1 Introduction

As a traditional Chinese medicine (TCM), Paeonia lactiflora Pall. (Paeoniaceae) was first utilized to treat diseases and documented in the Prescriptions for Fifty-two Aliments that dates back to more than 2000 years ago (Tan et al., 2020). Radix Paeoniae Alba (RPA, also called baishao in Chinese), in the form of the dried root with its bark removed, has been used for centuries to treat various disorders including inflammation and pain (He and Dai, 2011, Jang et al., 2021, Lee et al., 2022). In TCM, RPA is used to tonify blood and smoothen the liver (Zhao et al., 2022). TCM practitioners often combined RPA with other herbs to create remedies that are believed to have synergistic effects and balance body systems. Modern pharmacological studies have shown that RPA has analgesic, anti-inflammatory, immuno-modulatory and antioxidant effects; therefore, it is used clinically for the treatment of various illnesses, including fever, muscle cramps, rheumatoid arthritis, systemic lupus erythematosus, hepatitis, dysmenorrhea, and spasms (Li et al., 2017, Chen et al., 2021). Various active components (e.g., paeoniflorin, oxypaeoniflorin, benzoylpaeoniflorin, lactiflorin and paeonol have been isolated and characterized from various parts of P. lactiflora (root, stem, leaf, flower and fruit), with albiflorin (C₂₃H₂₈O₁₁) as the key compound.

Albiflorin (C₂₃H₂₈O₁₁), a monoterpene glycoside with a molecular weight of 480.5 Da, contains a unique cage-like pinane skeleton (Zhou et al., 2019). It consists of a glucose molecule (glycone) linked to a cyclic monoterpene aglycone with 10 carbon atoms derived from isoprene units. A glycosidic bond connects the glycone to the hydroxyl group of monoterpene aglycone. Albiflorin can undergo various transformations including hydrolysis, oxidation or enzymatic reactions depending on specific conditions such as pH, temperature and the presence of catalysts. For example, the microbial conversion between albiflorin and paeoniflorin occurs in the presence of two fungi (Liu et al., 2010).

Recently, albiflorin has been demonstrated to exhibit strong pharmacological effects in combating inflammation, oxidation, apoptosis, cancer, bacterial infection, depression and cognitive dysfunction, indicating its great potential for treating related illnesses (Hu et al., 2021, Zhang et al., 2022, Han et al., 2023, Liu et al., 2023b). Albiflorin can be readily obtained from the root of P. lactiflora's, with seversl other medicinal plants, including P. emodi, P. obovata, P. suffruticosa, P. anomala and P. veitchii containing albiflorin. However, the natural production of albiflorin is not restricted to the Paeoniaceae family. Kunzea pomifera, a shrub from the family Myrtaceae native to Australia, has also been reported to produce albiflorin (Table 1).

In this review, a total of 282 articles were identified by searching the PubMed and Web of Science databases from February 6, 2024, using albiflorin and alibiflorin (a synonym for albiflorin) as key words. The same parameters were applied to the China National Knowledge Infrastructure (CNKI) database, which identified 368 items. This review captured 650 publications from these three public repositories. The focus was on understanding the origin, anti-inflammatory effects, mechanism, pharmacokinetics, and toxicity of albiflorin.

2 Biological profile of albiflorin and P. lactiflora

In the 1970s, albiflorin was extracted from the roots of Radix Paeoniae Alba (RPA) and its absolute structure was reported for the first time (Kaneda et al., 1972). In Latin, alba means white and albiflorin perfectly embodies the intimate relationship between this compound and the source plant P. lactiflora. As a well-known bulk medicinal material in China, P. lactiflora is grown in multiple provinces to produce large quantities of RPA, which is a stable source for the purification and application of albiflorin. P. lactiflora, native to China and commonly known as the perennial herbaceous peony, exhibits distinctive characteristics. The plant features thick roots and dark brown branches, with hairless stems reaching a height of 70 cm. The lower stem leaves contain two or three compound leaves, whereas the upper stem leaves are composed of three compound leaves. The leaflets adopt an elliptic, lanceolate and ovate shape with a pointed apex and base that is either wedge-shaped or oblique. The edges are white and finely toothed, and the leaves are smooth on both sides, with occasional sparse hair along the veins on the back. The flowers are positioned at the top of the stem and on the leaf axils with diameters ranging from 8 to 11.5 cm. Petals are obovate, 3.5–6 cm long, 1.5–4.5 cm broad, and mostly white with sporadic deep purple spots at the bottom. They range in size from 9 cm to 13 cm. The flowers of P. lactiflora blossom from May to June followed by fruiting in August (Editorial Board of Flora of China, 1979). RPA and Radix Paeoniae Rubra (RPR, also called chishao in China), both derived from the radix of P. lactiflora, are used as crude pharmaceuticals and listed as distinct Chinese medicines in the Chinese Pharmacopoeia. RPR is processed by directly drying fresh roots in the sun. In contrast, boiling the root in water is necessary for the processing of RPA to remove impurities and soften its tough texture, followed by peeling. The root is then dried under the sun or a gentle heat source. Albiflorin is present in both RPA and RPR (Fig. 1).

