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Open Access   Full Text Article                                                                                                                       Research Article 

In-silico Absorption, Distribution, Metabolism, Elimination and Toxicity profile of Isopulegol from Rosmarinus officinalis

R.V. Kalaimathi1, A. Jeevalatha2, A.N. Basha1, C. Kandeepan1, S. Ramya3, T. Loganathan4, R. Jayakumararaj3

PG & Research Department of Zoology, Arulmigu Palaniandavar College of Arts & Culture, Palani – 624601, TamilNadu, India

Department of Zoology, GTN College, Dindigul, TamilNadu, India

Department of Botany, Government Arts College, Melur – 625106, Madurai, TamilNadu, India

Department of Plant Biology and Plant Biotechnology, LN Government College (Autonomous), Ponneri - 601204, TN, India

Article Info:

________________________________________

Article History:

Received 17 December 2021      

Reviewed 30 December 2021

Accepted 09 January 2022  

Published 15 January 2022  

________________________________________

Cite this article as: 

Kalaimathi RV, Jeevalatha A, Basha AN, Kandeepan C, Ramya S, Loganathan T, Jayakumararaj R, In-silico Absorption, Distribution, Metabolism, Elimination and Toxicity profile of Isopulegol from Rosmarinus officinalis, Journal of Drug Delivery and Therapeutics. 2022; 12(1):102-108

DOI: http://dx.doi.org/10.22270/jddt.v12i1.5188                  ________________________________________

*Address for Correspondence:  

R. Jayakumararaj, Department of Botany, Government Arts College, Melur – 625106, Madurai, TamilNadu, India

Abstract

____________________________________________________________________________________________________

Plant Based Natural Products (PBNPs) have contributed to the development of many drugs for diverse indications. Worldwide interest in use of plants based natural products (PBNPs) has been growing, and its beneficial effects being rediscovered for the development of new drugs. Literature survey on indigenous traditional knowledge bestows ethnopharmacological potentials of PBNPs, which has inspired research in drug discovery; further it provides a baseline for the development of novel drug leads against selected pharmacological targets. Studies report that rosemary essential oil (ROEO) extracts have hepatoprotective, antifungal, insecticide, antioxidant and antibacterial properties. However, their application is limited because of their odor, color and taste. Owing to the widespread applications of phyto-compounds in ROEO - GCMS was performed. GCMS analysis detected 22 compounds of which 6 compounds were in abundant. In the present study, isopulegol - a Prenol Lipid (Monoterpenoid) from Rosmarinus officinalis has been ADMET characterized from biomedical application point of view.

Keywords: Rosmarinus officinalis; Rosemary officinalis Essential Oils (ROEO); Pharmacological Activity; ADMET; GCMS; 

 

 


 

INTRODUCTION 

Rosmarinus officinalis L. (Rosemary) is a medicinal plant native to the Mediterranean region and cultivated around the world1. Besides, therapeutic application, it is commonly used as a condiment and preservative. R. officinalis is contains many bioactive molecules, phyto-compounds, endowed with pharmacological activities, such as anti-aging, anti-inflammatory, antioxidant, antimicrobial, anti-proliferative, antitumor, tumor-protective, tumor-inhibitory and attenuating activities2

Essential oils (EOs) a major group of phytogenic bioactive compounds (PBAC) have been used for variety of purposes over thousands of years. Due to their strong aromatic properties and bioactive nature, EOs has been used in aromatherapy, as flavor and fragrances in cosmetics, foods, and more recently as pharmaceuticals, natural preservatives, additives, and biopesticides3. EOs are concentrated form of liquid mixtures of volatile compounds of plant origin with unique structural chemistry including terpenoid and non-terpenoid hydrocarbons and their oxygenated derivatives, with natural color, odor and flavor, or “essence” of their source - volatile/ odoriferous oil. Essential oils are isolated from various plant components such as leaves, fruit, bark, root, wood, heartwood, gum, balsam, berries, seeds, flowers, twigs, and buds4

