Review Article | Open Access
A Comprehensive Review on Pharmacokinetic Profile of Some Traditional Chinese Medicines
Herbal medicines are the oldest and most widely used form of treatment for welfare of mankind. Herbal medicines possess strong reputation as complementary treatment across the globe due to their easy accessibility and safety. Particularly traditional Chinese medicines (TCM) are very popular due to their desirable therapeutic effects. They already have been proven for their remarkable potential in treatment of wide range of disease ailments. The major drawback in using herbal medicines is lack of standardisation aspects due to the complexity of chemical constituents. Pharmacokinetics study of such medicines helps forecast a range of events related to efficacy, safety, and toxicity profile of them. Apart from this, pharmacokinetics studies also recommended by various regulatory agencies during diverse stages of herbal drug development. Thus it is highly essential to have knowledge about the pharmacokinetic properties of any herbal drug. Thus it was thought that it will be worthwhile to compile the pharmacokinetic data of TCM which will be helpful for the researchers involved in further research on TCM. To portray entire picture about absorption, distribution, metabolism, and excretion (ADME) of some TCM, this well-designed scientific review covers the pharmacokinetic profile of 50 TCM available from 2003 and onwards.
Since time immemorial traditional medicines play pivotal role in welfare of mankind. Ayurveda (India) and traditional Chinese medicine (China) are popular in culture specific clinical practices since thousands of years. These traditional medicines have already achieved unique reliability and reputation outside realm of traditional medicine due to their crucial therapeutic values. These are commonly employed as complementary treatment for various diseases and to maintain the health conditions. Traditional medicine has become a colloquial phrase which commonly points out to herbal medicinal product, phytomedicine, natural products, and botanicals. Traditional medicines have dominated the human pharmacopoeia for thousands of years [1, 2].
Predominantly herbal medicines are massive source of phytochemicals, including various primary and secondary metabolites. The therapeutic values of these herbal medicines are attributed to plethora of active compounds. Therapeutic efficacy of such herbal material is very difficult to interpret due to their multicomponent nature. As they are frequently used in community to strengthen health condition, it is essential to consider their scientific and biomedical scope. Pharmacokinetic data helps to explore the scientific and biomedical scope of such herbal medicines. In accordance with World Health Organization (WHO), the data available for efficacy and safety of herbal medicines was far away to meet for worldwide use . Apart from WHO, it is also of prime importance of regulatory aspects of various countries. Even though sophisticated analytical tools, molecular-biological models, and emerging clinical studies help to reveal the pharmacokinetics of multicomponent medicinal herbs and then also complete evidenced based pharmacokinetics, pharmacodynamics, and metabolisms studies are in paucity. Hence in current state, pharmacokinetic studies have become a fundamental part of drug development process. Pharmacokinetic profile of phytoconstituents serves as substrate for designing dosage form with optimal efficacy and minimal toxicity.
TCM play a greater role in the treatment of many ailments. Although there are numerous research papers that deal with pharmacokinetic properties of different phytoconstituents from TCM there are number of phytoconstituents yet to be scrutinized for their kinetic properties. The aim of the current review is to explore the ADME, pharmacokinetics, tissue distribution, and metabolism of various TCM. Present review offers crucial pharmacokinetic information about 50 medicinal plants of TCM gathered from various reputed electronic search engines from 2003 and onward. In addition, the analytical conditions utilised for the pharmacokinetics are also compiled which will be useful for the researchers to get prelim idea while developing analytical methods for new constituents or repeating the existing methods. The review provides researcher a significant platform to carry out further studies in domain of pharmacokinetics.
2.1. Scutellaria baicalensis Georgi
Roots of Scutellaria baicalensis Georgi (Skullcap) (Lamiaceae) are very well known in TCM for treatment of various disease conditions. Skullcap decoction is commonly used to treat fever. Additionally, skullcap tincture is also used to treat various allergic reactions. Baicalein (5,6,7-trihydroxyflavone) is a flavonoid obtained from skullcap roots. After oral administration it biotransforms to active metabolite, that is, baicalin (7-O-β-glucopyranuronoside). Baicalein shows variety of pharmacological actions that is anti-inflammatory, antifibrotic, antioxidant, and antiviral.
A high performance liquid chromatography (HPLC) system was equipped with mass spectrometer (6110 series, Agilent Technologies, USA) place at selective ion monitoring (SIM) mode. Chromatographic separation was achieved using SB-C18 (2.1 × 50 mm, 2.7 μm, 40°C) Agilent Poroshell 120 column. The mobile phase is composed of water containing 0.1% formic acid and acetonitrile (78 : 22, v/v). The total run time and flow rate were 13 min and 0.3 mL/min, respectively. Luteolin (purity > 98%) was used as internal standard (IS). Lowest limit of quantification (LLOQ) for baicalein and baicalin was 8.0 and 12 ng/mL. The reported pharmacokinetic profile of baicalein and baicalin is given in Table 1. After oral administration of baicalein in monkey it undergoes first-pass metabolism and hence plasma concentration and area under the plasma concentration-time curve (AUC) of baicalin were much higher in comparison to the baicalein at each dose level. After intravenous administration of baicalein is quickly metabolized to baicalin, similar results are seen in rats and human beings. Parent molecule and its metabolite show nonlinear absorption and elimination after oral administration .
