Skip to main content

Effect of Andrographis paniculata extract and Andrographolide on the pharmacokinetics of Aceclofenac and Celecoxib in rats



In India, for the treatment of cold, fever and inflammation, people consume herbal remedies containing Andrographis paniculata Nees (APE) as main ingredient, along with NSAIDs. So the purpose of this study is to investigate the effect of APE and pure andrographolide (AN) on the pharmacokinetic of with aceclofenac (ACF) and celecoxib (CXB) after oral co-administration in wistar rats. After co-administration of APE (equivalent to 20 mg/kg of AN) and AN (20 mg/kg) with ACF (5 mg/kg) and CXB (5 mg/kg) in rats, orally, drug concentrations in plasma were determined using HPLC method. Non-compartment model was used to calculate pharmacokinetic parameters like Cmax, Tmax, t1/2, MRT, Vd, CL, and AUC.


Co-administration of ACF and CXB with APE and pure AN altered the systemic exposure level of each compound in vivo. The Cmax, Tmax, MRT of CXB were increased whereas Vd and Cl of CXB were decreased significantly after co-administration of CXB with APE. Whereas co-administration of CXB with AN significantly decreased Vd, CL, and MRT of CXB. The concentration of ACF was increased significantly in co-administered groups with pure AN and APE. The AUC0-∞, AUMC0-∞, MRT, Vd and t1/2 of ACF were also significantly decreased in co-administered groups, hence CL of ACF was increased significantly.


This study concludes that APE and pure AN have effect on pharmacokinetic of CXB and ACF in rat. Not only patients but medical practitioners using Andrographis paniculata should have awareness regarding probable herb–drug interactions with ACF and CXB.


Aceclofenac is a phenylacetic acid derivative nonsteroidal anti-inflammatory drug (NSAID). It is a potent inhibitor of cyclooxygenase and possesses anti-inflammatory and analgesic properties [1]. Celecoxib is an effective COX 2 inhibitor NSAID and act as analgesic. It is also found to be effective in the management of wide range of painful conditions [2]. Andrographis paniculata Nees is a herb in South Asian countries used traditionally for the treatment of cold and fever, sore throat, snake bite, and COVID 19 [3,4,5,6]. Andrographolide, a key component of Andrographis paniculata Nees extract (APE), has been researched on a cellular level and has been shown to have anti-inflammatory, antioxidant, and anti-cancer activities [7]. In India, people frequently consume NSAIDs and herbal treatments with APE as the primary ingredient to cure colds, fevers, and inflammation [8,9,10,11].

Several bioanalytical methods have been developed for the determination of ACF and CXB in rats and humans [12,13,14,15]. Herb–drug interaction studies of CXB with Ojeok-san, and Genistein have been reported [16, 17]. Bioanalytical methods are available for the determination of andrographolide alone and in combination with other drugs [18, 19]. Theophylline, warfarin, ibuprofen, etoricoxib, nabumetone, and naproxen interactions with APE alone and with AN have been studied before [20,21,22,23,24].

In this study, two new validated HPLC methods for simultaneous determination of AN with ACF and CXB in rat plasma has been developed and applied it in pharmacokinetic study in rats. The aim of the study was to explore the herb–drug interactions of APE and pure AN with ACF and CXB by studying their pharmacokinetic profiles in rats.


Chemicals and reagents

Celecoxib (CXB) and aceclofenac (ACF) were received as generous gifts from Cipla Pharmaceutical Pvt. Ltd. Mumbai and Jain Pharmaceutical Pvt. Ltd. Pune, Maharashtra, India. Dexketoprofen trometamol (DKT) and Mefenamic acid (MA) were obtained as generous gifts from Sun Pharmaceuticals Pvt. Ltd. Mumbai and Alkem Laboratories Pvt. Ltd. Mumbai, Maharashtra, India. Andrographolide pure (AN) was purchaased by Research Organic Pvt. Ltd, Chennai (Purity 98%). Andrographis paniculata Nees extract (APE) was procured by Natural Remedies Pvt. Ltd, Bangalore (Batch No. FAPEX/2013110012). All chemicals and reagents were of analytical grade and purchased from Merck Chemicals, Mumbai, Maharashtra, India. High purity deionized water was obtained from Millipore, Milli-Q (Bedford, MA, USA) water purification system.


Male Wistar rats weighing 200–280 g were purchased from the National Institute of Biological Sciences. All animals were maintained at controlled room temperature (25 ± 2 ◦C) and humidity (60–70%) with day/night cycle (12 h/12 h). Animals were acclimated to food and water ad libitum 7 days prior to dosing. All experiments were performed as per the guidelines of CPCSEA after obtaining approval (1701/PO1C/12/CPCSEA & 1702/PO1C/12/CPCSEA) from the Institutional Animal Ethics Committee.