Role of PBNPs in drug development has been practiced and well documented since antiquity and recently increasing, not because the bioactive compounds are directly used as therapeutic agents but due to fact that they are used as raw material for drug synthesis, or as a base model for new biologically active compounds due to its GRAS nature5-13. As people are more concerned about the negative effect of synthetic chemicals in food, there is a need to find “GO” products with no or lesser side effects. Therefore, there is a growing interest in using natural extracts as alternatives for synthetic additives because of (a) their synergy with other preservation methods (b) generally regarded as safe, and (c) PBNPs have properties such as antioxidant, antidiabetic, antimutagenic, antitoxigenic and antibacterial. Among the most effective antioxidant constituents of ROEO, cyclic diterpene diphenols, carnosolic acid and carnosol have been identified. In addition, ROEO extract contains carnosic acid, epirosmanol, rosmanol, methylcarnosate and isorosmanol. However, validating and using plants as phyto-pharmaceutical chemistry requires a great deal of basic and applied research, in order to set this resource at the same level of importance of conventional pharmaceutical products14. 

Rosmarinus officinalis L. (Rosemary)

Rosmarinus officinalis L., commonly known as Rosemary, belongs to the family Lamiaceae. Plants - 2 m tall. Bark dark grey, irregularly fissured, exfoliating, young branches densely white stellate-tomentulose. Leaves tufted on branches, sessile to short petiolate; leaf blade 1-2.5 cm × 1-2 mm, leathery, adaxially somewhat shiny, sub-glabrous, abaxially densely white stellate-tomentose, base attenuate, margin entire, revolute, apex obtuse. Calyx ca. 4 mm, densely white stellate tomentose and glandular outside, upper lip sub-circular, teeth of lower lip ovate-triangular. Corolla blue-purple, less than 1 cm, sparsely pubescent outside, tube slightly exserted, apex of upper lip 2-lobed, lobes ovate, middle lobe of lower lip constricted at base into claw, lateral lobes oblong; Fl. Nov15,16

R. officinalis has been traced for its origin from the Mediterranean region. It is an aromatic plant, a unique spice commercially available for use as an antioxidant. ROEO extracts have been used for its hepatoprotective potential17, therapeutic potential for Alzheimer’s disease18, and its antiangiogenic effect19 On the other hand, it is used in food preservation, because they prevent oxidation and microbial contamination20. Therefore, rosemary extract could be useful for replacing or even decreasing synthetic antioxidants in foods. EFSA (European Food Safety Authority) recently, reviewed the safety of rosemary extracts and concluded that there are high-intake estimates ranging from 0.09 (elderly) to 0.81 (children) mg/kg per day.

Foliage is used as a common household culinary spice for flavouring. Main constituents of ROEO are camphor (5.0–21%), 1,8-cineole (15–55%), α-pinene (9.0–26%), borneol (1.5–5.0%), camphene (2.5–12%), β-pinene (2.0–9.0%) and limonene (1.5–5.0%) in proportions that vary according to the vegetative stage and bioclimatic conditions21ROEO composed of phenolic compounds, di and triterpenes and essential oils. In traditional medicine ROEO is used to treat minor wounds, rashes, headache, dyspepsia, circulation problems, and as an expectorant, diuretic and anti-spasmodic in renal colic. In addition to their antioxidant properties, ROEO play a very important role in plant defences against herbivores, pathogens and predators; therefore, used to control infectious agents in humans22.

A Prenol Lipid (Monoterpenoid) isopulegol (ISO) is an alcoholic monoterpene and has been reported to have a number of pharmacological properties. ISO is endowed with several pharmacological properties being reported in literature such as antihyperlipidemic activity, anxiolytic property, gastro-protective, analgesic, anticancer, antidiabetic and an anticonvulsant activity and even as a flavouring agent. Like other terpenes, ISO is a highly volatile compound that is slightly soluble in water, so its inclusion into cyclodextrins (CDs) is an interesting approach to increase its solubility and bioavailability. In the present study, isopulegol - a Prenol Lipid (Monoterpenoid) from Rosmarinus officinalis has been Absorption, Distribution, Metabolism, Elimination and Toxicity characterized from biomedical application point of view.

