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Metabolism and pharmacokinetics in drug development

Pharmacokinetic (PK) studies are performed in order to optimize the absorption, distribution, metabolism and excretion (ADME) properties of molecules in the discovery phase of drug development. The results also provide a solid scientific basis for the planning of efficacy and toxicological studies and for toxicokinetic (TK) analyses within these.

ADME

A desired pharmacological effect is achieved when the drug reaches its target site at the right concentration and for the right duration. Therefore, absorptional, distributional, metabolic and excretional (ADME) properties are important to study and optimize even from the very earliest phases in drug discovery. ADME studies are performed using biological systems in vitro, such as isolated liver cells, cell lines and plasma, as well as in pharmacokinetic studies in vivo. However, it is possible to predict physio-chemical and ADME properties based on the chemical structures (i.e., from the SMILES), even when designing compounds virtually by computational or in silico means. During drug discovery, results form in silico predictions and ADME studies are integrated with results from preclinical efficacy and toxicological studies, in order to predict whether a pharmacological effect can be achieved with a sufficient safety margin at a desired dose to humans. ADME properties are also needed for risk assessments in areas other than pharmaceuticals, such as food additives, pesticides and general industrial chemicals. For example, within the cosmetics industry it may be important to understand how cosmetics ingredients are absorbed and metabolized.

In silico predictions of physical chemical and ADME properties

Reliable in silico predictions of physico-chemical characteristics and ADME properties can significantly reduce costs in early project development. Virtual compounds with favorable predicted properties are identified and can be synthesized for further evaluation both in vitro and in vivo. Based on the chemical structure (SMILES), RISE can offer in silico predictions of physico-chemical properties, ADME parameters and potential metabolites using the ADMET Predictor® software from Simulations Plus, Inc. We help with evaluation of the results and offer consultation around optimization of ADME properties of your chemical series.

In vitro ADME

The interaction between a pharmacological target and a compound is dependent on the free concentration of this compound at the target site. It is also the free, unbound drug that is available for metabolism. Plasma protein binding and metabolic stability are therefore important parameters for the interpretation of efficacy and safety data. Within RISE we can measure plasma protein binding and perform metabolic stability studies in microsomes and isolated hepatocytes from humans and from different species of animals.

Pharmacokinetic evaluation

In the discovery phase of drug development, the chemical series is optimized towards a pharmacokinetic (PK) profile that can give the desired effect, without resulting in toxicity. Within RISE we can offer PK studies in mice or rats in order to determine exposure, bioavailability, clearance, volume of distribution and half-life. When you need PK data from species other than rodents, we can coordinate (outsource) and monitor appropriate studies through contract laboratories.

Biotransformation

Knowledge about the biotransformation of test a compound in vitro is important for not only the chemical design of new compounds with improved metabolic stability, but also to identify and avoid compounds that could give rise to potentially toxic metabolites in vivo. As a supplement to our in vitro metabolic stability studies and in vivo PK studies, we can offer investigations of biotransformation.

Toxicokinetic evaluation

Toxicokinetics (TK), i.e., kinetic characteristics of compounds in toxicological studies, are performed to relate observed effects in toxicological studies to exposure in vivo, with the aim to assess the safety margins of the studied compound. We can offer TK studies in rodents, carried out in our in-house animal facility. Moreover, bioanalysis and TK calculations can be performed separately, in the case when the in-life study is outsourced.

ADME partner

RISE can offer to be your “one stop shop” ADME partner in your drug discovery projects. We help you with interpretation and evaluation of ADME results and with integration of data throughout the optimization of your chemical series


Contact person

Matilda Bäckberg

Projektledare

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