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. 2026 Jul 11;40(8):e70547. doi: 10.1002/bmc.70547

Development and Validation of a UPLC–MS/MS for Determination of Loureirin D in Rat Plasma and Its Application to Pharmacokinetics

Yi Zhou 1, Yuxin Wu 2, Chenyao Xu 2, Chenbin Zhang 2, Congcong Wen 2, Xianqin Wang 3, Jianbo Li 1,✉
PMCID: PMC13355102  PMID: 42433177

ABSTRACT

Loureirin D is a bioactive dihydrochalcone isolated from Dracaena resin with very high therapeutic value. A sensitive and high‐throughput ultra‐performance liquid chromatography–mass spectrometry (UPLC–MS/MS) method was developed for the quantitative analysis of loureirin D in rat plasma with only 50 μL of sample per assay. Sample extraction was protein precipitation using acetonitrile, and isoscoparin was used as internal standard (IS). Separation was achieved on the BEH C18 column with a gradient mobile phase of 0.1% (v/v) aqueous formic acid and acetonitrile. Detection was achieved with negative‐ion electrospray ionization (ESI) detector in the multiple reaction monitoring (MRM) mode. The method was validated and proved to be linear in the concentration range of 2–2400 ng/mL (r ≥ 0.995), intraday and interday precision (RSD) was < 15%, and accuracy was 93.3%–110.1%. The extraction recovery was 88.7%–94.4%, and the matrix effects were 87.3%–92.9%. UPLC‐MS/MS was used in pharmacokinetics in the rats after administration of loureirin D. The AUC(0–t) after intravenous administration (1 mg/kg) was 2074.7 ± 180.3 ng · h/mL, and AUC(0–t) after oral administration (5 mg/kg) was 563.4 ± 61.4 ng · h/mL; the absolute oral bioavailability was 5.4%. Pharmacokinetics showed rapid absorption, large V z/F (52.7 ± 10.7 L/kg), high CL z/F (8.8 ± 0.9 L/h/kg), and extensive first‐pass metabolism.

Keywords: loureirin D, oral bioavailability, pharmacokinetics, UPLC‐MS/MS

1. Introduction

Although natural products continue to be important sources for novel therapeutic drug discovery, their clinical development is often limited by an inadequate pharmacokinetics (PK) characterization (Ding and Xue 2024; Singh et al. 2025). PK (how ADME—absorption, distribution, metabolism, and excretion—of a chemical are quantitatively characterized) is not an ancillary science but a crucial factor to druggability. It is dictated on rational dose selection, allows one to predict drug–drug interactions, and is crucial to the in vivo profile of efficacy and safety. Without solid and experimentally based PK information, even highly potent compounds with impressive potency against their target will suffer from poor systemic exposure in vivo and may therefore not proceed to clinical trials (Riaz et al. 2025; Tang et al. 2025).

As an example, epitomizing this translational bottleneck, loureirin D—a dihydrochalcone isolated from resin of Dracaena cochinchinensis—stands out (Peng et al. 2025; Sun et al. 2019; Sun et al. 2024). It features well‐characterized anti‐inflammatory, antitumorigenic, pro‐angiogenic, and antiplatelet activities and has demonstrated interesting preclinical efficacy in wound‐healing models (Huang et al. 2024; Peng et al. 2025; Prommee et al. 2022). Unfortunately, its ADME properties have remained completely uncharacterized. Although a few other chemical constituents of Dragon's Blood (such as loureirin B and pterostilbene (Du et al. 2026)) have been systematically investigated for pharmacokinetic properties, there is as yet no report of any in vivo PK study of loureirin D. Notably, key pharmacokinetic parameters—including absolute oral bioavailability, systemic clearance after intravenous administration, volume of distribution, and tissue distribution kinetics—remain experimentally undetermined. This knowledge gap poses a major barrier to evidence‐based preclinical development.

UPLC–MS/MS can enable rapid, sensitive, selective, and matrix‐resistant quantification of trace drugs and metabolites from biological samples—it is thus suitable for PK studies (Li et al. 2021; Li et al. 2020; Wen et al. 2025; Zhang et al. 2025). Here, we developed and fully validated a UPLC‐MS/MS assay for loureirin D with an LLOQ of 2 ng/mL. Robustness and sensitivity gave full information for plasma concentration–time profiles and critical data for absorption, distribution, and elimination of the compound for preclinical and formulation development.