MATERIALS AND METHODS

Collection of Plant material: Rosmarinus officinalis L. (Rosemary) were collected from Palani Hills, Western Ghats (2000 m above the mean sea level), and identity of the plant was confirmed by Botanical Survey of India, Southern circle, Coimbatore, Tamil Nadu. The collected leaves samples were rinsed with tap water dried and powdered and then stored at 4 °C. Plant extracts preparation 5g of each sample of R. officinalis was extracted with 100 ml of methanol using Soxhlet apparatus. The extract was filtered and methanol was evaporated by rotary evaporator and then stored at 4°C for future use. The methanolic extracts were subjected to chemical tests for the detection of different phytoconstituents using standard procedures. 

Preparation and extraction of sample 

Protocol for preparation of sample was according to the methods previously described by Eleyinmi (2007), but with modifications wrt temperature and duration of drying the sample. Sample was prepared according to the methods previously described by Rašković et al., (2015). 25 g of sample was suspended in 250 mL of distilled water in stoppered flasks and allowed to stand for 24 h, filtered with Whatman No 24 filter paper, concentrated in a rotary evaporator for 12 h at 50°C and dried in vacuum desiccator. Yield was calculated to be 6.06% w/w. Extract was suspended in ethyl acetate and subjected to GC-MS analysis.

GC-MS Analysis 

Phyto-components were identified using GC–MS detection system as previously described Rašković et al., (2015) but with minor modification, whereby portion of the extract was analysed directly by headspace sampling. GC–MS analysis was accomplished using an Agilent 7890A GC system set up with 5975C VL MSD (Agilent Technologies, CA, and USA). Capillary column used was DB-5MS (30 m × 0.25 mm, film thickness of 0.25 μm; J&W Scientific, CA, USA). Temperature program was set as follows: initial temperature 50°C held for 1 min, 5°C per min to 100°C, 9°C per min to 200°C held for 7.89 min, and the total run time was 30 min. The flow rate of helium as a carrier gas was 0.811851 mL/min. MS system was performed in electron ionization (EI) mode with Selected Ion Monitoring (SIM). The ion source temperature and quadruple temperature were set at 230°C and 150°C, respectively. Identification of phyto-components was performed by comparison of their retention times and mass with those of authentic standards spectra using computer searches in NIST 08.L and Wiley 7n.l libraries.

ADMET Prediction

Selected phytocompounds were subjected to ADMET prediction using QikProp (version 4.3, Suite 2015-1; Schrödinger, LLC: New York, NY) and toxicity prediction using TOPKAT (Accelrys, Inc., USA). QikProp develops and employs QSAR/QSPR models using partial least squares, principal component analysis and multiple linear regression to predict physic-chemically significant descriptors (Zhou et al., 2020).

RESULTS AND DISCUSSION 

Chemical properties and identifier

Chemical kingdom

Organic compounds

Superclass

Lipids and lipid-like molecules

Class

Prenol lipids

Subclass

Monoterpenoids

PubChem Identifier

170833

Synonyms

ISOPULEGOL;ALPHA-TERPINEOL;

