Aim: Isobutyrylcarnitine (IBC) is a possible biomarker for hepatic OCT1, as IBC plasma concentrations are reduced when OCT1 is inhibited. An accessible, characterized assay is needed to quantitate IBC in human plasma. Materials & methods: A triple quadrupole MS surrogate matrix assay for the quantitation of IBC was characterized to support a first-in-human study. Results: An assay for IBC quantitation was fully characterized for accuracy, precision, selectivity and parallelism. IBC was measured in a clinical study and the data were correlated to the in vitro model prediction. Conclusion: A triple quadrupole-based assay for IBC should broaden the monitoring of IBC for OCT1 inhibition in early clinical trials, generating the data needed to establish IBC as a valid biomarker.
Keywords: OCT1 transporter; biomarkers; characterization; drug–drug interaction; isobutyrylcarnitine.
The liver has specialized proteins that transport some approved pharmaceuticals in and out of the liver cells. It is important to understand if a new pharmaceutical is also moved by these transporters because if multiple co-taken pharmaceuticals compete for the same transporter, the plasma concentrations of the therapies can change so that one or more of the therapies may become ineffective or even dangerous. Isobutyrylcarnitine, (IBC), is a naturally occurring molecule that circulates in the plasma and whose concentration is reduced when there is competition for the OCT1 transporter. Therefore, IBC is a biomarker for OCT1 competition. We have developed an assay to quantitate IBC in human plasma using common laboratory instrumentation so that competition of a new pharmaceutical with the OCT1 transporter can be evaluated by measuring IBC plasma concentrations in early clinical trials.