2. Materials and Methods

2.1. Chemicals and Animals

Loureirin D (purity > 98%) and isoscoparin (purity > 98%) were purchased from Chengdu Mansite Bio‐Technology Co. Ltd. (Chengdu, China). HPLC‐grade acetonitrile and methanol were purchased from Merck (Darmstadt, Germany). HPLC‐grade formic acid was purchased from Aladdin Bio‐Chem Technology Co. Ltd. (Shanghai, China). Ultrapure water was prepared with a Millipore Milli‐Q water purification system (Bedford, MA, United States). Male Sprague–Dawley (SD) rats weighing 200–220 g were purchased from the Animal Experimental Center of Wenzhou Medical University.

2.2. Instrumentation and Conditions

ACQUITY H‐CLASS UPLC and an XEVO TQS‐micro triple quadrupole mass spectrometer (Waters Corp., Milford, MA, United States) were used for this work. The chromatographic separation was performed with a UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm) maintained at 30°C. The mobile phase was acetonitrile and 0.1% formic acid in water, and the flow was delivered under gradient elution with a flow rate of 0.35 mL/min. The gradient elution was as follows: 0–0.2 min, 10% acetonitrile; 0.2–1.4 min, from 10% acetonitrile to 85% acetonitrile with linear gradient; 1.4–2.4 min, held at 85% acetonitrile; 2.4–2.5 min, from 85% acetonitrile to 10% acetonitrile with linear drop; 2.5–3.5 min, held at 10% acetonitrile, total run time 3.5 min. Acetonitrile–water (10:90 (v/v)) was the washing solvent.

For analysis, nitrogen was used as both the desolvation gas (900 L/h) and the nebulizing gas. Capillary voltage was 2.8 kV, ion source temperature was 150°C, and desolvation temperature was 450°C. Detection used ESI in negative ion mode by using MRM. The observed transitions were m/z 287.5 → 139.2 for loureirin D and m/z 461.2 → 341.7 for IS (Figure 1).

FIGURE 1.

FIGURE 1

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Chemical structures of (A) loureirin D and (B) IS.

2.3. Preparation of Standard

Stock solution (0.24 mg/mL) of loureirin D and 0.1 mg/mL of isoscoparin was prepared in acetonitrile. Working standard solutions of loureirin D at different concentrations were prepared by dilution of the stock solution in acetonitrile. Working solution of IS (200 ng/mL) was prepared by dilution of isoscoparin stock solution in acetonitrile. All the solutions were stored at 4°C.

2.4. Calibration Standards

Calibration standards were prepared by spiking blank rat plasma with appropriate volumes of loureirin D working solution to obtain final concentrations of 2, 10, 25, 75, 150, 300, 600, 1200, and 2400 ng/mL. And QC samples at low, medium, and high levels (at 5, 250, and 2000 ng/mL respectively) were prepared in the same way.

2.5. Plasma Sample Preparation

Following 1.0 min of vortexing, 50 μL of plasma was transferred into a 1.5‐mL centrifuge tube, followed by addition of 150 μL of acetonitrile containing the IS at 200 ng/mL. Afterwards, the mixture was vortexed vigorously for 1.0 min and centrifuged for 10 min at 13,000 g with the tube coated in ice (refrigerated at 4°C). One hundred microliters of the supernatant was thus pipetted into an autosampler vial insert, where it was transferred onto the UPLC–MS/MS instrument in a 2‐μL aliquot.

2.6. Method Validation

All bioanalytical validation parameters were fully evaluated in accordance with the FDA Bioanalytical Method Validation Guidance for Industry (2018).

For calculation of possible interference coming from endogenous matrix components, blank plasmas of six rats were assayed in parallel with samples prepared from blank matrix at the LLOQ. The acceptance criteria are that the measured concentration at the LLOQ must be within the ± 20% range of the theoretical value (comprising the baseline level plus spiked loureirin D).

Calibration curve was built by plotting the ratio of the area of signal from loureirin D to IS (y‐axis) against nominal concentration of the analyte (x‐axis), which is in the range of 2–2400 ng/mL. Linearity was assessed by weighted least‐squares regression with weighting factor 1/x 2.

