A Validated Surrogate Analyte LC–MS/MS Assay for Quantitation of Endogenous Kynurenine and Tryptophan in Human Plasma

Miller, Donald E.; Tan, Lei; Dorshorst, Drew; Morrissey, Kari M.; Mahrus, Sami; Milanowski, Dennis; McKnight, Janine; Cape, Stephanie; Dean, Brian; Liang, Xiaorong

doi:10.4155/bio-2018-0044

Cited by 14 publications

(13 citation statements)

References 16 publications

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“…Development of this method was based on the assumption that the authentic and surrogate analytes shared the same physicochemical properties except for the molecular weight. However, because isotope standards may differ in MS sensitivity, we had to determine the response factor (Miller et al, 2018; Zhang et al, 2014), which is the ratio of the of the labeled analyte response to that of the non‐labeled analyte. However, to accurately correct the authentic analyte concentration, we determined the response factor in blank rat plasma.…”

Section: Methodsmentioning

confidence: 99%

“…Performing the analysis using surrogate analytes in the authentic matrix not only solves the problems associated with interference by the endogenous substance and the matrix effect but also ensures that the recorded results are reliable, because the authentic and the surrogate analytes, such as isotopes, differ only slightly in molecular weight, and they share identical or at least similar physicochemical properties that are critical for extraction, chromatography and detection. Minor differences can be corrected by a response factor, which is the ratio between the responses recorded for the surrogate and the authentic analyte at an equal concentration in the same matrix (Miller et al, 2018). Once the responses are balanced, parallelism is generally assured (Miller et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Minor differences can be corrected by a response factor, which is the ratio between the responses recorded for the surrogate and the authentic analyte at an equal concentration in the same matrix (Miller et al, 2018). Once the responses are balanced, parallelism is generally assured (Miller et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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A validated surrogate analyte UPLC–MS/MS assay for quantitation of TUDCA, TCDCA, UDCA and CDCA in rat plasma: Application in a pharmacokinetic study of cultured bear bile powder

Zan

Xin-hua

Zhao

et al. 2020

Biomedical Chromatography

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Bear bile is a valuable medicinal material used in traditional Chinese medicine for over 2000 years. However, developing a substitute has become necessary because of protection measures for this endangered species. The ingredients of in vitro cultured bear bile powder (CBBP) include tauroursodeoxycholic acid (TUDCA), taurochenodeoxycholic acid (TCDCA), ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA, and it has pharmacological properties that are similar to those of natural bear bile powder (NBBP). In this study, the pharmacokinetic parameters of both CBBP and NBBP were measured in rats with a new surrogate analyte LC–MS method using stable isotopes as surrogate analytes (D4‐TUDCA, D4‐TCDCA, D4‐UDCA and D4‐CDCA) with response factors validated in authentic matrix (plasma) for simultaneously monitoring the authentic analytes (TUDCA, TCDCA, UDCA and CDCA). The method validation was satisfactory for the linear regression (r, 0.9975–0.9994), precision (RSD intra‐day, 0.72–9.35%; inter‐day, 3.82–9.02%), accuracy (RE, −12.42–5.67%) and matrix effect (95.53–99.80%), along with analyte recovery (95.90–98.82%) and stability (89.48–101.81%) of surrogate analytes, and precision (RSD intra‐day, 1.06– 11.51%; inter‐day, 2.23– 11.38%), accuracy (RE, −7.40–10.76%) and stability (87.37–111.70%) of authentic analytes. We successfully applied this method to evaluate the pharmacokinetics of CBBP and NBBP in rats, which revealed the critical in vivo properties of both bear bile preparations.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A validated surrogate analyte UPLC–MS/MS assay for quantitation of TUDCA, TCDCA, UDCA and CDCA in rat plasma: Application in a pharmacokinetic study of cultured bear bile powder

Zan

Xin-hua

Zhao

et al. 2020

Biomedical Chromatography

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“…Blood was collected to monitor changes in plasma Kyn levels as a peripheral biomarker of IDO1 activity at the same timepoints as pharmacokinetic assessments. Validated LC/MS-MS assays were used to measure the concentration of Kyn in plasma samples, with a lower limit of quantitation of 25 ng/mL (15). Samples were analyzed at Covance Laboratories.…”

