Science Pool

Our popular, easy-to-follow guide: 'DDI Regulatory Guidance' is now on its 3rd edition.

Read about:

• an easy to follow summary and comparison of the latest DDI guidance from the FDA and the EMA
• a focus on reaction phenotyping, cytochrome P450 inhibition, cytochrome P450 induction, drug transporter substrate studies and drug transporter inhibition
• an overview of the regulatory methods and interpretation of data

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The skin is the largest organ in the human body. It contains enzymes capable of drug metabolism.

In this presentation, we focus on:

• the physiology of the skin and an overview of skin enzymology
• the role of skin metabolism in absorption, efficacy, homeostasis, drug delivery and toxicity
• adverse reactions in the skin including the mechanism behind skin sensitisation
• in vitro methods for investigating skin metabolism

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LC-MS provides the analytical endpoint for most discovery ADME assays. There is a constant drive to reduce LC-MS run times whilst maintaining quality. 

In this presentation, we focus on:

• a comparison of triple quadrupole MS/MS vs TripleTOF MS
• validation data for performance of the TripleTOF MS 
• use of the TripleTOF in high throughput ADME screening including intrinsic clearance assays and soft spot analysis.

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Due to an aging population, polypharmacy is increasing. Drug-drug interactions account for 5% of UK hospital admissions, and are a particular concern for common co-meds such as statins.

In this presentation, we focus on:

• a background to drug-drug interactions (DDI)
• the use of the mechanistic static models in the prediction of transporter-mediated DDI
• a comparison of the different published models and their performance 

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Reducing the sample cycle time for LC-MS analysis is critical in increasing throughput and improving efficiency.

In this poster, we focus on:

• the development of a ultra-fast chromatography method with rapid cycle time
• the analysis of the sensitivity, linearity, reproducibility, robustness and matrix effects for the method
• applicability to intrinsic clearance determination

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In order to accurately predict human pharmacokinetics and efficacious dose, a robust measurements of clearance is essential.

In this poster, we focus on:

• a novel primary human hepatocyte media supplement (HepExtend^TM)
• a comparison of HepExtend^TM with the widely used CM4000 with and without a Geltrex overlay
• a correlation of scaled in vitro human intrinsic clearance with in vivo human intrinsic clearance

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Real time mass defect filtering (MDF) on independent acquisition (IDA) scans enable the generation of simultaneous selective MS and MSMS data in one injection.

In this poster, we focus on:

• the use of high resolution mass spectrometry and mass defect filtering combined with rapid chromatographic run times and semi-automated commercial software for soft-spot identification of metabolites
• demonstration of the metabolite soft-spot method using verapamil and dextromethorphan

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Pre-incubating with inhibitor can influence inhibitory potency for some drug transporters such as OATP1B1. It is thought that this phenomenon is a consequence of the time taken for some inhibitors to accumulate inside the cell.

In this poster, we focus on:

• a comparison of a 30 min pre-incubation time with a 15 min pre-incubation time for OATP1B1
• the impact of inhibitor pre-incubation on P-gp and BCRP inhibition in a polarised cell monolayer

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Incubation times for in vitro hepatocyte stability assays are usually relatively short in order to maintain cell viability and enzymatic activity. This can limit the accuracy of clearance prediction for stable compounds. 

In this poster, we focus on:

• a comparison of three human models of in vitro clearance; the HμREL coculture model, 2D hepatocyte monoculture model and suspension hepatocyte model 
• data were scaled to predict in vivo human clearance
• the suitability of each system to accurately predict the clearance of stable compounds was assessed

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Rosuvastatin is used in the treatment of dyslipidemia. The drug transporter BCRP (breast cancer resistant protein) has been identified as the rate limiting barrier to rosuvastatin absorption.

In this poster, we focus on:

• whether estrone 3-sulfate can be applied as a surrogate in vitro BCRP probe substrate for predicting rosuvastatin DDI 
• a comparison of BCRP inhibition assessment using rosuvastatin or estrone 3-sulfate as probe substrate for six established BCRP inhibitors for which a clinical DDI with rosuvastatin has been characterised

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