Canonical SMILES

C[C@@H]1CC[C@H]([C@@H](C1)O)C(=C)C

InChI Key

ZYTMANIQRDEHIO-KXUCPTDWSA-N

GCMS analysis of Rosmarinus officinalis (Rosemary) essential oil

The chemical composition of EOs depends on plant genetics, growth conditions, development stage at harvest, and processes of extracting active compounds. Different parts of the plant (bark, leaf, fruit and seed) have been extensively investigated for their bioactive phytochemical constituents in various plants (Ramya et al., 2012). GC-MS analysis revealed that the extract of Rosmarinus officinalis contained different volatile oils α-Pinene - (C10H16O), RT - 6.94 min, PA - 13.64 %; Camphene - (C10H16), RT - 7.38 min, PA - 2.42 %; β-Myrcene - (C10H16), RT - 8.88 min, PA - 1.19 %; α-Terpinine - (C10H16), RT - 9.70 min, PA - 0.41 %; p-Cymene - (C10H14), RT - 9.98 min, PA - 6.23 %; trans-3-Caren-2-ol - (C10H16O), RT - 10.10 min, PA - 0.20 %; 1,8-Cineole - (C10H18O), RT - 10.38 min, PA - 41.75 %; γ-Terpinene - (C10H16), RT - 11.25 min, PA - 0.59 %; α-Terpinolene - (C10H16), RT - 12.30 min, PA - 0.35 %; Linalool - (C10H18O), RT - 12.78 min, PA - 1.19 %; Isopulegol - (C10H16O), RT - 14.44 min, PA - 13.66 %; Eucalyptol - (C10H18O), RT - 15.21 min, PA - 6.71 %; Terpinen-4-ol - (C10H18O), RT - 15.56 min, PA - 1.24 %; 2-Naphthalenol - (C10H18O), RT - 16.14 min, PA - 6.35 %; (-)-Myrtenol - (C10H16O), RT - 16.27 min, PA - 0.16 %; Verbenone - (C10H14O), RT - 16.67 min, PA - 0.42 %; Terpine - (C12H20O2), RT - 19.42 min, PA - 2.80 %; α-Copaene - (C15H24), RT - 22.49 min, PA - 0.20 %; β-Caryophyllene - (C15H24), RT - 23.92 min, PA - 1.40 %; γ-Cadinene - (C15H24), RT - 27.16 min, PA - 0.34 %; Caryophyllene oxide - (C15H24O), RT - 28.90 min, PA - 0.32 % respectively (Table 1; Fig. 1). 

Physicochemical Properties - Molecular weight (154.25 g/mol); LogP (2.36); LogD (2.32); LogSw (-2.59); Number of stereocenters (3); Stereochemical complexity (0.300); Fsp3 (0.800); Topological polar surface area (20.23 Å2); Number of hydrogen bond donors (1); Number of hydrogen bond acceptors (1); Number of smallest set of smallest rings (SSSR) (1); Size of the biggest system ring (6); Number of rotatable bonds (1); Number of rigid bonds (7); Number of charged groups (0); Total charge of the compound (0); Number of carbon atoms (10); Number of heteroatoms (1); Number of heavy atoms (11); Ratio between the number of non-carbon atoms and the number of carbon atoms (0.1); 

Druggability Properties of Isopulegol - Lipinski's rule of 5 violations was calculated as 0; Veber rule for Isopulegol was predicated as Good; Egan rule for Isopulegol was predicated as Good; Oral PhysChem score (Traffic Lights) was calculated as 0; GSK's 4/400 score for Isopulegol was predicated as Good; Pfizer's 3/75 score for Isopulegol indicated a Warning; Weighted quantitative estimate of drug-likeness (QEDw) score was calculated as 0.576; Solubility was calculated as 11585.15; Solubility Forecast Index for Isopulegol was ascertained as Good.

ADMET Properties - Human Intestinal Absorption (HIA+) had a predicted probability value - 0.989; Blood Brain Barrier (BBB+) had a predicted probability value - 0.887; Caco-2 permeable (Caco2+) had a predicted probability value - 0.819; P-glycoprotein substrate (Substrate) had a predicted probability value - 0.515; P-glycoprotein inhibitor I (Non-inhibitor) had a predicted probability value - 0.692; P-glycoprotein inhibitor II (Non-inhibitor) had a predicted probability value - 0.972.

