More than once, Pharmacelsus has been challenged by customers to explain unexpected results observed in PK studies, such as uncommonly low plasma levels after intravenous administration or an incomplete mass balances in early distribution studies.
In order to explain such results, Pharmacelsus scientists started to “think outside the box” and also considered the neglected compartments in pharmacokinetics.
Pharmacelsus established bioanalytical methods to analyse compound levels in matrices that are usually not analysed in early drug discovery programs.
Pharmacelsus conducted a series of PK studies for a customer. Drug candidate levels were surprisingly low in plasma after intravenous application.
Pharmacelsus suggested to analyse not only plasma but also whole blood, since partitioning to red blood cells was hypothesised. Reanalysis of whole blood samples demonstrated that the majority of compound was bound to red blood cells, thus analysis of plasma did not reflect the true compound concentrations in the circulation.
Subsequently performed in vitro blood partitioning experiments confirmed the high affinity of these type of compounds for red blood cells. As a consequence for this class of compounds, analysis of both plasma and whole blood was routinely included into client´s early PK program.
Another promising compound resulted in an incomplete recovery in a mass balance study. When compound levels in plasma, whole blood, most common organs, urine and faeces were quantified, Pharmacelsus hypothesised that this compound might be distributed to e.g. adipose tissue due to its lipophilic nature.
Adipose tissue was subjected to bioanalysis, and indeed substantial levels were measured in this initially neglected compartment.