse brain tissue section, thousand compounds can be imaged from the same tissue section at same time.

mice brain mass imaging .jpg

PKMS Knowledge Center | UM College of Pharmacy (4)

M/Z 253.08 M/Z 314.11 M/Z 495.02 M/Z 831.45

PKMS Case study 2: MALDI-Ion mobility mass spectrometry imaging for pacl*taxel ditribution in solid tumor tissue.

Mice tumor tissue Pacl*taxel Mass Imaging .jpg

PKMS Knowledge Center | UM College of Pharmacy (5)

Instruments application notes from Waters®to describe the capability of the SYNAPT G2-Si High Definition Mass Spectrometry.

  1. Biomarker Discovery Directly from Tissue Xenograph Using High Definition Imaging MALDI Combined with Multivariate Analysis.
  2. Data Independent MALDI Imaging HDMSE for Visualization and Identification of Lipids Directly from a Single Tissue Section.
  3. Distribution of Biomarkers of Interest in Rat Brain Tissues Using High Definition MALDI Imaging.
  4. MALDI Imaging of Distribution of Xanthohumol and Its Metabolites in Rat Tissues.
  5. Successful Application for Distribution Imaging of Chloroquine Ocular Tissue in Pigmented Rat Using MALDI-Imaging Quadrupole Time-of-Flight Mass Spectrometry.
  6. MALDI-Ion Mobility Separation-Mass Spectrometry Imaging of Glucose-Regulated Protein 78 kDa (Grp78) in Human Formalin-Fixed, Paraffin-Embedded Pancreatic Adenocarcinoma Tissue Sections.
  7. Tissue Imaging of Pharmaceuticals by Ion Mobility Mass Spectrometry.
  8. Direct Tissue Imaging and Characterization of Phospholipids Using MALDI SYNAPT HDMS System.
  9. Localizing Diazepam and its Metabolite in Rat Brain Tissue by Imaging Mass Spectrometry using MALDI Q-Tof Premier MS.
  10. Matrix-Assisted Laser Desorption/Ionization-Ion Mobility Separation-Mass Spectrometry Imaging of Vinblastine in Whole Body Tissue Sections.

Edited by Bo Wen, 05/2020

The use of bioanalytical technologies such as quantitativeliquid chromatography-mass spectrometry(LC-MS/MS) has been accepted as the gold-standard technology to support PK and drug metabolism studies. It comes significant improvements in assay sensitivity, selective and specificity, plus the potential to reduce assay time per samples, and the detection of compounds of interest in different matrices, no matter how complex - including plasma, blood, serum, urine, faces, spinal fluid, skin, muscle, artery, myocardium, liver and kidney, and a variety of tumor types. Below is list of drug that have been tested in our core with an validated LC-MS assay.