2.2. Mangifera indica L
Mangiferin (2-b-D-glucopyranosyl-1,3,6,7-tetrahydroxyxanthone) is a bioactive flavonoid isolated from Mangifera indica L. (Anacardiaceae). It shows antidiabetic, hepatoprotective, antioxidation, antitumor, anti-HIV, immunomodulatory, and anti-inflammatory activities.
HPLC system was composed of single quadrupole mass spectrometer with electrospray ionization (ESI) source in negative ion mode. Chromatographic separation was performed on Waters Symmetry C18 analytical column (250 × 4.6 mm, 5.0 μm, and 40°C.) The isocratic mobile phase is composed of methanol and 0.5% aqueous formic acid (30 : 70, v/v). The elution run time, flow rate, and volume of injection were 10 min, 1.0 mL/min, and 10 μL, respectively. The limit of detection (LOD) and limit of quantitation (LOQ) were found to be 2.0 and 5.0 ng/mL, respectively. The pharmacokinetic parameters after administration of mangiferin to human volunteers are given in Table 2. In present investigation mangiferin exhibits nonlinear pharmacokinetic behavior. It gets absorbed in gastrointestinal tract (GIT) and shows hepatic first-pass metabolism. It is one of the crucial reasons for low bioavailability of mangiferin. To improve health-promoting effects we have to tailored new kinds of dosage forms .
|Compared with 0.1 g group, . Compared with 0.3 g group, .|
2.3. Smilax glabra Roxb
Astilbin is a flavonoid compound isolated Smilax glabra Roxb. (Liliaceae). Astilbin undergoes extensive biotransformation specifically due to enzyme catechol-O-methyl transferase. It gives rise to 3′-O-methylastilbin, a major metabolite of astilbin, which plays important role against the inhibition activated T lymphocytes.
HPLC system was equipped with quadrupole mass spectrometer (LC-MS-2010A, Shimadzu, Japan) with an ESI probe using selective ion monitoring (SIM) mode. Chromatographic separation was achieved on a Shim-pack C18 column (150 × 2.0 mm, 5.0 μm, 40°C, LC-10AD, Shimadzu, Japan). The binary gradient mobile phase consists of 5.0% methanol : 95% water and 95% methanol : 5% water. Both mixtures contain 0.01% formic acid. The flow rate was 0.2 mL/min. Silybin was used as IS. The pharmacokinetic parameters of astilbin and 3′-O-methylastilbin are given in Table 3. The pharmacokinetic data, that is, , indicate that exposure of 3′-O-methylastilbin was slightly lower than that of unchanged drug .
2.4. Erigeron breviscapus (Vaniot)
Erigeron breviscapus (Vaniot) (Compositae) contains scutellarin (scutellarein 7-O-β-D-glucuronide) as major bioactive flavonoid glucuronides in it. Scutellarin is also present in Scutellaria lateriflora, Tripora divaricata, and Teucridium parvifolium. It shows wide range of pharmacological actions ranging from cardiovascular diseases, migraine to memory impairment. Presently scutellarin was used as treatment for platelet aggregation, dilating blood vessels, decreasing the viscosity of blood, and improving microcirculation and also in case of reduced blood platelet count.
A HPLC (Agilent 1100, Wilmington, DE) system was composed of mass spectrometer (Finnigan LCQ, San Jose, CA) with ESI in positive ion mode. Chromatographic separation was achieved using a Diamonsil C18 column (200 × 4.6 mm, 5.0 μm, 25°C, Dikma, Beijing, China) and protected by a 4.0 × 3.0 mm Security Guard C18 (5.0 μm) guard column (Phenomenex, Torrance, CA). The gradient mobile phase was composed of water and methanol; both contain 0.1% formic acid in it. The flow rate was 0.5 mL/min. Baicalin (98.0% purity) was used as IS. The pharmacokinetic parameters of isoscutellarin are given in Table 4. In intestine scutellarin undergoes hydrolysis due to β-glucuronidase, followed by conjugation with glucuronic acid in liver. Scutellarin shows positional selectivity and species variation in conjugation. In human being, 6-OH group was more susceptible for glucuronosyl conjugation in comparison to other 4′-, 5-, and 7-OH groups .
2.5. Ixeris sonchifolia (Bge.) Hance
Traditional Chinese medicine Ixeris sonchifolia (Bge.) Hance (Compositae) is also well known as “Kudiezi.” Kudiezi injection is commonly prescribed for various disease conditions like relieving pain, platelet aggregation, thrombosis, and improving microcirculation. Moreover it is also used in various cardiovascular diseases. The major bioactive flavonoids present in Kudiezi injection are luteolin-7-O-gentiobioside, luteolin-7-O-β-d-glucoside, and luteolin-7-O-β-d-glucuronide.
