Metabolomic Profiling and Drug Interaction Characterization Reveal Riboflavin As a Breast Cancer Resistance Protein–Specific Endogenous Biomarker That Demonstrates Prediction of Transporter Activity In Vivo

Zhang, Yueping; Shipkova, Petia; Warrack, Bethanne M.; Nelson, David M.; Wang, Linna; Huo, Runlan; Chen, Jian; Panfen, Erika; Chen, Xueqing; Fancher, Marcus; Ruan, Qian; Christopher, Lisa J.; Xue, Yongjun; Sinz, Michael; Shen, Hong

doi:10.1124/dmd.123.001284

Cited by 8 publications

(2 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Antioxidants are often added to oral pharmaceuticals to improve drug stability, but their potential impact on drug absorption by inhibiting these major intestinal drug transporters has not been extensively tested. Inhibition of these transporters can significantly alter drug bioavailability, as evidenced in clinical studies [20][21][22][23]. In the current work, we screened a panel of 30 molecular excipients with antioxidant properties to assess their ability to modulate the function of OATP2B1 using HEK-293 cells expressing this transporter.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous clinical studies have shown that inhibition of these transporters can modulate drug bioavailability or exposure. For example, (i) erythromycin, a P-gp inhibitor, increased the bioavailability of the P-gp substrates digoxin and talinolol [20]; (ii) ML753286, a potent BCRP inhibitor, increased exposure to the BCRP substrates sulfasalazine in monkeys [21]; and (iii) grapefruit, apple, and orange juices were reported to reduce exposure to the OATP2B1 drug substrates fexofenadine and aliskiren [22,23].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of Antioxidants in Medicinal Products on Intestinal Drug Transporters

Kulkarni,

Yang,

Koleske

et al. 2024

Pharmaceutics

View full text Add to dashboard Cite

The presence of mutagenic and carcinogenic N-nitrosamine impurities in medicinal products poses a safety risk. While incorporating antioxidants in formulations is a potential mitigation strategy, concerns arise regarding their interference with drug absorption by inhibiting intestinal drug transporters. Our study screened thirty antioxidants for inhibitory effects on key intestinal transporters—OATP2B1, P-gp, and BCRP in HEK-293 cells (OATP2B1) or membrane vesicles (P-gp, BCRP) using 3H-estrone sulfate, 3H-N-methyl quinidine, and 3H-CCK8 as substrates, respectively. The screen identified that butylated hydroxyanisole (BHA) and carnosic acid inhibited all three transporters (OATP2B1, P-gp, and BCRP), while ascorbyl palmitate (AP) inhibited OATP2B1 by more than 50%. BHA had IC50 values of 71 ± 20 µM, 206 ± 14 µM, and 182 ± 49 µM for OATP2B1, BCRP, and P-gp, respectively. AP exhibited IC50 values of 23 ± 10 µM for OATP2B1. The potency of AP and BHA was tested with valsartan, an OATP2B1 substrate, and revealed IC50 values of 26 ± 17 µM and 19 ± 11 µM, respectively, in HEK-293-OATP2B1 cells. Comparing IC50 values of AP and BHA with estimated intestinal concentrations suggests an unlikely inhibition of intestinal transporters at clinical concentrations of drugs formulated with antioxidants.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of Antioxidants in Medicinal Products on Intestinal Drug Transporters

Kulkarni,

Yang,

Koleske

et al. 2024

Pharmaceutics

View full text Add to dashboard Cite

show abstract

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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

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.

show abstract

Metabolomic Profiling and Drug Interaction Characterization Reveal Riboflavin As a Breast Cancer Resistance Protein–Specific Endogenous Biomarker That Demonstrates Prediction of Transporter Activity In Vivo

Cited by 8 publications

References 51 publications

Effect of Antioxidants in Medicinal Products on Intestinal Drug Transporters

Effect of Antioxidants in Medicinal Products on Intestinal Drug Transporters

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

Contact Info

Product

Resources

About