In vivo pharmacokinetic study in rats

Drug administration and blood sampling

Animals were divided in three subgroups for both the studies as given in the Table 1. Acute toxicity studies for andrographolide were previously reported. The previous data and pilot studies were considered before finalizing the dose [25, 26]. Blood samples were collected at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72 and 96 h after drug administration, for CXB and at 0.08, 0.17, 0.33, 0.50, 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 10 h for ACF. Blood samples were collected by retro-orbital plexus under light ether anesthesia. The samples were transferred to EDTA tubes and centrifuged at 15,000 rpm for 20 min. Plasma was separated from blood and stored at − 80 ◦C until further analysis.

Table 1 Details of animal groups and dose for CXB and ACF

Sample preparation

To 450 μl of drug-free plasma, 10 μl each of AN (100 μg/ml) and CXB (100 μg/ml) solutions were added. To this, 50 μl of internal standard DKT (250 µg/ml) and 50 μl of 1% formic acid solution was added and vortexed for 2 min. After adding 2 ml of ethyl acetate, it was vortexed for 2 min. After centrifugation at 20,000 rpm for 20 min at 4 °C, the supernatant was separated, the solvent was evaporated and dried at 35 °C under a gentle stream of nitrogen gas. Reconstituted by adding 200 µl mobile phase and 20 µl aliquots were injected onto the HPLC system for analysis. The quality control (QC) samples were also prepared in the same manner at concentrations of 10, 200, 800 and 1000 µg/ml. Similarly, ACF samples were prepared with Diclofenac as I.S. at concentrations of 100, 450 and 900 µg/ml.

HPLC analysis

The HPLC analysis was performed using a Jasco PU-2080 gradient liquid chromatography instrument, with an autosampler and a UV detector UV-2075 with a Thermo Hypersil ODS column (250 × 4 mm, 5 μm). Mobile phase for CXB consisted of the mixture of solvent A acetonitrile, solvent B methanol and solvent C water, pH adjusted to 3 with ortho phosphoric acid (50: 10: 40v/v/v) for 15 min at a flow rate of 1 mL/min. The detection was performed with a UV detector at a wavelength of 254 nm. The CXB and I.S. were detected at 9.25 ± 1 and 5.40 ± 1 min respectively.

For ACF, mobile phase consisted of the mixture of solvent A acetonitrile, solvent B 0.025 M potassium dihydrogen phosphate buffer (pH 3.5) in the ratio of 55: 45(V/V), for 15 min at a flow rate of 1 mL/min. The detection was performed with a UV detector at a wavelength of 254 nm. The ACF, DCF, and MA were detected at 7.008 ± 1 min, 8.758 ± 1 min, and 11.908 ± 1 min, respectively.

Method validation

Method validation was executed as per the Food and Drug Administration (FDA) guidelines for quality control samples (QCs), selectivity and specificity, sensitivity, accuracy, precision, recovery, and stability of the analyte in the matrix [27]. Selectivity was checked by comparing blank plasma from six rats to the spiked plasma samples. Analysis of calibration standards was completed twice on three consecutive days. Calibration curve was generated by means of the peak area ratio of analyte to IS versus analyte concentration. A 1/x2 weighted linear least-squares regression model used for the calibration curve. A signal-to-noise ratio of at least 10:1 is used to calculate the limit of quantitation (LLOQ). Accuracy and precision was checked by analyzing six replicates of the QC samples at three concentrations on three successive days and relative error (RE) and relative standard deviation (RSD) were calculated. Precision limits were ≤ 20% for LLOQ and ≤ 15% for QC samples. Accuracy was found to be within ± 20% for the LLOQ and ± 15% for the QC samples. Recovery study was performed at the three levels of QC samples (n = 3). Matrix effects were determined by comparing the average response of the extracted analytes with the average response of the unextracted samples. The stability of CXB and ACF was carried out at three levels of QC samples (n = 6) in various conditions. Short-term stability was determined after storing the samples at room temperature for 2 h. Freeze–thaw stability was checked in triplicate from − 20 to 25 °C. Long term stability was performed by keeping the plasma samples at − 20 °C for 14 days.