Section: Biomarker Assessmentsmentioning

confidence: 99%

Phase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors

Jung

LoRusso

Burris

et al. 2019

Clinical Cancer Research

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202

155

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Purpose: IDO1 induces immune suppression in T cells through L-tryptophan (Trp) depletion and kynurenine (Kyn) accumulation in the local tumor microenvironment, suppressing effector T cells and hyperactivating regulatory T cells (Treg). Navoximod is an investigational small-molecule inhibitor of IDO1. This phase I study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of navoximod in combination with atezolizumab, a PD-L1 inhibitor, in patients with advanced cancer.Patients and Methods: The study consisted of a 3 þ 3 doseescalation stage (n ¼ 66) and a tumor-specific expansion stage (n ¼ 92). Navoximod was given orally every 12 hours continuously for 21 consecutive days of each cycle with the exception of cycle 1, where navoximod administration started on day À1 to characterize pharmacokinetics. Atezolizumab was administered by intravenous infusion 1,200 mg every 3 weeks on day 1 of each cycle.Results: Patients (n ¼ 157) received navoximod at 6 dose levels (50-1,000 mg) in combination with atezolizu-mab. The maximum administered dose was 1,000 mg twice daily; the MTD was not reached. Navoximod demonstrated a linear pharmacokinetic profile, and plasma Kyn generally decreased with increasing doses of navoximod. The most common treatment-related AEs were fatigue (22%), rash (22%), and chromaturia (20%). Activity was observed at all dose levels in various tumor types (melanoma, pancreatic, prostate, ovarian, head and neck squamous cell carcinoma, cervical, neural sheath, nonsmall cell lung cancer, triple-negative breast cancer, renal cell carcinoma, urothelial bladder cancer): 6 (9%) doseescalation patients achieved partial response, and 10 (11%) expansion patients achieved partial response or complete response.Conclusions: The combination of navoximod and atezolizumab demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Although activity was observed, there was no clear evidence of benefit from adding navoximod to atezolizumab.

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“…KPMs have been historically measured using thin layer chromatography, and detected under UV light, or via radioactive metabolites (Musajo et al, 1955, 1956; McMillan, 1960; McManus and Jackson, 1968; Shibata, 1988). Today, KPMs are more often measured using more sensitive methods and equipment such as high performance liquid chromatography (HPLC), Gas chromatography mass spectrometry (GCMS), and liquid chromatography tandem mass spectrometry (LC-MS/MS) (Heyes and Markey, 1988; Bizzarri et al, 1990; Smythe et al, 2003; de Jong et al, 2009; Pedersen et al, 2013; Miller et al, 2018). The most commonly measured KPMs are TRP, KYN, and KYNA, and are often presented as ratios.…”

Section: The Kynurenine Pathwaymentioning

confidence: 99%

Kynurenine Pathway Metabolites as Biomarkers for Amyotrophic Lateral Sclerosis

Tan

Guillemin

2019

Front. Neurosci.

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Amyotrophic Lateral Sclerosis (ALS) currently lacks a robust and well-defined biomarker that can 1) assess the progression of the disease, 2) predict and/or delineate the various clinical subtypes, and 3) evaluate or predict a patient’s response to treatments. The kynurenine Pathway (KP) of tryptophan degradation represent a promising candidate as it is involved with several neuropathological features present in ALS including neuroinflammation, excitotoxicity, oxidative stress, immune system activation and dysregulation of energy metabolism. Some of the KP metabolites (KPMs) can cross the blood brain barrier, and many studies have shown their levels are dysregulated in major neurodegenerative diseases including ALS. The KPMs can be easily analyzed in body fluids and tissue and as they are small molecules, and are stable. KPMs have a Janus face action, they can be either or both neurotoxic and/or neuroprotective depending of their levels. This mini review examines and presents evidence supporting the use of KPMs as a relevant set of biomarkers for ALS, and highlights the criteria required to achieve a valid biomarker set for ALS.

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A Validated Surrogate Analyte LC–MS/MS Assay for Quantitation of Endogenous Kynurenine and Tryptophan in Human Plasma

Abstract: A robust, specific and simple LC-MS/MS method was developed and validated with a fit-for-purpose style for measuring tryptophan and kynurenine in human plasma samples.

Cited by 14 publications

References 16 publications

A validated surrogate analyte UPLC–MS/MS assay for quantitation of TUDCA, TCDCA, UDCA and CDCA in rat plasma: Application in a pharmacokinetic study of cultured bear bile powder

A validated surrogate analyte UPLC–MS/MS assay for quantitation of TUDCA, TCDCA, UDCA and CDCA in rat plasma: Application in a pharmacokinetic study of cultured bear bile powder

Phase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors

Kynurenine Pathway Metabolites as Biomarkers for Amyotrophic Lateral Sclerosis

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