CYP450 2C9 substrate (Non-substrate) had a predicted probability value - 0.846; CYP450 2D6 substrate (Non-substrate) had a predicted probability value - 0.853; CYP450 3A4 substrate (Substrate) had a predicted probability value - 0.569; CYP450 1A2 inhibitor (Non-inhibitor) had a predicted probability value - 0.808; CYP450 2C9 inhibitor (Non-inhibitor) had a predicted probability value - 0.917; CYP450 2D6 inhibitor (Non-inhibitor) had a predicted probability value - 0.926; CYP450 2C19 inhibitor (Non-inhibitor) had a predicted probability value - 0.856; CYP450 3A4 inhibitor (Non-inhibitor) had a predicted probability value - 0.848; CYP450 inhibitory promiscuity (L-CYP Inhibitory Promiscuity) had a predicted probability value - 0.883.

Ames test (Non AMES toxic) had a predicted probability value - 0.956; Carcinogenicity (Non-carcinogens) had a predicted probability value - 0.891; Biodegradation (Ready biodegradable) had a predicted probability value - 0.553; Rat acute toxicity (1.875 LD50, mol/kg) had a predicted probability value - NA; hERG inhibition (predictor I) (Weak inhibitor) had a predicted probability value - 0.655; hERG inhibition (predictor II) (Non-inhibitor) had a predicted probability value - 0.837.

Mutagenic property of Isopulegol was none; Tumorigenic property of Isopulegol was none; Irritant property of Isopulegol was none; Effect on reproduction of Isopulegol was none; Drug Likeliness of Isopulegol towards Drugability/ Drug Score was calculated as -21.93; Drugability Score of Isopulegol towards Drugability/ Drug Score was calculated as 0.46 respectively. 

Sienkiewicz et al. (2013) reported that rosemary essential oil contains mainly 1,8-cineole (46.4%), camphor (11.4%) and α-pinene (11.0%). The composition of the rosemary essential oil used by Jiang et al. (2011), was composed mainly by 1,8-cineole (26.54%) and α-pinene (20.14%) Table 2. Biological activities of these secondary metabolites of R. officinalis have been reported for its antitumor, antioxidant, anti-infectious, anti-inflammatory, and analgesic activities and effects on the central nervous system, endocrine system, disorders such ascardiac remodeling after myocardial infarction, body weight changes, dyslipidemia, cerebral ischemia, hepato-nephrotoxicity, stress, and anxiety. Anti-inflammatory activity of rosemary has been attributed to the presence and synergistic activity of carnosol and carnosic, rosmarinic, ursolic, oleanolic, and micromeric acids20.  Specifically, anti-inflammatory activity has been attributed to synergic effects of ursolic and micromeric acids present in ROEO. These natural drugs can be proposed for preclinical and clinical studies in different diseases and pathological conditions.

CONCLUSION 

Rosemary contains a large variety of bioactive molecules with great therapeutic potential such as triterpenes (e.g., ursolic and oleanolic acid), tricyclic diterpenes (e.g., carnosic acid and carnosol), phenolic acids (e.g., caffeic acid and rosmarinic acid), and essential oils. These secondary metabolites have been formulated in topical dosages. ROEO has anti-inflammatory, antimicrobial, and antioxidant properties, which have been extensively reported in oral formulations. However, development of new formulations containing other less common ROEO extracts is warranted through trials to evaluate and establish the potentials of pharmacologically active phyto-compounds towards safety and efficacy, in treating various pathological conditions.

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image

Fig. 1 GCMS analysis of Rosmarinus officinalis (Rosemary) essential oil

 

Table 1 GCMS profile of Rosmarinus officinalis (Rosemary) essential oil

S.No

Compound

Molecular Formula

Retention Time (min)

Percentage (%)

  1.  

α-Pinene 

C10H16O

6.94

13.64

  1.  

Camphene 

C10H16

7.38

2.42

  1.  

β-Myrcene 

C10H16

8.88

1.19

  1.  

α-Terpinine 

C10H16

9.70

0.41

  1.  

p-Cymene 

C10H14

9.98

6.23

  1.  

trans-3-Caren-2-ol 

C10H16O

10.10

0.20

  1.  

1,8-Cineole 

C10H18O

10.38

41.75

  1.  

γ-Terpinene 

C10H16

11.25

0.59

  1.  

α-Terpinolene 

C10H16

12.30

0.35

  1.  