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Fig. 1

P. lactiflora and albiflorin. (A) vegetative body of P. lactiflora; (B1) Radix Paeoniae Alba; (B2) Decoction pieces made of RPA; (C1) Radix Paeoniae Rubra; (C2) Decoction pieces made of RPR; (D) Structure of albiflorin.

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The biosynthesis of albiflorin begins with the condensation of two cinnamic acid derivatives, coniferyl alcohol and coumaryl alcohol, which are derived from the general phenylpropanoid pathway. The subsequent modifications, such as hydroxylation, methylation, and glycosylation, give rise to the final albiflorin molecule. 4-coumarate-CoA ligase (4CL), an enzyme that catalyzes the conversion of coniferyl alcohol and coumaryl alcohol into the CoA thioester, is one of the essential enzymes in the biosynthesis of albiflorin. To the best of our knowledge, no detailed information is available on the biosynthetic pathway of albiflorin. However, albiflorin and paeoniflorin are both isomers and therefore understanding the biosynthetic pathway of the latter can provide valuable insights into the potential pathway of albiflorin, given their structural similarities (Gao et al., 2015). The terpene routes, namely the 1-deoxy-d-xylulose-5-phosphate/methyl-erythritol-4-phosphate (DXP/MEP) and mevalonate (MVA) pathways, control the manufacture of the monoterpene glucoside paeoniflorin. The commonly occurring precursor, isopentenyl-PP (IPP), is synthesized via the DXP/MEP and MVA pathways. Geranyl diphosphate synthase catalyzes the condensation of one IPP and one DMAPP to generate geranyl diphosphate (GPP), the monoterpene precursor form, in the second stage. The final stage then involves the development and post-modification of the basic pinane skeleton. GPP is directly catalyzed by terpenoid synthase, which is situated near the isoprenoid pathway’s branch point, to create the monoterpenoid skeleton (Yuan et al., 2013).

3 Anti-inflammatory activity of albiflorin

Investigations on albiflorin, a prominent bioactive constituent of P. lactiflora have revealed its notable and multifaceted anti-inflammatory effects. In this review, we combine and organize relevant research on albiflorin trials conducted in China and abroad, emphasizing the anti-inflammatory properties of the compound. To sort distinct symptoms that are related to or caused by inflammation, the contents are organized according to diseases in different systems (Table 2), and an overview of the findings regarding the mechanisms of action are also provided.

4 Metabolism and tissue distribution

Pharmacokinetic studies are essential for monitoring dynamic changes of drugs in the body and for rational drug use in clinical settings (Nakamura et al., 2023). By reviewing the literature, we focused on albiflorin pharmacokinetic parameters, including peak time (t_max), biological half-life (t_1/2), peak concentration (C_max), clearance (CL/F), area under the concentration–time curve (AUC), and the binding rate of plasma protein (BRPP). The pharmacokinetic behavior of albiflorin was compared between acute cholestatic hepatitis and normal rat models. In the low-dose control group (LDCG) and model group (LDMG), rats were orally administered powdered RPR at a dose of 7 g/kg (equivalent to 99 mg/kg albiflorin). In the high-dose control group (HDCG) and model group (HDMG), the same intervention was administered, except that the dose was doubled. By employing liquid chromatography-mass spectrometry (LC-MS/MS) at ten intervals for observation, LDMG plasma albiflorin showed a higher AUC_0-∞ (3.16 ± 2.41 vs 1.18 ± 0.25), a longer t_max (0.17 ± 0.09 vs 0.08 ± 0.00), and a lower CL/F (31.37 ± 11.98 vs 87.06 ± 17.90) than those in the LDCG, with the same trend identified when the HDCG and HDMG were compared. Furthermore, the abliflorin concentrations in the model group were higher than those in the normal group at most monitoring points (Jiang et al., 2012). Liu (2009) used equilibrium dialysis to determine the BRPP of albiflorin in two mediators (human and mouse plasma) at different concentrations (1.0, 5.0, 10.0, 15.0, 20.0, 30.0 µg/ml); using high-performance liquid chromatography (HPLC) examination, the highest amount of albiflorin binding to plasma protein in vitro was 10 µg/ml and the BRPP of albiflorin in human plasma was 85.65%.