Compound NameClassificationTransition Ions ( M/Z)Limit of Detection
AcalabrutinibBruton's tyrosine kinaseinhibitor466.0→372.30.2 ng/mL in rat plasma
AdenosineNucleoside268.0→136.05 ng/ml in plasma
AfatinibTyrosine kinase inhibitor486.1→370.90.5 ng/mL in human plasma
AmifostineChemoprotective agentHRMSHRMS
Aminocaproic AcidClotting promoter132.1→95.910 ng/mL in human plasma
AmlexanoxAnti-inflammatory agent297.1→253.21 ng/mL in mice serum
ApcinCell cycle inhibitor438.1→224.02 ng/mL in mice plasma
ApixabanAnticoagulant460.2→443.21 ng/mL in human plasma
Arachidonoyl GlycineLipids362.5→278.01 ng/mL in acetonitrile
AripiprazoleAtypical antipsychotic448.2→285.21 ng/mL in plasma or brain
ArtemetherAntimalarial316.2→267.22 ng/mL in human plasma
AzithromycinAntibiotic479.5→591.41 ng/mL in rat blood or brain
BuprenorphineNarcotic468.1→396.20.1 ng/mL in mice plasma
BupropionAntidepressant240.0→184.00.5 ng/mL in human plasma
CarprofenNonsteroidal anti-inflammatory drug272.0→228.15 ng/mL in mouse plasma
CefaclorSecond-generationcephalosporinantibiotic368.0→174.02 ng/mL in human plasma
CefazolinAntibiotic455.2→323.010 ng/mL in human plasma
ChlorambucilChemotherapy303.9→192.050 ng/mL in mouse plasma
CholesterolSterol369.3→369.310 ng/mL in solution
CisplatinChemotherapy492.0→426.01 ng/ml in urine
Clofaziminesubstituted iminophenazine dye473.0→431.11 ng/ml in mouse serum
Concanamycin Aplecomacrolide antibiotic888.8→515.20.1 ng/mL in mouse plasma
CyclophosphamideChemotherapy261.0→140.01 ng/mL in human plasma
DabrafenibKinase inhibitors520.0→343.11 ng/ml in mouse plasma
Dacomitinibmulti-kinase receptor inhibitor470.0→385.01 ng/mL in rat plasma
DaptomycinAntibiotic811.3→ 341.41 ng/mL in feces
DasatinibChemotherapy488.3→ 401.21 ng/mL in plasma
DeoxyuridineAntiviral237.1→137.05 ng/ml in plasma
DexamethasoneCorticosteroid393.0→373.02.5 ng/mL in plasma
DocetaxelChemotherapy808.4→225.91 ng/mL in plasma
DoxorubicinChemotherapy544.0→361.02 ng/mL in plasma
DoxycyclineAntibiotic445.2→321.02.5 ng/mL in plasma
EchinomycinAntibiotic1101.1→1053.20.1 ng/mL in plasma
EliglustatGastrointestinal system drug405.1→316.21 ng/mL in plasma
EntrectinibChemotherapy561.0→302.11 ng/mL in plasma
ErtapenemAntibiotic476.1→346.1100 ng/mL in plasma
EtonogestrelContraceptive drug325.2→257.20.25 ng/mL in plasma
EverolimusImmunosuppressive agent980.2→389.11 ng/mL in plasma
FedratinibInhibitor of myelfobrosis525.1→525.11 ng/mL in plasma
FentanylNarcotic337.2→188.21 ng/mL in plasma
FerioxamineSupply of iron614.4→414.40.48 nM in water
FingolimodImmunosuppressive drug308.4→255.11 ng/mL in plasma
FloxuridineChemotherapy245.1→155.02 ng/mL in liver sample
FluticasoneAntiallergy medicine501.0→293.23 ng/mL in plasma
Fluticasone PropionateSteroid and Decongestant501.2→293.21 ng/mL in plasma
FulvestrantChemotherapy605.2→427.40.1 ng/mL in plasma
GalleinChemotherapy365.1→189.05 ng/mL in plasma
GlucoraphaninSupplement438.0→196.02 ng/mL in urine
IbrutinibChemotherapy441.1→138.11 ng/mL in plasma
IbuprofenNonsteroidal anti-Inflammatory drug205.1→125.05 ng/mL in plasma
ImatinibChemotherapy372.5 → 176.30.5 ng/mL in plasma
LarotrectinibChemotherapy429.0 → 342.01 ng/mL in plasma
LeuprolideHormones605.5 → 2210.1 ng/mL in plasma
MesalamineNonsteroidal anti-Inflammatory drug152.0 → 108.01 ng/mL in plasma
MetforminDiabetes medication130.1 → 71.15 ng/mL in plasma
MetoprololBeta blocker268.2→116.21 ng/mL in human serum
metronidazoleAntibiotic172.1→12810 ng/mL in tissue
MianserinAntidepressant266.0→209.01 ng/mL in plasma
NalbuphineNarcotic358.2→340.20.5 ng/mL in mouse plasma
NaloxoneNarcotic327.6→309.60.5 ng/mL in monkey plasma
NeratinibChemotherapy557.1→512.01 ng/mL in plasma
NilotinibChemotherapy530.1→307.21 ng/mL in mouse plasma
OlaparibChemotherapy435.3→281.21 ng/mL in mouse plasma
OsimertinibChemotherapy500.2→71.81 ng/mL in plasma
oxalatenature compoundHRMS1 ug/mL in plasma
Pacl*taxelChemotherapy854.4→286.11 ng/mL in human plasma
PanobinostatChemotherapy350.2→158.11 ng/mL in mouse plasma
ParoxetineAntidepressant330.1→192.21 ng/mL in mouse plasma
PazopanibChemotherapy438.1→357.21 ng/mL in human plasma
PemetrexedChemotherapy428.3→281.125 pg/mL in urine
PiperacillinAntibiotic518.0→359.05 ng/mL in plasma
PomalidomideImmunomodulatory drug274.02→201.000.1 ng/mL in mouse plasma
PonatinibChemotherapy533.3→231.91 ng/mL in mouse plasma and brain
Propranolol HydrochlorideBeta-blocker260.3→260.35 nM for dissolution studies
RafarmIron supplementChelatable iron is detected by HPLC-UV15.6 µM in saline and rat serum
SelumetinibChemotherapy459.0→301.110 ng/mL in rat plasma
SimvastatinAntilipemic agent436.3→285.20.1 ng/mL in mouse plasma and liver
SirolimusImmunosuppressive drug931.5→864.60.5 ng/mL in human blood
SolifenacinBladder relaxant363→1930.5 ng/mL in human plasma
sorafenibChemotherapy465→25210 ng/mL in human plasma
SulfadiazineAntibiotic251.1→156.0400 µM for dissolution studies
SulforaphaneSupplement178 → 113.61 ng/mL in rat plasma
TacrolimusImmunosuppressive drug821.4→768.50.5 ng/mL in human blood
TamifluAntiviral drug313.2→166.10.5 ng/mL in human plasma
TamoxifenChemotherapy372.1→72.01 ng/mL in mouse plasma and tissues
TazobactamAntibiotic299.0→138/254.90.25 µg/mL in human plasma
TofacitinibAntineoplastic313.1→173.11 ng/mL in mouse plasma
TrametinibChemotherapy616→491.01 ng/mL in mouse plasma
Triamcinolone AcetonideSteroid435→41510.0 pg/mL in rabit plasma
Valproic AcidAnticonvulsant143.0→143.05 µg/mL in human plasma
VancomycinAntibiotic725.6 → 100.20.05 ng/mL in human plasma
VareniclineSmoking Cessation Agent212.1 → 169.10.1 ng/mL in human plasma
VemurafenibChemotherapy490.1→383.1100 ng/mL in mouse plasma
VenoferIron supplementChelatable iron is detected by HPLC-UV15.6 µM in saline and rat serum
Withaferin ASupplement471.1→2812 ng/mL in rat plasma and tissues
ZanamivirAntiviral drug333→601 ng/mL in human plasma

Edited by Bo Wen, 06/09/20

PKMS Knowledge Center | UM College of Pharmacy (2024)


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