Ultra-Fast Liquid Chromatography (UFLC, Shimadzu Prominence TM) was composed of AB SCIEX 4000 QTRAP™ mass spectrometer with a turbo ion spray interface in negative ionization mode (Foster City, CA, USA). Chromatographic separation was performed on a C18 column (100 × 2.1 mm, 3.0 μm, 30°C, Venusil MP, Bonna-Agela Technologies, China). The gradient mobile phase was composed of 0.05% formic acid and acetonitrile. The injection volume and flow rate were 5.0 μL and 0.4 mL/min, respectively. Pharmacokinetic parameters of three flavonoids are given in Table 5. The pharmacokinetics data showed that the plasma concentrations of three flavonoids persistently increased during intravenous drip and attained the maximum plasma concentrations around the end time of intravenous drip; then the plasma concentrations decreased quickly. Additionally, three flavonoids were eliminated quickly with the mean elimination half time between 1.10 h and 1.33 h .
2.6. Chrysanthemum morifolium Ramat
The flower of Chrysanthemum morifolium Ramat. (Flos Chrysanthemi) (Asteraceae) is very well known in TCM for various pharmacological actions. It is commonly used as antioxidation, cardiovascular protectant, hepatoprotectant, and being antiarrhythmic and in acute respiratory conditions. Currently, Flos Chrysanthemi extract (FCE) was under clinical investigation for cardiovascular ailments in China. Luteolin (3′,4′,5,7-tetrahydroxy flavone) and apigenin (4′,5,7-trihydroxy flavone) are two major bioactive flavonoids present in FCE. Both are exhibited as anticancer, anti-inflammatory, and neuroprotective also. Chrysoeriol (4′,5,7-trihydroxy-3′-methoxy flavone) and diosmetin (3′,5,7-trihydroxy-4′-methoxy flavone) are the two methylated metabolites of luteolin. Both metabolites are known for anti-inflammatory, antioxidant, and osteoporosis treatment.
HPLC system was equipped with variable wavelength detector (VWD) detector. Chromatographic separation was performed on C18 column (250 × 4.6 mm, 5.0 μm, °C, Zorbax SB, Agilent, USA). The mobile phase was composed of 0.1% formic acid, acetonitrile, and methanol. The flow rate and injection volume were 1.0 mL/min and 50 μL, respectively. The detection wavelength was set at 350 nm. Quercetin was used as IS. The LLOQ of all analytes was 0.025 μg/mL. The pharmacokinetic parameters are given in Table 6. Entacapone shows 1.50 and 1.47-fold improvement in AUC of apigenin and luteolin, respectively. Additionally, it shows approximately 1.40-fold improvement in of apigenin and luteolin, while entacapone shows 1.44- and 1.23-fold depletion in AUC of chrysoeriol and diosmetin, respectively. Entacapone does not show any significant change on mean residence time (MRT) of both bioactive flavonoids .
|Data are expressed as mean SD, ; ; compared with the FCE group.|
2.7. Citrus aurantium L
Naringin, hesperidin, neohesperidin, naringenin, and hesperetin are the major bioactive flavonoids present in the dried, mature fruit of Citrus aurantium L. (Rutaceae), that is, Fructus Aurantii (Zhiqiao). It shows antioxidant, antiviral, antiallergic, vasoprotective, anticarcinogenic, antitumor, antihypertension, and antishock actions.
HPLC (Surveyor TM) was composed of TSQ Quantum triple quadrupole mass spectrometer with ESI in negative ion mode. Chromatographic separation was achieved on a C18 column (150 × 2.1 mm, 5.0 μm, 30°C, Zorbax SB, Agilent, USA) in presence of a C18 guard column (5 μm, Phenomenex, USA). The gradient mobile phase was composed of acetonitrile and water containing 0.1% formic acid. The flow rate and injection volume were 0.3 mL/min and 20 μL, respectively. Liquiritin was used as IS. The pharmacokinetic parameters and LLOQ values are given in Table 7. of naringenin and hesperetin were much superior than those of naringin, hesperidin, and neohesperidin, although the administered doses of aglycones were rather less than those of the glycosides. This trend may be due to the hydrolysis of flavanone glycosides (naringin, hesperidin, and neohesperidin) by gastrointestinal bacteria .
2.8. Kaempferia parviflora
5,7-Dimethoxy flavone (DMF), 5,7,4′-trimethoxy flavone (TMF), and 3,5,7,3′,4′-penta-methoxy flavone (PMF) are the methoxy flavones present in the Kaempferia parviflora (KP) (Zingiberaceae). It shows aphrodisiac, antipeptic ulcer, anti-inflammatory, antiallergenic, antimutagenic, antidepressive, antimicrobial, anticancer, cardioprotective, and antiobesity activity.
