Pharmacokinetics, Bioanalysis and Metabolite Identification

Sygnature Discovery offers a dedicated team and complete support to pharmacokinetics, bioanalysis and metabolite identification which is adapted to each project needs. Our vast experience is complemented with a suite of state-of-the art dedicated bioanalytical and metabolic identification mass spectrometry equipment.

Pharmacokinetics

Pharmacokinetics evaluation is required during the drug optimisation phase to inform projects of in vivo disposition of lead candidates. Typically, the first in vivo experiment during an oral drug discovery project would be a single IV bolus dose in a preclinical species. Usually, the compounds are first tested in rodent species followed by non-rodent studies as the programme approaches a preclinical candidate selection. This discipline describes the relationship between drug concentration and time in an organism following administration. 

• IV bolus study allows the determination of key PK parameters such as AUC, Cmax, t½, Vss and clearance.
• After a test compound has successfully passed this first PK hurdle, further PK studies are used to build a more detailed picture of all aspects of ADME.
• Oral PK, in combination with the above IV data allows the determination of oral bioavailability (F). Low oral Bioavailability can be caused by poor absorption and/or high first-pass metabolism.
• Collection of urine or bile allows calculation of renal and biliary clearance and identification of metabolites.

Bioanalysis

Sygnature Discovery offers state-of-the-art non-GLP bioanalysis using matrix-matched calibration curves to deliver a full quantification of unknown samples. For most drug discovery applications, our UPLC-MS/MS services allow rapid, accurate and sensitive quantification from a wide variety of biological matrices.

• Using ultra high performance liquid chromatography (UHPLC) on a range of different columns provides a significant improvement in resolution and throughput over conventional high performance liquid chromatography (HPLC) and combining this with tandem mass spectrometry (MS/MS) as the detector guarantees excellent specificity and sensitivity.
• This allows the bioanalysis of a wide range of compounds from very small polar molecules using hydrophilic interaction liquid chromatography (HILIC) to more conventional drug-like molecules and peptides.

Metabolite Profiling and Identification (MetID)

We have a dedicated team specialised in profiling and identification of metabolites formed during in vitro or in vivo studies. We aim to provide you with a broad understanding of which metabolites are likely to be formed through interpretation of pharmacological, pharmacokinetic and toxicological data.

We are equipped with state-of-the-art high-resolution accurate mass spectrometry capabilities. Such instruments provide increased sensitivity and enhanced structural characterisation.  Sygnature’s metabolite identification team can access either the Sciex QTRAP® 5500 or the Waters Xevo® G2-S QTof to determine high-resolution accurate mass of any metabolites.

We offer a range of metabolite profiling services depending upon the level of detail and interpretation required. We deliver consistent, high-quality data in line with regulatory guidelines, and can adapt protocols based on specific customer requirements.

• Metabolite profiling and identification
• Reactive metabolite (Glutathione reactivity/trapping and cyanide trapping)

Metabolites can be investigated in several different matrices across species including in vitro microsomal incubations, hepatocyte incubations, expressed enzyme incubations as well as in vivo samples from various tissues and fluids. Our scientists will work together with you to devise the most appropriate, efficient and cost-effective strategy for every stage of your drug discovery program.