Sekisui XenoTech, LLC

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In vivo ADME lab offerings through Sekisui:
- Drug plasma concentration
- Absorption site investigation
- Tissue distributions
- QWBA (Quantitative Whole Body Autoradiography)
- Plasma protein binding
- Blood/plasma partition rate
- Lymphatic partition rate
- Metabolic profile (plama, urine, bile and tissue)
- Metabolite Identification
- Excretion rate (urine, feces, expiration air and bile)
- Enterohepatic circulation
- Radiolabeled Synthesis
- Bioanalysis by ECL
- Radioreceptor Assay (RRA)
- Ocular Pharmacokinetics

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Our Analytical Services group offers custom method validation, dose solution analysis, in vivo metabolite profiling studies and small-molecule bioanalytical services. The group's focus is on applying LC/MS technology to maximize both the quality and throughput of the data we generate to ensure that your project needs are met.

Toxicology Services: In vitro toxicity testing - XenoTech utilizes the MatTek EpiOcular™ platform, a validated test system for the classification of chemicals for ocular irritation according to the OECD (Organization for Economic Cooperation & Development) Test Guideline 492. The EpiOcular™ platform is a 3D tissue culture model comprised of non-keratinized epithelium prepared from normal human keratinocytes, which simulate the physiological properties of the cornea epithelium (RhCE) cells. The assay is able to assess test chemicals with a variety of physical properties including liquid, semi-solid, or waxy.

db/db Diabetic Mice
fa/fa Zucker Diabetic Rats

Overview

XenoTech's study design evaluates drug candidates as direct, time-dependent and metabolism-dependent inhibitors of CYP enzymes in human liver microsomes. Our design allows us to screen for inhibition due to the drug added to the test system as well as inhibition due to metabolites formed during preincubation. The design features low protein concentrations and short incubation times to minimize artifacts caused by protein binding, metabolic instability of the test article and excessive metabolism of the marker substrate. We offer various options for follow-up studies to support the further characterization of those drug candidates that are identified as potent direct or metabolism-dependent inhibitors (for example: Ki determinations, XTRA: XenoTech's Reversibility Assay, KI/kinact determinations).

Assay Selection
| Enzyme | Substrate |
|----------------|------------------------------------------------|
| CYP1A2 | Phenacetin O-dealkylation |
| CYP2A6 | Coumarin 7-hydroxylation |
| CYP2B6 | Efavirenz 8-hydroxylation |
| CYP2B6 | Bupropion hydroxylation |
| CYP2C8 | Amodiaquine N-dealkylation |
| CYP2C8 | Paclitaxel 6-hydroxylation |
| CYP2C9 | Diclofenac 4´-hydroxylation |
| CYP2C19 | S-Mephenytoin 4´-hydroxylation |
| CYP2D6 | Dextromethorphan O-demethylation |
| CYP2E1 | Chlorzoxazone 6-hydroxylation |
| CYP3A4/5 | Testosterone 6β-hydroxylation |
| CYP3A4/5 | Nifedipine oxidation |
| CYP3A4/5 | Midazolam 1´-hydroxylation |
| CYP3A4/5 | Atorvastatin ortho-hydroxylation |
| CYP4A11 | Lauric acid 12-hydroxylation |

Test System
XenoTech's inhibition assays are typically performed with a dedicated pool of human liver microsomes (pool of 16) to provide Km and Vmax values for each marker substrate reaction. This allows the same pool of human liver microsomes (and often the same experimental conditions, for example, protein concentrations and incubation time) to be used to study all CYP enzymes of interest.

Incubation Conditions
Protein concentration ≤0.1 mg/mL
Incubation time: 5 minutes
Pre-incubation time (in the presence and absence of NADPH): 30 minutes

Results
Direct, time-dependent and metabolism-dependent IC50 values are determined from seven concentrations of the drug candidate.

XenoTech offers non-regulated small molecule bioanalysis services through its Analytical Services group. Highlights of XenoTech's bioanalytical capabilities include:
- Protein precipitiation extraction (others as required)
- Matrices include plasma, serum, blood and urine
- Development of single or multiple analyte methods to support parent and metabolite(s) analysis or cassette analysis
- Method qualification (optional)
- Duplicate standard curves (bracketed samples)
- Flexible standard curve ranges up to 5000-fold (modify as needed)
- Sample analysis by LC-MS/MS
- Electronic data summary outlining analytical method and sample preparation, calibration curve and calculated sample concentrations
- Rapid turnaround times

Toxicology Services: In vitro toxicity testing - XenoTech utilizes the MatTek EpiDerm™ platform, a validated test system for the classification of chemicals for dermal irritation, according to the OECD Test Guideline 439. The EpiDerm™ platform is a 3D tissue culture model comprised of reconstructed human epidermal (RhE) cells differentiated into keratinocytes, which stimulate the physiological properties of the human skin. The assay is able to assess test chemicals with a wide variety of physical properties including solids, liquids, semi-solids or waxy.
Cell viability following chemical exposure is measured using the MTT assay. The test article is then classified according to the UN GHS (United Nations Globally Harmonized System of Classification and Labelling Chemicals) according to viability following chemical exposure.