A Pilot Study To Assess the Suitability of Riboflavin As a Surrogate Marker of Breast Cancer Resistance Protein in Healthy Participants

Shen, Hong; Huo, Runlan; Zhang, Yueping; Wang, Linna; Tong, Nian; Chen, Weiqi; Paris, Andrew J.; Mensah, Kofi; Chen, Min; Xue, Yongjun; Li, Wenying; Sinz, Michael

doi:10.1124/jpet.123.002015

J Pharmacol Exp Ther

2024

DOI: 10.1124/jpet.123.002015

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A Pilot Study To Assess the Suitability of Riboflavin As a Surrogate Marker of Breast Cancer Resistance Protein in Healthy Participants

Hong Shen,

Runlan Huo,

Yueping Zhang

et al.

Abstract: Abbreviations: AUC, area under the plasma concentration-time curve; AUCR, area under the plasma concentration-time curve ratio; BCRP, breast cancer resistance protein; CCK-8, cholecystokinin octapeptide; CI, confidence interval; C max , maximum plasma concentration; C max,u , unbound maximum plasma concentration; C max,inlet,u , predicted unbound maximum plasma liver inlet concentration; CPI, coproporphyrin I; DDI, drug-drug interaction; E3S, estrone-3-sulfate; E17βG, estradiol-17β-glucuronide; EMA, European M… Show more

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Cited by 6 publications

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Ticagrelor modestly raises plasma riboflavin concentration in humans and inhibits riboflavin transport by BCRP and MRP4

Deng,

Hämäläinen,

Lehtisalo

et al. 2024

Clin Pharma and Therapeutics

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Riboflavin (vitamin B2) has been proposed as a biomarker for breast cancer resistance protein (BCRP) activity. In recent studies in mice, cynomolgus monkeys, and humans, BCRP‐inhibiting drugs increased the plasma concentration of riboflavin. We showed recently that ticagrelor inhibits BCRP and raises the plasma concentrations of the BCRP substrate rosuvastatin in healthy volunteers. In the same drug–drug interaction study, we now investigated whether ticagrelor affects the plasma concentrations of riboflavin. Intake of 90 mg ticagrelor increased the ratio between the peak plasma riboflavin concentration and the fasting riboflavin concentration before ticagrelor administration by 1.20‐fold (90% confidence interval, 1.10–1.32; P = 0.006) compared to placebo. In vitro, riboflavin was transported by BCRP and multidrug‐resistance‐associated protein 4 (MRP4) but no clear transport was observed by MRP2, MRP3, or the P‐glycoprotein. Moreover, ticagrelor inhibited the transport of riboflavin in BCRP‐ and MRP4‐expressing membrane vesicles with unbound 50% inhibitory concentrations of 0.020 and 1.1 μM, respectively. Based on vesicle and tissue protein expression data, the small intestinal MRP4‐mediated efflux clearance of riboflavin (1.2–1.4 nL/min/mg) was estimated to be similar to that mediated by BCRP (0.23–1.3 nL/min/mg). As MRP4 is expressed in the basolateral membrane of enterocytes, it may facilitate the absorption of riboflavin and impair the utility of riboflavin as a biomarker of intestinal BCRP. To conclude, ticagrelor modestly raises the plasma concentration of riboflavin probably by inhibiting intestinal BCRP. Inhibition of intestinal MRP4 may have reduced the absorption of riboflavin and limited the effect of ticagrelor on riboflavin levels.