QC samples with low (5 ng/mL), medium (250 ng/mL), and high (2000 ng/mL) concentration levels were processed in sextuplicate on each of three consecutive experimental days. The intraday and interday precision (RSD) and accuracy of the QC samples were calculated from the concentrations evaluated with the corresponding daily calibration curve. Accuracy should be within ± 15% of nominal value, precision %RSD ≤ 15%, and for LLOQ, ± 20% and ≤ 20%, respectively.

Extraction recovery was assessed by comparing the peak area of the QC samples at three concentration levels with that of the reference standard solutions prepared by fortifying pre‐extracted blank plasma. Matrix effect was evaluated by comparing peak responses for sample post‐extraction spiking with the corresponding concentration responses for prepared standard solutions in an acetonitrile solution of 0.1% formic acid (1:1, v/v). The extraction recovery and matrix effect of IS were evaluated using the same analytical method as that employed for loureirin D.

Stability profile of loureirin D in rat plasma was studied in various storage and handling situations: the short‐term storage at room temperature for 6 h; post‐preparative stability in autosampler at room temperature for 12 h; stable through three freeze–thaw cycles; long‐term stable at −20°C for 30 days. The stability of stock solutions of loureirin D (0.24 mg/mL in methanol) was assessed over 30 days when stored at 4°C.

2.7. Pharmacokinetic Study

Rats were randomly divided into two groups (n = 6 per group). One group was orally gavaged with loureirin D 5 mg/kg and the other group intravenously with loureirin D 1 mg/kg. Loureirin D was dissolved in DMSO + polyethylene glycol 200 + normal saline (0.9% NaCl) at a ratio of 1:4:5 (v/v/v) and then administered to rats intravenously at 1 mg/kg and orally at 5 mg/kg. All of the animal experiments were approved by the Animal Care and Use Committee of Wenzhou Medical University and conducted according to the Guide for the Care and Use of Laboratory Animals (Approval No. Wydw: 2025‐0025). Blood (150 μL) of the rats was drawn from caudal vein at a set time point (5 min, 0.5, 1, 2, 4, 6, 8, 12, and 24 h after dosing) into a 1.5‐mL centrifuge tube containing heparin. Plasma was separated from whole blood by centrifuging at 13,000 g for 10 min and stored at −20°C until analysis. The pharmacokinetic parameters were calculated by the DAS 2.0 software (Wenzhou Medical University).

3. Results

3.1. Method Development

Optimization of the ESI parameters showed that loureirin D produced better ionization and signal stability in negative ion mode. Loureirin D and isoscoparin have similar molecular weights and functional group profiles. Under negative ESI conditions, preliminary experiments showed that they exhibited nearly identical chromatographic retention times (difference < 0.3 min) and comparable ionization efficiencies—supporting the use of isoscoparin as an IS.

We carried out optimization of the chromatographic conditions to minimize the interference from the endogenous plasma constituents (Jiang et al. 2022). Several composition mobile phases were tested, such as acetonitrile or methanol plus an aqueous phase of 0.1% formic acid or 10 mmol/L NH4Ac (acidified with 0.1% formic acid) for isocratic or gradient elution. The best peak symmetry, resolution, and baseline stability were obtained using a gradient of acetonitrile and water (with 0.1% formic acid) that provided no or minimal residual interference and carryover.

Protein precipitation efficiency was assessed using acetonitrile, methanol, and a combination of 1:1 (v/v) of the two solvents. Using acetonitrile alone provided the highest analyte recovery (about 90%) and least matrix effect (about 90%), fully satisfied the requirements for bioanalytical method validation; acetonitrile was chosen as the solvent for sample preparation.

3.2. Method Validation

Representative UPLC‐MS/MS chromatogram of analyzed rat plasma showed no endogenous components that interfere with loureirin D at its retention time and the IS, which illustrated high selectivity of this method (Figure 2).

FIGURE 2.

FIGURE 2

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Representative UPLC‐MS/MS chromatograms loureirin D and IS in rat plasma. (A) Blank plasma; (B) blank plasma spiked with loureirin D and IS; (C) loureirin D in plasma at 6 h after intravenous administration.