Data analysis

The plasma drug concentration versus time plot was determined by a non-compartment model using WinNonlin software (Pharsight Corporation, Mountain View, CA, USA). The highest plasma concentration Cmax and Tmax were finalized directly from the independent plasma concentration–time data. The area under the curve (AUC0-t) was estimated with the linear trapezoidal rule, by extrapolating to infinity (AUC0-∞) from the last concentration detected using the elimination rate constant (ke) calculated by linear regression of the drug concentration–time curve. Apparent elimination half-life (t1/2) was determined from t1/2 = 0.693/ke, total body clearance (Cl) as dose/AUC0-∞, and apparent volume of distribution (Vd) as Cl/ke. One-way ANOVA (Bonferroni post-test) was applied to the results and significant differences were considered at *P < 0.05, **P < 0.01, ***P < 0.001.


Method development

For CXB and ACF, the representative HPLC chromatograms of plasma samples and I.S. are shown in Figs. 1 and 2 respectively.

Fig. 1
figure 1

Chromatogram of A blank plasma sample B blank plasma sample with DKT (IS) C plasma sample spiked with I. S. DKT (10 µg/ml) and CXB (10 µg/ml) D a plasma sample obtained from rat at 1.5 h after oral administration of CXB

Fig. 2
figure 2

Chromatogram of A blank plasma sample B blank plasma sample with MA (IS) C plasma sample spiked with I. S. MA (10 µg/ml) and ACF (10 µg/ml) D a plasma sample obtained from rat at 1.5 h after oral administration of ACF

Method validation

The linear response of the peak ratios versus concentrations was recorded over the plasma concentration range of 5–1000 ng/mL for CXB and 50–900 ng/mL for ACF. Calibration curve equation of the of CXB was y = 0.002x − 0.005 with correlation coefficient (r2 = 0.9988) and for ACF, y = 0.002460 ± 0.00003435 with correlation coefficient (r2 = 0.9987). Intra and inter batch precisions were in limit (R.S.D. ˂ 15%) and accuracy was in between 85 and 115%.

The LLOQs of CXB and ACF in rat plasma were 1 ng/mL and 50 ng/mL respectively. The intra- and inter-day precision and accuracy data for the QC samples is given in Table 2. The intra and inter-day precision for CXB was less than 2.36% and for ACF was less than 3.42, while accuracy was within ± 2.23% and ± 3.42 for CXB and ACF respectively. The matrix effect was in-between 94.12 and 97.15% for CXB and 90.25 to 94.03% for ACF at three levels of QC samples (Table 3). The matrix effect of IS was 95.97% and 91.38% for CXB and ACF respectively. The results showed that suppression or enhancement of ions by the plasma matrix was not significant under the conditions specified. The recoveries were from 1.27 to 8.90% for CXB and from 0.36 to 2.56% for ACF (Table 3). The recovery of IS of CXB at 400 ng/mL was 386.4 ± 9.37% and of ACF at 200 ng/mL was 195.5 ± 2.57%. Degradation of CXB and ACF was not significant during the 2 h, and 24 h storage at room temperature, three freeze–thaw cycles, or 14 day storage at − 70 °C. The responses varied less than 1.2% for CXB and less than 3.67% for ACF at each concentration (Table 4).

Table 2 Accuracy and precision for the analysis of CXB in rat plasma (n = 3 days, six replicates per day)
Table 3 Recovery and matrix effect of CXB and IS in rat plasma (n = 6)
Table 4 Stability studies for the determination of CXB (n = 5)

Pharmacokinetic herb–drug interaction study

For celecoxib—The plasma concentration–time plots of CXB and ACF after oral administration with or without AN and APE are shown in Fig. 3. During the studies after 24 h, significant conc. of CXB was found in the blood plasma. Hence the blood sample collection for CXB was extended up to 96 h. It increased elimination half-life of CXB which indicates plasma protein binding of CXB and should be studied further [28, 29]. The pharmacokinetic parameters of CXB after the pretreatment of rats with AN for continuous seven days reduced (P > 0.05) the Cmax of CXB, further when the rats were pretreated with APE at a daily dose equivalent to AN for continuous seven days resulted in a significant increase (P < 0.001) in Cmax of CXB. The Cmax of CXB decreased with AN pretreatment was 2.67 μg/mL and with APE pretreatment it was significantly increased to 3.40 μg/mL when compared to the control group 2.97 μg/mL. The Tmax after oral administration with AN (P < 0.001) was 4 h and APE was 6 h (P < 0.001). The elimination half-life of CXB did not show any significant effect after the pretreatment with AN and APE, but a significantly reduced to 28.89 (P < 0.001) and 30.57 (P < 0.001) in total clearance of CXB resulted following the pretreatment with APE and AN compared to control group. The mean residence time (MRT) of CXB after oral administration of AN significantly decreased to 5.97 (P < 0.001) and APE to 6.14 (P > 0.05) when compared to the control group (Table 5).

