In Vitro ADMET Services
At Peakdale we offer a range of in vitro ADMET predictive models, delivering accurate and reproducible data, maintaining a focus on efficient turnaround times to facilitate our customers' drug discovery programs.
In addition to our core assays, we also offer our clients the flexibility of bespoke assay design. The majority of our assays utilise sensitive "state of the art" triple quad LC-MS/MS ESI detection.
Complementing our laboratory facilities, we have an in silico capability dedicated to virtual high throughput screening, optimising ADMET properties to aid rational compound selection for in vitro experiments.
We support our clients with results interpretation and direct communication with our assay experts.
Poor aqueous solubility limits oral absorption and causes poor oral bioavailability. We determine the thermodynamic solubility of a research compound utilising the equilibrium shake flask method at controlled temperature.
Lipophilicity influences drug activity, and has been correlated with solubility, permeability, metabolism, toxicity, protein binding and distribution. We estimate the Log D, log of the distribution coefficient between octanol and buffer, using a scaled-down shake flask method at pH 7.4 or pH as requested.
Permeability has a major influence on gastrointestinal drug absorption and tissue penetration e.g. blood-brain barrier (BBB).
PAMPA, Parallel Artificial Membrane Permeability Assay, models passive transcellular transport, the method by which most drugs are absorbed, and can be modified to simulate the lipid bilayer of various cell types, including intestinal epithelium or blood brain barrier. It is relatively fast (4-24 hours) and inexpensive.
Caco-2 cell monolayer, over-expressing P-gp, models intestinal absorption, but is a multi-mechanism assay modelling passive diffusion, active influx and efflux.
BBB model. Limited penetration across the blood-brain barrier presents a major challenge for successful CNS drug delivery. Our primary bovine cell monolayer model retains functional P-gp efflux transport - essential for monitoring efficient brain permeability of neuropharmaceuticals.
Plasma protein binding
Plasma protein binding is critical as it reduces free drug concentration thereby influencing compound dosing, efficacy, clearance rate and potential for drug-drug interactions. Our modern ultrafiltration technique has good in vivo correlation, is rapid, reproducible, and sensitive. (Species as requested).
Metabolic stability has a profound influence on the therapeutic efficacy and toxicity of drugs. Most are biotransformed by metabolic enzymes into more polar molecules that are readily excreted. Rapid metabolism, or clearance, reduces bioavailability resulting in lower exposure at the therapeutic target. Our assays utilise liver microsomes, hepatocytes and plasma (human & other species, single or multiple time-points as requested) to determine t1/2(half-life), which can be scaled to predict human in vivo clearance.
CYP450 metabolic inhibition
CYP450 metabolic inhibition can occur during co-administration of two or more drugs that compete for the same enzyme, resulting in one drug being excluded from metabolism to an extent dependent on the potency of inhibition by the second drug. In this type of drug-drug interaction the excluded drug may increase to toxic concentrations, which could potentially be fatal. We use "drug-like" substrates with human recombinant Bactosomes to screen compounds for inhibitory potential generating an IC50 against each of the 5 major human CYP450s.
CYP induction may result in elevated levels of CYP enzyme in response to repeat administration of certain compounds. This can lead to drug-drug interactions due to increased metabolism of the inducing compound, or other co-administered drugs. We utilise human hepatocytes in culture to determine the extent with which drugs increase levels of the major inducible CYP450s, CYP1A2 & CYP3A4.
Cytotoxicity triggers cell death. We utilise cultured primary human hepatocytes, retaining CYP450 & UGT metabolic activity, since metabolite(s) as well as the test drug can cause toxicity.
Customer specific assays
..... as requested.
In silico modelling
We employ cutting edge methodologies from CADD (computer aided drug design) along every step of the drug discovery process through to virtual HTS array design and lead optimisation. Our core capabilities facilitate prediction of important drug-like properties and development of predictive QSAR models.