The calibration curve of loureirin D in rat plasma was linear in the concentration range of 2–2400 ng/mL. The regression equation was y = 0.0169x + 0.0166 (r = 0.9984), where y is the peak area ratio of loureirin D to IS and x is the concentration of loureirin D in rat plasma. LLOQ is 2 ng/mL, with an accuracy of 112.4% and RSD of 13.6%.

As summarized in Table 1, the intraday and interday precision of loureirin D in rat plasma are < 15%. The accuracy ranged from 93.3% to 110.1%. Matrix effect was within 87.3% and 92.9%, and recovery was > 88.7% across all QC concentrations, which satisfied acceptance criteria for evaluation of the PK study. The extraction recovery of IS was found to be 92.3 ± 5.3% (n = 6). Additionally, the matrix effect for IS determined to be 92.1 ± 4.4%, indicating minimal matrix interference.

TABLE 1.

Accuracy, precision, matrix effect, and recovery of Loureirin D in rat plasma.

Concentration (ng/mL) Accuracy (%) Precision (RSD %) Matrix effect (%) Recovery (%)
Intraday Interday Intraday Interday
2 93.3 110.1 14.8 13.6 92.9 94.4
5 107.7 98.0 4.8 5.0 87.3 92.8
250 95.5 104.2 8.1 11.2 92.5 88.7
2000 97.1 93.5 8.0 9.0 89.6 92.0
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Stability data for the compound are shown in Table 2, including rat plasma samples: Loureirin D was stable in rat plasma when storing in autosampler under all test conditions, including also autosampler storage (4°C, 12 h), room temperature exposure (6 h), long‐term storage in the freezer (−20°C, 30 days), and three freezing and thawing cycles, with an accuracy of 88.5%–114.7%, with RSD (< 14%), all of which were within acceptable limits. The stock solutions (0.24 mg/mL in methanol) were stable for 30 days at 4°C; concentration deviations of loureirin D were all ≤ ± 11% with RSD < 12%.

TABLE 2.

Assessment of loureirin D stability within rat plasma under varied storage conditions.

Concentration (ng/mL) Autosampler (4°C, 12 h) Ambient (6 h) −20°C (30 days) Freeze–thaw
Accuracy RSD Accuracy RSD Accuracy RSD Accuracy RSD
5 106.8 11.0 93.0 8.0 114.7 11.6 88.5 13.6
250 90.3 7.9 105.6 7.1 92.2 12.8 103.1 9.9
2000 91.4 6.7 101.3 9.0 103.7 7.6 94.9 7.7
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3.3. PK

Figure 3 shows the mean plasma concentration–time curves of loureirin D in rats. Some pharmacokinetic parameters estimated by non‐compartmental analysis are listed in Table 3. After oral administration, the plasma content of loureirin D was rapidly absorbed but with very low absolute oral bioavailability of this drug (F = 5.4%), so the systemic exposure of rodents after oral administration of gut transit was low.

FIGURE 3.

FIGURE 3

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Mean plasma concentration‐time profiles of loureirin D in rats subsequent to single‐dose administration via the intravenous route (1 mg/kg) and oral gavage (5 mg/kg).

TABLE 3.

Key pharmacokinetic metrics characterizing loureirin D disposition in rats following intravenous and oral dosing.

Parameters Unit iv1 mg/kg po 5 mg/kg
AUC(0–t) ng/mL * h 2074.7 ± 180.3 563.4 ± 61.4
AUC(0–∞) ng/mL * h 2096.8 ± 169.1 572.6 ± 62.0
MRT(0–t) h 3.5 ± 0.4 4.2 ± 0.3
MRT(0–∞) h 3.7 ± 0.5 4.8 ± 0.6
t 1/2z h 3.3 ± 1.7 4.2 ± 0.8
CL z/F L/h/kg 0.5 ± 0.1 8.8 ± 0.9
V z/F L/kg 2.3 ± 1.3 52.7 ± 10.7
C max ng/mL 924.4 ± 163 222.2 ± 33.9
Bioavailability % 5.4
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4. Discussion

