A Multiplex HRMS Assay for Quantifying Selected Human Plasma Bile Acids as Candidate OATP Biomarkers

Abstract

Six BAs are quantified in human plasma using a multiplexed high-resolution mass spectrometry method. Glycodeoxycholic acid 3-sulfate and glycodeoxycholic acid 3-O-β-glucuronide are proposed as potential biomarkers based on observed four- to fivefold increase in plasma AUC (vs placebo), following administration of a compound known to present as an OATP1B1/3 inhibitor in vitro.

Dose‐Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate Biomarkers and OATP1B Probe Drugs

“…18 As clinical biomarkers, GCDCA-S and GCDCA-G have also been shown to respond to a known inhibitor NCE at doses ranging from 100 to 600 mg (AUCR 1.7-2.3); the compound was a weaker OATP1B inhibitor in vitro (vs. rifampicin) and triggered agency cutoffs for OATP1B inhibition. 23 Furthermore, the K i,app of rifampicin for GCDCA-S and GCDCA-G was close to the K i,app for the probe drugs ( Table 1). These data support that GCDCA-S and GCDCA-G are suitable as endogenous OATP1B biomarkers in addition to CP-I, a widely studied OATP1B biomarker.…”

“…Additional information describing the quantitation of GCDCA-G and GDCA-G in human plasma has been described. 23 Pharmacokinetic analysis C max represents the maximum plasma concentrations observed. AUC was calculated from time zero to 24 hour or infinity.…”

Identification of Glycochenodeoxycholate 3‐O‐Glucuronide and Glycodeoxycholate 3‐O‐Glucuronide as Highly Sensitive and Specific OATP1B1 Biomarkers

“…5 GCDCA-3G could therefore be a useful biomarker for OATP1B1 activity in DDI risk estimation. 8,27 Moreover, it could be useful in elucidating the mechanisms of DDIs, similar to what was recently demonstrated with other OATP biomarkers such as coproporphyrin I, chenodeoxycholic acid 24-O-glucuronide, GCDCA-S, and GDCA-S. 8,10,31,41 Unlike coproporphyrin I, chenodeoxycholic acid 24-O-glucuronide, and GCDCA-S, which present as substrates of both OATP1B1 and OATP1B3 in vitro, GCDCA-3G is more selective for OATP1B1. 7,8 As discussed, it is hypothesized that the fraction transported by OATP1B1 (vs. other OATP forms and liver SLCs) is higher for GCDCA-3G vs. GDCA-3G, GDCA-S, GCDCA-S, coproporphyrin I, and chenodeoxycholic acid 24-O-glucuronide.…”

“…30,42,43 If this phenomenon is widespread with new chemical entities entering the clinic, beyond extensively described perpetrators such as rifampicin and cyclosporine, then GCDCA-3G could be deployed as a useful phenotyping tool and used in conjunction with statin probe drugs and other OATP biomarkers such as coproporphyrin I, GCDCA-S, and GDCA-S. As described by others, it is possible to quantitate multiple OATP1B biomarkers in plasma and generate AUCR signatures at increasing doses of perpetrator drug. 10,31 Such "biomarker multiplexing" is useful when assessing OATP1B DDI risk in healthy volunteers and diseased individuals, when considering the impact of SLCO1B1 genotype on DDI magnitude, and evaluating DDI with new chemical entities presenting different OATP1B1 vs. OATP1B3 inhibition signatures in vitro.…”

Analysis of bile acids in human biological samples by microcolumn separation techniques: A review

“…The benefit of HRMS was clearly demonstrated as it enables quick analysis of BAs with complicated or no fragmentation in common HPLC-MS/MS. Measuring with high resolution together with high mass accuracy at the same time allows the separation of endogenous and isobaric interferences and collection of full-scan spectra [106,107]. HRMS was also used in the work of Jäntti et al [53] to measure the elemental composition of 28 unknown BAs.…”