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Ticagrelor modestly raises plasma riboflavin concentration in humans and inhibits riboflavin transport by BCRP and MRP4

Deng,

Hämäläinen,

Lehtisalo

et al. 2024

Clin Pharma and Therapeutics

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A close examination of BCRP's role in lactation and methods for predicting drug distribution into milk

Sychterz,

Shen,

Zhang

et al. 2024

CPT Pharmacom & Syst Pharma

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Breastfeeding is the most complete nutritional method of feeding infants, but several impediments affect the decision to breastfeed, including questions of drug safety for medications needed during lactation. Despite recent FDA guidance, few labels provide clear dosing advice during lactation. Physiologically based pharmacokinetic modeling (PBPK) is well suited to mechanistically explore pharmacokinetics and dosing paradigms to fill gaps in the absence of extensive clinical studies and complement existing real‐world data. For lactation‐focused PBPK (Lact‐PBPK) models, information on system parameters (e.g., expression of drug transporters in mammary epithelial cells) is sparse. The breast cancer resistance protein (BCRP) is expressed on the apical side of mammary epithelial cells where it actively transports drugs/substrates into milk (reported milk: plasma ratios range from 2 to 20). A critical review of BCRP and its role in lactation was conducted. Longitudinal changes in BCRP mRNA expression have been identified in women with a maximum reached around 5 months postpartum. Limited data are available on the ontogeny of BCRP in infant intestine; however, data indicate lower BCRP abundance in infants compared to adults. Current status of incorporation of drug transporter information in Lact‐PBPK models to predict active secretion of drugs into breast milk and consequential exposure of breast‐fed infants is discussed. In addition, this review highlights novel clinical tools for evaluation of BCRP activity, namely a potential non‐invasive BCRP biomarker (riboflavin) and liquid biopsy that could be used to quantitatively elucidate the role of this transporter without the need for administration of drugs and to inform Lact‐PBPK models.

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Advancing structural elucidation of conjugation drug metabolites in metabolite profiling with novel electron‐activated dissociation

Yao,

Tong,

Rahul

et al. 2024

Rapid Comm Mass Spectrometry

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RationaleThis study focuses on the advantage of using the novel electron‐activated dissociation (EAD) technology on the QTOF system for structural elucidation of conjugation metabolites. In drug metabolite identification, conceptual “boxes” are generally used to represent potential sites of modifications, which are proposed based on MS/MS data. Electron‐activated dissociation (EAD) provides unique fragmentation patterns, potentially allowing for more precise localization of the metabolic modification sites compared to CID, particularly for conjugations.MethodKnown compounds were incubated with rat liver microsomes in the presence of nicotinamide adenine dinucleotide phosphate (NADPH), uridine dihosphate‐glucuronic acid (UDPGA), and glutathione. Conjugation metabolites were analyzed using the QTOF system. High‐resolution MS/MS spectra were collected using EAD and CID fragmentations along with TOF MS full scan for tested drugs and metabolites. Fragmentation patterns were compared to evaluate their efficiency in structural elucidation.ResultsMetabolite profiling identified conjugation metabolites (glucuronides and GSH adducts), using characteristic mass shifts. A comparison of EAD and CID fragmentation revealed EAD‐specific fragments for most conjugates. EAD was able to break the relatively stable bonds on parent drug motifs while keeping relatively weak conjugation bonds intact, despite the generally low intensity of EAD. EAD effectively narrowed the conceptual “box” representing modification sites, providing more definitive information on conjugation sites and facilitating the structural elucidation of conjugated metabolites.ConclusionEAD is a powerful tool for metabolite profiling in drug development, particularly for identifying conjugation sites. EAD‐enabled MS/MS spectra offer a greater variety of signature fragments compared to CID, resulting in more comprehensive and unique structural information for metabolic modification analysis. Overall, EAD, complementary to CID, has the potential to narrow down potential modification sites, significantly enhancing the precision of conjugation metabolite structure elucidation.

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A Pilot Study To Assess the Suitability of Riboflavin As a Surrogate Marker of Breast Cancer Resistance Protein in Healthy Participants

Cited by 6 publications

References 49 publications

Ticagrelor modestly raises plasma riboflavin concentration in humans and inhibits riboflavin transport by BCRP and MRP4

Ticagrelor modestly raises plasma riboflavin concentration in humans and inhibits riboflavin transport by BCRP and MRP4

A close examination of BCRP's role in lactation and methods for predicting drug distribution into milk

Advancing structural elucidation of conjugation drug metabolites in metabolite profiling with novel electron‐activated dissociation

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