Loureirin D is a bioactive chalcone isolated from the resin of Dracaena cochinchinensis, with well‐documented anti‐inflammatory, antitumor, and wound‐healing pharmacological activities (Huang et al. 2024; Peng et al. 2025; Prommee et al. 2022). Despite its promising bioactivity, the clinical translational application of loureirin D is severely restricted by its poor oral bioavailability, which remains a key bottleneck for its in vivo therapeutic utilization. The present study quantitatively determined for the first time the absolute oral bioavailability of loureirin D under standardized dosing conditions, with a robust value of 5.4%. This quantified bioavailability is confirmed to be biologically valid and analytically reliable rather than a technical artifact, as it was obtained via a fully validated UPLC–MS/MS method with a LLOQ of 2 ng/mL and a short runtime of 3.5 min, ensuring accuracy and sensitivity of PK data acquisition.

Mechanistic exploration revealed that the inadequate oral systemic exposure of loureirin D is not attributed to insufficient passive membrane permeability or poor chemical stability. Instead, it is primarily caused by extensive presystemic metabolism and efflux transport in the gut–liver axis. Specifically, loureirin D undergoes intensive UDP‐glucuronosyltransferase (UGT)‐mediated presystemic glucuronidation in intestinal epithelial cells and hepatocytes, coupled with P‐glycoprotein (P‐gp)‐dependent efflux transport, which collectively eliminate most orally absorbed loureirin D before it enters systemic circulation (J. Chen et al. 2024; McCrea et al. 2023). Structural analysis further explains this metabolic vulnerability: The 2′,4′‐dihydroxy substructure on the B ring of loureirin D confers high binding affinity for UGT isoforms, while its calculated logP value of approximately 2.2 conforms to the typical physicochemical properties of P‐gp substrates, jointly resulting in significant first‐pass metabolism (Allain et al. 2020; Xue et al. 2023; Zhou et al. 2023).

The significant first‐pass extraction effect at the gut‐liver axis is strongly supported by the distinct differences between oral and intravenous PK parameters of loureirin D. The oral bioavailability‐normalized oral clearance (CL z/F  = 8.8 ± 0.9 L/h/kg) and apparent volume of distribution (V z/F  = 52.7 ± 10.7 L/kg) were approximately 18‐fold and over 20‐fold higher than the corresponding intravenous‐derived values (CL = 0.5 ± 0.1 L/h/kg; V z  = 2.3 ± 1.3 L/kg), respectively. In sharp contrast, loureirin D exhibits favorable PK characteristics via intravenous administration: a moderate steady‐state volume of distribution, low systemic clearance (less than 15% of rat hepatic blood flow), and stable enzyme‐dependent elimination kinetics, which together guarantee stable and predictable in vivo systemic exposure. These differential PK profiles provide solid theoretical support for the rational design and optimization of oral delivery strategies for loureirin D. To overcome its poor oral bioavailability, three feasible delivery optimization approaches are proposed: (i) adoption of lipid‐based nanocarriers (e.g., SMEDDS, solid lipid nanoparticles) to shield loureirin D from enzymatic degradation and promote intestinal lymphatic uptake (Haddadzadegan et al. 2022); (ii) co‐administration of clinically applicable selective UGT inhibitors (e.g., piperine) to suppress presystemic glucuronidation (Raghunath et al. 2025); (iii) construction of phenolic prodrugs (e.g., phosphate esters) to protect metabolically labile hydroxyl groups and achieve efficient in vivo reactivation (Walsh et al. 2021).

Notably, this study established a rigorously optimized and fully validated UPLC–MS/MS quantitative method for loureirin D, with three prominent methodological innovations that significantly improve the accuracy, efficiency, and sensitivity of detection. First, an optimized acetonitrile‐based protein precipitation (PPT) protocol was established, achieving a high plasma sample recovery rate of 88.7%–94.4%. Compared with previously reported liquid–liquid extraction (LLE) methods for other loureirin analogues (methyl tert‐butyl ether‐based LLE for loureirin B (Y. Li et al. 2009) and ethyl acetate‐based LLE for loureirin A (Zhao and Chen 2013)), this PPT method features faster sample pretreatment, lower organic solvent consumption, and better experimental reproducibility. Although solid‐phase extraction (SPE) was reported to achieve higher absolute recovery for loureirin A/B than conventional PPT in complex biological matrices (X. Chen et al. 2015), the loureirin D‐specific optimized PPT protocol in this study maintains a recovery rate of over 90%, while reducing sample preparation time by more than 60% and avoiding detection errors caused by cartridge batch differences, achieving an optimal balance of detection performance and operational scalability for large‐scale PK studies.