Using triple-quadrupole linear ion-trap tandem mass spectrometry in conjunction with ultra-high performance liquid chromatography to investigate Weikangling Capsules containing albiflorin as the active ingredient, Liu et al., (2023a) separated rats into two groups: the chronic gastritis model group (MG) and the normal group (NG), each of which was administered the capsules at a dose of 2.16 g/kg following a 12-hour fast. Subsequently, samples from eight organ tissues were collected four times. The results showed that albiflorin reached its C_max in the liver, kidneys and stomach after 1 h in the NG. Albiflorin could be rapidly taken up by the small intestine and circulate through the bloodstream to reach the stomach. To reduce drug buildup in the body, the liver and kidneys quickly process and eliminate albiflorin. The amount of albiflorin in the stomach and small intestine of the MG were noticeably higher than that in the NG. Albiflorin was administered intragastrically to 10 rats at a dose of 5 mg/kg and urine was collected from five rats within 24 h. Five rats were first administered 10% chloral hydrate intraperitoneally, and bile was collected through a catheter within 24 h after oral administration. The main metabolic pathway of albiflorin is determined to be via the hydrolysis of ester bonds to produce M4, M5, and M6, loss of C₇H₄O fragment to produce M7 and subsequently followed by the hydrolysis of glycoside bonds (M1, M2) and metabolic binding with glucuronic acid (Fig. 2) (Cao et al., 2015).

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Fig. 2

Graphic scheme of pharmacokinetics of albiflorin in vivo. Albiflorin reaches the stomach by gavage. It is then absorbed in the digestive system and distributed to various organs (liver, kidney and small intestine) through blood circulation. In the liver, albiforin is further metabolized into M4, M5 and M7 catalyzed by CYP450s. Most of the parent components and its metabolites are mainly excreted through urine.

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5 Toxicity

Toxicity research is of great significance for clinically rational and safe drug use; however, toxicological studies on albiflorin are rare. Zhao collected the blood samples from the forelimb veins of Beagles at 12 time points after oral administration of albiflorin (1 mg/kg) for 7 days, and used LC-MS/MS to measure the amount of albiflorin present in the plasma. The results showed that albiflorin was absorbed and eliminated rapidly in Beagles dogs (t_1/2 of was 2 h), and the bioavailability was 2.66%, with no significant drug accumulation, induction or inhibition after repeated administration (Zhao, 2015). Han et al. (2018) used a traditional approach (acute oral toxicity) to evaluate the potential toxicity of albiflorin. It was found that albiflorin administered orally at a dose of 5000 mg/kg (3000 times the clinical dose) did not cause significant changes in the food intake and body weight of Beagles. To further investigate the potential subtle toxicities, next-generation metabolomics was used for retesting. Urine metabolites were analyzed in model rats after oral administration of albiflorin (7 mg/kg) and the top 30 metabolites with the greatest differences before and after albiflorin treatment were determined by data mining using Metaboanalyst 3.0. Disease-related metabolite databases found no statistically significant differences, which again indicated that albiflorin did not have tangible toxic effects on rat metabolism (Han et al., 2018). In summary, low toxicity or non-toxicity of albiflorin is important for a wide range of rational clinical application.

6 Conclusion

This comprehensive review of albiflorin, a pivotal compound derived from P. lactiflora, highlights its therapeutic potential in traditional and modern medicine. Through an intricate examination of its biological profile, anti-inflammatory capabilities, metabolism, tissue distribution, and toxicity, albiflorin has emerged as a promising candidate for treating a diverse array of health conditions involving inflammation (Fig. 3).