Liquid chromatography (LC) system was composed of mass spectrometry (Thermo Fisher Scientific TSQ Quantum) with ESI in positive ion mode. Chromatographic separation was performed on C18 column (2.0 × 50 mm, 5.0 μm, Chromolith, EMD/Millipore, Billerica, MA). The gradient mobile phase was composed of 0.5% formic acid in water and acetonitrile. The flow rate and injection volume were 200 μL/min and 20 μL, respectively. The pharmacokinetic parameters, LOD, LOQ values, and tissue distribution of methoxyflavones are given in Tables 8 and 9, respectively. The oral bioavailability of the methoxyflavones was very low. After oral administration of KP extract methoxyflavones rapidly reached a maximal plasma concentration within 1 to 2 h. After reaching maximum plasma concentration methoxyflavones were extensively distributed to various organs followed by slow elimination. Methoxyflavones mainly excreted via urine. Demethylated glucuronide and sulfide are the metabolites present in the urine. Only demethylated methoxyflavones were found in feces .
|Data are expressed as mean SD (). IV, intravenous. Polyethylene glycol 400: significance higher than the others in the same route at . Significance lower than the others in the same route, . Significance lower than the other route.|
|Data are mean SD (). Significance lower than TMF at . Significance lower than DMF at . Significance lower than that of TMF and DMF at . Significance higher than that of TMF and DMF at .|
2.9. Cirsium japonicum DC
Cirsium japonicum DC. (Compositae) is very well-known perennial herb in China, Japan, and Korea. It is used as being antihemorrhagic, antihypertensive, and antihepatitis agent and as being uretic.
Traditionally, it is used as remedy for epistaxis and metrorrhagia. Additionally, it is also used to improve blood circulation. It contains seven different flavonoids like acacetin, apigenin, diosmetin, hispidulin, linarin, pectolinarin, and pectolinarigenin.
HPLC (1200 series, Agilent Technologies, USA) system was composed of tandem mass spectrometer with a turbo ion spray interface in both positive and negative modes. Chromatographic separation was performed on a C18 column (150 × 4.6 mm, 5.0 μm, 25°C, Diamonsil, DIKMA Company, USA). The gradient mobile phase was composed of methanol and aqueous solution of 0.1% formic acid. The injection volume and flow rate were maintained at 10 μL and 0.8 mL/min, respectively. Pharmacokinetics parameters of seven flavonoids are given in Table 10. Isomer pair of hispidulin and diosmetin does not indicate any significant difference in pharmacokinetic profile. Due to enterohepatic recirculation apigenin shows double-peak phenomenon. After oral administration acacetin, diosmetin, hispidulin, linarin, pectolinarin, and pectolinarigenin exhibited quick plasma concentration followed by tapering .
2.10. Morus alba L
Rutin, isoquercitrin, and astragalin are the three major flavonoids present in Morus alba L. Mulberry is commonly used in China, India, and Japan to treat fever, improve eyesight, and protect liver. It is also shown as antihyperglycemic, antioxidant, neuroprotective, antihypertensive, and antiatherogenic.
Agilent 1200 liquid chromatography system was composed of an API 3200 triple quadrupole mass spectrometer with ESI in negative ionization mode. Chromatographic separation was performed on C18 column (2.1 × 150 mm, 3.5 μm, 30°C, Eclipse Plus, Agilent, USA). The mobile phase was composed of 0.1% formic acid in water and acetonitrile. The flow rate and injection volume were 0.3 mL/min and 10 μL, respectively. Pharmacokinetic parameters of the six flavonoids are given in Table 11. Six phytoconstituents divided in two parts, that is, flavonoid glycosides (rutin, isoquercitrin, and astragalin) and their metabolites (quercetin, kaempferol, and isorhamnetin). Three flavonoid glycosides were rapidly absorbed and eliminated from rat plasma. Double peaks phenomenon was observed for quercetin, kaempferol, and isorhamnetin. AUC of quercetin was much higher than that of the other five compounds .
2.11. Daphne genkwa Sieb. et Zucc
Genkwanin is a flavonoid present in the Chinese plant Daphne genkwa Sieb. et Zucc. (Thymelaeaceae). The roots and buds of Daphne genkwa exhibit various pharmacological actions. It is used as being abortifacient, antitussive, antileukemia, antitumor, diuretic, and expectorant also. Genkwanin is a flavonoids present in plant. It mostly exhibits anticancer, anti-inflammatory, and analgesic effects and it also shows modulatory effects of cellular immune system. It also serves as marker for quality control of Daphne genkwa.