Linalool 

C10H18O

12.78

1.19

  1.  

Isopulegol

C10H16O

14.44

13.66

  1.  

Eucalyptol

C10H18O

15.21

6.71

  1.  

Terpinen-4-ol 

C10H18O

15.56

1.24

  1.  

2-Naphthalenol 

C10H18O

16.14

6.35

  1.  

(-)-Myrtenol 

C10H16O

16.27

0.16

  1.  

Verbenone 

C10H14O

16.67

0.42

  1.  

Terpine

C12H20O2

19.42

2.80

  1.  

α-Copaene 

C15H24

22.49

0.20

  1.  

β-Caryophyllene 

C15H24

23.92

1.40

  1.  

γ-Cadinene 

C15H24

27.16

0.34

  1.  

Caryophyllene oxide 

C15H24O

28.90

0.32

 

 

 

 

 

 

Table 2 Physicochemical, Druggability, ADMETox properties of Isopulegol

Physicochemical Properties of Isopulegol

Value

Molecular weight

154.25 g/mol

LogP

2.36

LogD

2.32

LogSw

-2.59

Number of stereocenters

3

Stereochemical complexity

0.300

Fsp3

0.800

Topological polar surface area

20.23 Å2

Number of hydrogen bond donors

1

Number of hydrogen bond acceptors

1

Number of smallest set of smallest rings (SSSR)

1

Size of the biggest system ring

6

Number of rotatable bonds

1

Number of rigid bonds

7

Number of charged groups

0

Total charge of the compound

0

Number of carbon atoms

10

Number of heteroatoms

1

Number of heavy atoms

11

Ratio between the number of non-carbon atoms and the number of carbon atoms

0.1

Druggability Properties of Isopulegol

 

Lipinski's rule of 5 violations

0

Veber rule

Good

Egan rule

Good

Oral PhysChem score (Traffic Lights)

0

GSK's 4/400 score

Good

Pfizer's 3/75 score

Warning

Weighted quantitative estimate of drug-likeness (QEDw) score

0.576

Solubility

11585.15

Solubility Forecast Index

Good 

ADMET Properties of Isopulegol

Property

Value

Probability

Human Intestinal Absorption

HIA+

0.989

Blood Brain Barrier

BBB+

0.887

Caco-2 permeable

Caco2+

0.819

P-glycoprotein substrate

Substrate

0.515

P-glycoprotein inhibitor I

Non-inhibitor

0.692

P-glycoprotein inhibitor II

Non-inhibitor

0.972

CYP450 2C9 substrate

Non-substrate

0.846

CYP450 2D6 substrate

Non-substrate

0.853

CYP450 3A4 substrate

Substrate

0.569

CYP450 1A2 inhibitor

Non-inhibitor

0.808

CYP450 2C9 inhibitor

Non-inhibitor

0.917

CYP450 2D6 inhibitor

Non-inhibitor

0.926

CYP450 2C19 inhibitor

Non-inhibitor

0.856

CYP450 3A4 inhibitor

Non-inhibitor

0.848

CYP450 inhibitory promiscuity

L-CYP Inhibitory Promiscuity

0.883

Ames test

Non AMES toxic

0.956

Carcinogenicity

Non-carcinogens

0.891

Biodegradation

Ready biodegradable

0.553

Rat acute toxicity

1.875 LD50, mol/kg

NA

hERG inhibition (predictor I)

Weak inhibitor

0.655

hERG inhibition (predictor II)

Non-inhibitor

0.837

Toxicity Risk of Isopulegol towards Drugability/ Drug Score

 

Mutagenic property

None

Tumorigenic property

None

Irritant property

None

Effect on reproduction

None

Drug Likeliness

-21.93

Drugability Score

0.46

NOTE: Physicochemical properties: FAF-Drugs4/ RDKit open-source cheminformatics platform. Druggability properties were computed using FAF-Drugs4/ FAF-QED open source platform. ADMET properties were predicted admetSAR open-source tool