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Fig. 3

Graphic scheme of potential targets for albiflorin’s anti-inflammatory effects. Albiflorin influences LPS-induced inflammatory responses via inhibiting LPS binding to the lipopolysaccharide complex (CD14, MD-2, and TLR) on the cell membrane. As a result, it interferes with the MARKs and AKT/PI3K pathways. Subsequently, the activation of TRAF6 and the phosphorylation and degradation of IKK are inhibited. Eventually, downstream of p-NF-κB is inhibited by albiflorin, which reducing the production of relevant pro-inflammatory factors.

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At present, paeoniflorin is normally regarded as the marker component for RPA and RPR. The European Pharmacopoeia stipulates that the content of paeoniflorin should not be less than 1.6% in RPA and 1.8% in RPR, which is also documented in the 2020 edition of the Chinese Pharmacopoeia (European pharmacopeia, 2023; Chinese pharmacopeia, 2020). On the other hand, according to the Japanese Pharmacopoeia, its content in peony root and powdered peony root should not be less than 2% (Japanese pharmacopeia, 2021). Xu et al. (2022) determined the contents of albiflorin and paeoniflorin in RPA decoction pieces and found that both compounds were abundant. For example, results from 15 different batches indicated that the concentrations of albiflorin were 3.000, 3.259, 3.490, 1.634, 2.690, 2.067, 2.265, 2.238, 2.044, 1.789, 2.079, 1.705, 1.807, 2.200, 2.225 mg/g, while those of paeoniflorin were 2.737, 2.500, 3.365, 3.586, 3.666, 3.966, 3.035, 4.161, 4.028, 3.659, 3.456, 3.266, 3.866, 4.042, 4.175 mg/g. Based on such findings, it is advisable to investigate the use of albiflorin as a characteristic compound for quality evaluation in the future.

Moreover, researchers have suggested that albiflorin could be extracted from other parts of Paeonia suffruticosa in addition to its roots, and found that it can also be obtained from Paeonia rockii pollen (Wang et al., 2018, Wang et al., 2019).

This study elucidates the multifaceted roles of albiflorin in treating diseases across various systems, including respiratory, urinary, gastrointestinal, metabolic, rheumatic, blood system disorders, mental illness, and pain management. Its pharmacokinetic properties and metabolic pathways underscore its compound’s efficient absorption and elimination, suggesting favorable bioavailability and minimal toxicity. This aligns with findings of toxicity studies, which indicate the safety of albiflorin for clinical use at the recommended therapeutic doses. The broad spectrum pharmacological effects of albiflorin, particularly its anti-inflammatory and analgesic properties, make it a valuable resource in the pharmacopeia of natural compounds. The absence of significant toxic effects, even at doses substantially higher than the clinical recommendations, further supports its safe therapeutic application. However, the limited scope of the toxicological studies requires further research to establish its safety profile.

In conclusion, albiflorin is a compound with potent therapeutic benefits, rooted in centuries of TCM use and has been validated by contemporary scientific research. Its efficacy in treating a wide range of diseases, coupled with its favorable pharmacokinetics and safety profile, underscores the need for continued exploration of its mechanisms of action, potential applications, and long-term effects on human health. Despite the positive pharmacological finding on albiflorin, one cold fact is noteworthy. A large proportion of the research deals with formulas containing albiflorin other than the compound itself. The interpretation of albiflorin efficacy might be distorted by the presence of other chemicals; in other words, studies on pure albiflorin deserve more attention. Future studies are warranted to fully harness the therapeutic potential of albiflorin, integrate it into modern medical practices, and strategically utilize its versatile resources, thereby bridging the gap between traditional knowledge and scientific innovations.

CRediT authorship contribution statement

Shasha Sun: Formal analysis, Methodology, Validation, Writing – original draft. Rutendo Betty Jimu: Investigation. Abdillah Khatib Lema: Investigation. Hanaa Elmamoune: Formal analysis, Investigation. Zhiwei Fan: Data curation, Investigation. Chuanshan Jin: Funding acquisition, Methodology. Xiaohui Tong: Conceptualization, Project administration, Writing – review & editing. Rongchun Han: Conceptualization, Supervision, Writing – original draft.