HPLC (1200 series, Agilent Technologies, USA) system was composed of triple quadrupole mass spectrometer (6410 series, Agilent Technologies, USA) with ESI in negative ion mode. The mobile phase was composed of 65% methanol and 35% water containing 5 mM ammonium acetate with 0.1% formic acid. Chromatographic separation was performed on Agela Venusil MP-C18 analytical column (2.1 × 50 mm, 5 μm, 30°C, Agela Technologies Inc.). The flow rate, injection volume, and run time were 0.30 mL/min, 5.0 μL, and 4.0 min, respectively. Genistein (purity > 98%) was used as IS. The LLOQ of genkwanin was found to be 3.84 ng/mL. Pharmacokinetic parameters of genkwanin are given in Table 12. Genkwanin shows efficacy on intravenous administration as compared to oral administration. Low bioavailability (1.10%) of genkwanin was attributed to poor intestinal permeability and rapid first-pass metabolism .
2.12. Juglans mandshurica Maxim
Six flavonoids (myricitrin, quercitrin, taxifolin, myricetin, quercetin, and naringenin), gallic acid, and 5,8-dihydroxy-1,4-naphthoquinone are major bioactive components in Cortex Juglans mandshurica (CJM) extract. CMJ is the bark of Juglans mandshurica Maxim. (JMM) (Juglandaceae). CJM shows various pharmacological actions like antioxidant, antitumor, anti-inflammatory, anti-HIV, and antiparasitic action.
Ultrahigh performance liquid chromatography (UHPLC, ACQUITYTM, Waters Corp., Milford, USA) system was composed of triple quadrupole tandem mass spectrometer (Waters Corp., Milford, USA) with ESI in negative ionization mode. Chromatographic separation was performed on a Venusil ASB C18 column (2.1 × 100 mm, 5.0 μm, 20°C). The gradient mobile phase was composed of acetonitrile and 0.1% formic acid. The flow rate and injection volume were 0.2 mL/min and 20 μL, respectively. The temperature of autosampler was maintained at 4°C. Chloromycetin was used as IS. Pharmacokinetic parameters after oral administrations of Cortex Juglans mandshurica extract and LLOQ values are given in Table 13. The significant difference in pharmacokinetic parameters for each analyte is due to the complex constituents in plant extract, which could induce drug-drug interactions and affect the pharmacokinetic behavior of each substance. Apart from 5,8-dihydroxy-1,4-naphthoquinone, metabolite is also found in rat plasma .
3.1. Gypsophila oldhamiana
Bidesmosidic triterpenoid saponin (BST-1) is the oleanane type saponin present in roots of Gypsophila oldhamiana (Caryophyllaceae). These saponins exhibit anticancer and antidiabetic activities.
LC-2010 instrument (Shimadzu, Japan) was equipped with a UV detector and it was set at 210 nm. Chromatographic separation was performed on C18 column (250 × 4.6 mm, 5.0 μm, 30°C, Welch Materials Inc., USA) and protected by a C18 guard column (7.5 × 4.6 mm). The mobile phase was composed of aqueous formic acid 0.05% and acetonitrile. The flow rate and injection volume are 1.0 mL/min and 20 μL, respectively. The LOD and LLOQ were found to be 0.032 and 0.089 mg/mL, respectively. Glycyrrhizic acid (purity 98.0%) was used as IS. The pharmacokinetic data of BTS-1 is given in Table 14. After oral administration of BTS-1 to rats, it was rapidly absorbed and then eliminated slowly, the elimination involving metabolism to secondary glycosides and aglycones with α-glucosidase inhibitory activity .
3.2. Radix Phytolaccae
Esculentoside A (EsA) is the principal pentacyclic triterpene saponin isolated from the root of Radix Phytolaccae (Phytolacca acinosa Roxb. or Phytolacca americana L.) (Phytolaccaceae). It shows anti-inflammation, antitumor, protective effect on radiation-induced dermatitis, fibrosis, and immunity regulation like activities.
LC-MS/MS system (Thermo Fisher scientific, San Jose, CA, USA) was equipped with EIS in positive ion mode. Chromatographic separation was performed on a Diamonsil C18 analytical column (2.1 × 50 mm, 3.0 μm, 25°C, DIKMA, USA) and protected by a Hypersil Gold C18 guard column (2.1 × 10 mm, 5 μm, Thermo Scientific, USA). The mobile phase was composed of methanol-water containing 0.1% acetic acid (70 : 30, v/v). The flow rate, injection volume, and total analysis time were 0.2 mL/min, 10 μL, and 5.0 min/sample, respectively. The LLOQ was 5.0 ng/mL. The pharmacokinetic parameters after oral administration of EsA are given in Table 15. In 2.5 to 10 mg/kg dose range pharmacokinetic behavior of EsA was found be more linear but on the same line AUC did not increase in direct proportion with administration dosage. The reason behind that is that the blood-taking spots were too dense in the absorption phase .