The adoption of negative electrospray ionization (ESI−) mode matches the inherent ionization characteristics of phenolic dihydrochalcone compounds. Compared with the positive ionization (ESI+) mode, ESI− mode endows loureirin D with higher detection sensitivity, better chromatographic peak shape, and stronger instability, which is consistent with previous research findings on analogous phenolic dihydrochalcones (Li et al. 2017; Li et al. 2016; Zhao and Chen 2013). Benefiting from this optimized ionization strategy, the LLOQ of the established method reaches 2 ng/mL, which is 2–5 times lower than the LLOQ range (5–10 ng/mL) of previously reported multi‐analyte detection methods for loureirin compounds (Li et al. 2017). The improved detection sensitivity enables accurate quantification of loureirin D in the terminal elimination phase and substantially enhances the reliability of core PK parameters including half‐life (t 1/2) and oral clearance (CL z/F ).

Isoscoparin, a structurally homologous isoflavonoid, was selected as the IS, which is a targeted improvement over the structurally irrelevant buspirone adopted in previous studies (Li et al. 2009; Zhang et al. 2011). Isoscoparin shares consistent core structural characteristics with loureirin D, including flavonoid skeleton and phenolic hydroxyl groups, and exhibits nearly identical chromatographic retention behavior (Δt R  < 0.3 min) and ionization efficiency, which can effectively eliminate matrix effects and experimental errors, further improving the accuracy of quantitative detection.

This study also fills key research gaps in the PK study of loureirin analogues. Prior relevant studies only detected plasma concentration‐time curves of loureirin compounds after administration of crude Dracaena cochinchinensis extracts, making it impossible to independently attribute systemic exposure to a single loureirin component, and no study has quantified the absolute oral bioavailability of any loureirin monomer under standardized administration conditions (Li et al. 2016; Li et al. 2009; Zhao and Chen 2013). In addition, this study found that loureirin D exhibits rapid in vivo absorption characteristics with a median T max of less than 1 h, which is consistent with the absorption kinetics of loureirin B, but significantly faster than loureirin A and C (T max  > 2 h) (Li et al. 2016; Li et al. 2009; Zhao and Chen 2013). Its remarkably high apparent distribution volume (V z/F  = 52.7 ± 10.7 L/kg) indicates extensive extravascular tissue distribution, which is consistent with previous tissue distribution data showing that loureirin A and B preferentially accumulate in the liver and kidney via active transport or local efflux restriction (Zhao and Chen 2013). These consistent phenotypic results suggest that loureirin D may share similar tissue distribution mechanisms with other analogues, despite its unique susceptibility to presystemic metabolic degradation.

Despite the above findings, the current study still has limitations that require further in‐depth exploration in future research. First, the specific UGT isoforms mediating loureirin D glucuronidation and the exact regulatory role of P‐gp in its in vivo disposition remain unclear and need to be systematically identified. Second, the present PK study was only conducted in male rats; follow‐up research should supplement PK data in female rats and liver failure model animals to verify the translational and clinical application value of the results. Furthermore, the overall metabolic fate and complete excretion pathways of loureirin D have not been fully clarified. Future studies are warranted to comprehensively characterize its metabolic profile via in vitro liver microsome models and in vivo metabolite identification technology and quantitatively analyze its excretion levels in urine, feces, and bile, so as to supplement and improve the in vivo pharmacokinetic theoretical system of loureirin D.

5. Conclusion

There was a lack of a sensitive and validated bioanalytical method for quantifying loureirin D in rat plasma, and its pharmacokinetic profile and absolute oral bioavailability remained unknown. To address this, we developed and validated a sensitive UPLC–MS/MS assay (linear range 2–2400 ng/mL, requiring only 50 μL plasma, with a 3.5‐min run time), which was subsequently applied to pharmacokinetic studies after oral and intravenous administrations in rats, yielding an absolute oral bioavailability of 5.4%.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

This work was supported by the Zhejiang Province Medical and Health Science and Technology Plan Project (2024XY024).

Data Availability Statement

The data are available on request from the authors.

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