3.3. Dioscorea zingiberensis C.H. Wright
Total steroid saponins (TSSN) extracted from the rhizomes of Dioscorea zingiberensis C.H. Wright (Dioscoreaceae) are the major potential bioactive constituents. It is commonly used for cough, anthrax, rheumatoid arthritis, and sprain as well as cardiac diseases. TSSN contains five saponins which are protodioscin (A), huangjiangsu A (B), zingiberensis (C), dioscin (D), and gracillin (E).
Liquid chromatography system (2695 serious, Waters, Milford, MA, USA) was composed of a Varian triple quadrupole mass spectrometer (320-MS) with ESI in positive ion interface. Chromatographic separation was performed on Inersil ODS-3 column (250 × 4.6 mm, 5.0 μm, 25°C). The gradient mobile phase was composed of 0.1% formic acid in water and acetonitrile. The sample injection volume was 10 μL. Ginsenoside Rb1 (98% purity) was used as IS. The pharmacokinetic parameters of five steroid saponins are given in Table 16. Single dose and extract administration show the different pharmacokinetic characteristics. Double-peak absorption phenomenon was observed in steroid saponins A and B (furostanol type saponin) while it is absent in reaming three (spirostanol type saponin) steroidal saponins, respectively, due to F ring cleavage and closed F ring. The spirostanol saponins are more stable than furostanol saponins .
3.4. Platycodon grandiflorum
Platycosides are bidesmosidic saponins present in the root of Platycodon grandiflorum (PG), (Campanulaceae). Variety of saponins like platycodins (A, D, D2, and D3), polygalacin D2, platyconic acid A, and platycosides (A, B, C, D, E, and F) are present in it. They show anti-inflammation, antiallergy, antitumor, immune response augmentation, antiobesity, antihyperlipidemia, and treatment of respiratory symptoms also.
Liquid chromatographic (Accela) system was composed of quadrupole tandem mass spectrometer (Thermo Fisher Scientific Inc., Waltham, MA, USA) with ESI in positive ion mode. Chromatographic separation was performed on Sepax Polar-Imidazole HILIC HPLC (100 × 2.1 mm, 3.0 μm, Sepax Technologies, Delaware, USA) column and protected by a C18 guard column (4 × 2 mm, Phenomenex, Torrance, CA, USA). The mobile phase was composed of 0.1% formic acid (2 μM sodium acetate) water/acetonitrile (30 : 70, v/v). The flow rate was 350 μL/min. Notoginsenoside R1 was employed as an IS. The pharmacokinetic parameters of Platycodin D (PD) and Platycodin D3 (PD3) are given in Table 17. PD and PD3 showed remarkable difference in oral bioavailability due to two prime reasons. The first possible reasons were might be the extraction method of PD and PD3 form Platycodon grandiflorum. Second probable reason for the difference in oral absorption of these saponin molecules in vivo was the coexisting ingredients .
|Data are mean SD (standard deviation). Median (ranges).|
3.5. Rhizoma Anemarrhenae
Timosaponins, that is, Timosaponin B-II and Timosaponin A-III (TB-II and TA-III), are main two bioactive steroidal saponin moieties present in Rhizoma Anemarrhenae (Asparagaceae). TB-II and TA-III show various pharmacological actions like anti-inflammatory, antioxidant, improving memory and learning dysfunction and anticancer, and antirespiratory syncytial virus properties, respectively. Rhizoma Anemarrhenae are clinically used with the Phellodendron chinense Schneid. to treat the seminal emission, eczema with itching, febrile diseases with high fever, diabetes due to internal heat, and constipation.
HPLC (Shimadzu Corporation, Japan) system was composed of API4000 triple quadrupole mass spectrometer with a turbo ion spray ionization source (AB SCIEX Instruments, USA) in negative ionization mode. Chromatographic separation was performed on XDB-C8 column (150 × 2.1 mm, 5.0 μm, Agilent, USA) with a Security Guard C18 guard column (4 × 2.0 mm, 35°C, Phenomenex, Torrance, CA, USA). The isocratic mobile phase was composed of acetonitrile (2 mmol/L) and ammonium acetate (55 : 45, v/v). The flow rate, injection volume, and total run time were 0.25 mL/min, 5 μL, and 4.0 min, respectively. The LLOQ of TB-II and TA-III was 3.0 and 0.3 ng/mL, respectively. Ginsenoside Rg2 was used as IS. The pharmacokinetic parameters of TB-II, TA-III and timosaponins-Huangbai alkaloids are given in Tables 18 and 19. Huangbai alkaloids help to improve the absorption of both saponins, that is, TB-II and TA-III. Huangbai alkaloids show approximately 9.0-fold improvement in AUC and of TB-II when administered in 1 : 1 ration, while they exhibit 2.55-, 1.53-, and 1.43-fold improvement in AUC, , and MRT of TA-III, respectively, when administered in 1 : 1 ratio .
| < 0.05 versus oral administration of timosaponins (TB-II 300 mg/kg).|
| < 0.05 versus oral administration of timosaponins (TA-III 1.17 mg/kg).|
3.6. Aralia elata (Miq.) Seem
Aralia-saponin V and Aralia-saponin VI are the two major bioactive triterpenoid saponins present in Aralia elata (Miq.) Seem. (Araliaceae). Root bark and young leaves of plant are used to treat the neurasthenia, rheumatic arthritics, hepatitis virus, and diabetes in Northeast China, Korea, Japan, and Russia.
UHPLC (1290 series, Agilent, Waldbronn, Germany) was composed of a 6430 QQQ-MS mass spectrometer with ESI in negative ion mode. Chromatographic separations were performed on an Agilent SB-C18 column (50 × 2.1 mm, 1.8 μm, 30°C). The isocratic mobile phase was composed of acetonitrile-5 mM ammonium acetate (90 : 10, v/v). The flow rate and injection volume were of 0.2 mL/min and 5.0 μL, respectively. Shengmaxinside C was used as IS. Pharmacokinetic parameters and LLOQ of Aralia-saponin V, Aralia-saponin VI, and extract of A. elata leaves are given in Table 20. Triterpenoid saponins show poor absorption and limited oral bioavailability due to their poor membrane permeability. Extract of A. elata leaves helps to postpone the elimination of Aralia-saponin VI in rat plasma due to which they show approximately 1.50-fold improvement in and .
3.7. Aesculus hippocastanum
Aesculus hippocastanum seeds contain mixture of triterpenic saponins known as escin. Escin Ia is a main bioactive principal present in escin. Escin Ia was also used as marker for seeds of the horse chestnut. It exhibits various pharmacological actions like anti-inflammatory, antidiabetic, anti-ischemic, and gastro protective actions.
Liquid chromatographic separation (1100 series, Agilent Technologies, Palo Alto, CA, USA) was composed of an Applied Biosystems SCIEX API 4000 Mass Spectrometer (Applied Biosystems SCIEX, Ontario, Canada) with an ESI source. Chromatographic separation was performed on HC-C18 column (150 × 4.6 mm, 5.0 μm, 25°C, Agilent Technologies). The gradient mobile phase was composed of 45% purified water containing 45% 10 mM ammonium acetate with 0.05% formic acid and acetonitrile containing 55% methanol (50 : 50). The flow rate was 1.0 mL/min. The pharmacokinetic parameter are given in Tables 21 and 22. Regardless the dose escin Ia was rapidly and extensively isomerized to isoescin Ia. Escin Ia increased significantly with increasing i.v. doses. Volume distribution and clearance exhibit the dose-dependent pharmacokinetic .
3.8. Rhododendron molle G. Don
In Southern China Rhododendron molle G. Don (Ericaceae) was very well recognized as poisonous shrub. Dried flower of this shrub, that is, Rhododendri Mollis Flos (RMF), is traditionally used for rheumatoid arthritis but it is also used associated with cardiotoxicity. Main bioactive principal present in RMF are Rhodojaponins I, II, and III (R-I, II, and III). Both efficacy and toxicity of RMF are attributed to Rhodojaponins.
HPLC (1200 series, Agilent Technologies, Germany) system was composed of quadruple mass spectrometer (SL G1946D, Agilent Technologies, USA) with ESI in negative ion mode. Chromatography separation was achieved on C18 column (Poroshell 120 SB, 75 × 4.6 mm, 2.7 μm) and protected by guard SB-C18 (10 × 4.6 mm, 5 μm) column. The mobile phase was composed of 30% acetonitrile and 70% aqueous formic acid (0.3%). The flow rate and injection volume were 0.8 mL/min and 5.0 μL, respectively. LLOQ of RI, RII, and RIII was 0.041, 0.013, and 0.0084 (μg/mL), respectively. Triptolide was used as IS. Pharmacokinetic parameters after oral administration of RMF extract are given in Table 23. Rhodojaponins exhibit myocardial damage in dose-dependent manner and the biochemical indicator of LDH and CK-MB in plasma might serve as potential markers of RMF induced cardiotoxicity .
4.1. Centella asiatica
Asiatic acid is a triterpenoid component found in Centella asiatica. Asiatic acid could be used for wound healing, various skin conditions, inflammatory, diabetes, hyperlipidemia, also depression, relieving anxiety, and improving cognition.
An Agilent 1100 liquid chromatography system was composed of an Agilent G1946D mass spectrometer (Agilent, USA) with ESI in negative ion mode. Chromatography separation was achieved on C18 column (Waters X bridge, mm2, 3.0 μm, 25°C) and protected by guard column (XDB-C18, mm, 5.0 mm, Agilent, USA). The isocratic mobile phase was composed of acetonitrile and 5 mM aqueous ammonium acetate (50 : 50, v/v). The total analysis time, injection volume, and flow rate were 8.0 min, 5.0 μL, and 0.8 mL/min, respectively. LLOD and LLOQ were 20.50 and 51.25 ng/mL, respectively. Pharmacokinetic parameters of asiatic acid are given in Table 24. Absolute oral bioavailability of asiatic acid in rats was very low. Passive diffusion was the main absorption style of asiatic acid and jejunum is the main absorption region in rats. It can be metabolized rapidly in rat liver microsomes. Additionally, it also has good permeability across Caco-2 monolayer cell and rat intestine perfusion. Low bioavailability of asiatic acid was mainly attributed to poor solubility and rapid metabolism .
4.2. Salvia miltiorrhiza Bunge
Salvia miltiorrhiza Bunge (SMB) (Lamiaceae) is very well known as “danshen” in TCM. There are two type of bioactive compounds in roots of SMB. Former one is hydrophilic phenolic acids, that is, danshensu (DS) and rosmarinic acid (RA), and tanshinone lipophilic compounds, that is, tanshinone I (TI), dihydro-tanshinone I (DT), tanshinone IIA (TS), and cryptotanshinone (CT). It is widely used in treatment of coronary heart diseases and liver diseases. Moreover, it also exhibits anti-inflammatory, antibacterial, and antineoplastic actions.
HPLC (1100 series, Agilent technology, USA) system was composed of ion trap spectrometer using ESI (Thermo Finnigan, San Jose CA, USA) in negative ion mode. Chromatographic separation was performed on a Capcell Pak MG C18 column (100 × 2 mm, 5.0 μm, Shiseido, Japan) protected with a C18 guard column (10 × 2 mm, 5.0 μm, Shiseido, Japan) containing the same packing material. The gradient mobile phase was composed of acetonitrile-water and glacial acetic acid (0.5% (v/v) with pH of 2.5). The run time, flowrate, temperature, and sample injection volume were 13 min, 0.2 mL/min, 25°C, and 10 μL, respectively. The plasma drug concentration-time data determine by two-compartment open model. The pharmacokinetic parameters after a single oral dose of danshen extracts in rat are given in Table 25. After oral administration both phenolic acids and tanshinone lipophilic components showed relatively moderate absorptions, distribution, and elimination. Plasma concentration also exhibits the accumulation of TS which is due to biotransformation of CT to TS .
4.3. Alisma orientale (Sam.) Juz
Alisol A and Alisol B 23-acetate are the two major active triterpenoid compounds isolated from Alisma orientale (Sam.) Juz. (Alismataceae). It is used to treat various diseases, including hyperlipidemia, diabetes, hypertension, and urological diseases.
XR LC 20AD Prominence™ UFLC system was composed of QTRAP 4000 MS/MS system from Applied AB SCIEX with a turbo positive ion spray source (Foster City, CA, USA). Chromatographic separation was performed on a Venusil MP C18 column (100 × 2.1 mm, 3.0 mm, 30°C, China) and protected by a high pressure column prefilter (2.0 mm, Shimadzu, Japan). The gradient mobile phase was composed of 0.1% acetic acid in water and methanol. The flow rate and sample injection volume are 0.4 mL/min and 5.0 mL, respectively. The pharmacokinetic data for Alisol A and Alisol B 23 acetate are given in Table 26. The concentration-time curves showed that Alismatis Rhizoma was rapidly absorbed in blood, and then the concentration decreased slightly and appeared to be a small peak. It shows double-peak phenomenon. Double-peak phenomenon is due to intertransformed of Alisol B to Alisol A or due to enterohepatic circulation .
4.4. Isodi Rubescentis
Herba Isodi Rubescentis is very well-known Chinese remedy for treatment of different ailments, including bacteriostasis, inflammation, and fever and nowadays it is also used to treat the cancers. It is composed of various active components like diterpenoid oridonin, ponicidin, and rosmarinic acid also.
HPLC (Shimadzu, Kyoto, Japan) system was equipped with tandem mass spectrometer (API 4000 QTRAP MDS SCIEX, Applied Biosystems SCIEX, Concord, Canada) with ESI in both modes. The entire analysis process was divided into two periods. Period I was conducted in negative ion mode for rosmarinic acid during the first 2.0 min. Period II was performed in positive ion mode for oridonin and ponicidin in the remaining 3.0 min. Present chromatographic elution was performed over C18 (BDS Hypersil, 2.1 × 100 mm, 2.4 μm, 40°C) column. The mobile phase was composed of water 75% (v/v) containing 5.0 mM ammonium acetate and acetonitrile 25% (v/v) containing 0.5% acetic acid with flow rate of 0.2 mL/min. The injection volume was 5.0 mL. LOD and LOQ were found to be 0.5 and 2.0 ng/mL, respectively. Reported pharmacokinetic profile of these terpenoids is given in Table 27. Diterpenoid oridonin, ponicidin, and rosmarinic acid are poorly water soluble. As we know bioavailability was ultimately attributed to solubility of the compound and hence all three bioactive components exhibit poor bioavailability. Moreover they also show quick metabolism in rat model .