Fig. 3
figure 3

Mean plasma concentration versus time plot for CXB and ACF

Table 5 Summary of pharmacokinetic data of CXB and ACF in all three groups

For ACF, pretreatment of rats with AN and APE for continuous seven days resulted in a significant increase (P < 0.001) in Cmax of ACF. Cmax of ACF increased to 5.91 μg/ml in AN co-administered group and 6.79 μg/ml in APE co-administered group from 3.86 μg/ml in ACF alone administered group. The increase in the Cmax was found to be more with APE co-administered group compared to AN co-administered group. Tmax was significantly decreased in both AN co-administered group at 0.08 h and in APE co-administered group at 0.17 h compared to ACF alone administered group at 0.33 h. Significant decrease (P < 0.001) in AUC0-t, AUC0-∞, AUMC0-t and AUMC0-∞ of ACF in AN and APE co-administered groups was observed. AN and APE co-administered groups showed a significant decrease (P < 0.001) in Vd, MRT0-t, MRT0-∞ and t1/2 compared to ACF alone administered group.


AN is one of the active constituents of the APE. APE and AN have anti-inflammatory properties and used in cold, fever and anti-inflammatory treatment. In India, people for the treatment of cold, fever, and arthritis, commonly consume herbal formulations containing APE as the main ingredient, along with NSAID drugs such as ACF and CXB. As per literature, AN has CYP1A and CYP2B inducer activity while APE has CYP1A inhibitory activity [30, 31]. CXB is largely metabolized by CYP2C9 in humans and also by CYP1A1, CYP1A2, CYP2B1, and CYP2B2 to a lesser extent [32, 33]. As CYP2C9 is not present in rats, the possible pathway of metabolism of CXB in rats may be through CYP1A1, CYP1A2, CYP2B1 and CYP2B2. ACF has been shown to be metabolized by different mechanisms in rats and humans. In human, ACF is converted into 4’-hydroxy aceclofenac through CYP2C9 enzyme by oxidation, but only traces of DCF was detected in previous studies. Whereas in the rat plasma CYP2C9 is absent and hence 4’-hydroxy aceclofenac is not detected [34, 35]. Instead, in rats, ACF after oral administration reaches the liver via the portal vein and is rapidly hydrolyzed to DCF by hepatic esterases. From the previous studies, it is evident that several CYP450 chemical inhibitors have the potential to inhibit liver microsomal esterase enzyme activity [36]. CYP450 1A inducers also suppress the carboxylesterase [37]. The hypothesis for the study was any substance influencing the CYP1A2 enzyme is likely to affect the metabolism of ACF and CXB [20]. To decrease the probability of herb–drug interaction, studies on pharmacokinetic effects on co-administration of AN and APE with ACF and CXB would be helpful.

In ACF study, it can be assumed that significant changes in the pharmacokinetic parameters of ACF may be due to the interference in the activity of esterase enzyme through CYP1A induction and CYP2C11 inhibition activity of AN and APE which needs to be confirmed. However, the appearance of DCF in both AN and APE co-administered groups clearly confirmed the conversion of ACF to DCF due to esterase enzymes. But from the AUC0-∞ the ratio of ACF and DCF which was found to be 61.36%, 45.47%, and 49.75% for groups ACF alone, AN and APE co-administered groups respectively it is evident that AN and APE reduced the conversion of ACF to DCF, and hence this reduction may be correlated with either by partial inhibition or reduction in activity of esterase enzymes although there is no direct evidence. The reduction in Vd of ACF leads to another assumption that AN and APE might have occupied the distribution sites of ACF thus the increase in Cmax and Cl. Hence ACF is eliminated faster and it might have not been available for further conversion into DCF. These assumptions however need to be confirmed.


New, simple, sensitive validated HPLC methods were developed for the quantification of CXB and ACF in rat plasma and applied in pharmacokinetic herb–drug interaction study of CXB and ACF with AN and APE. In CXB pharmacokinetic study, an increase in Cmax and Tmax of CXB was observed. A significant effect was observed on the elimination of the drug, Cl was reduced and t1/2, MRT was increased. ACF pharmacokinetic results showed that the concentration of ACF was increased significantly in co-administered groups with pure AN and APE. The AUC0-∞, AUMC0-∞, MRT, Vd, and t1/2 of ACF were also significantly decreased in co-administered groups, hence Cl of ACF was increased significantly. AN and APE decreased the AUC0-∞ and increased Vd and Cl of the DCF. The results showed that APE affected the pharmacokinetics of CXB and ACF. Administration of APE along with CXB might result in an increase in the bioavailability of CXB and can lead to toxicity. Further studies should be done to understand the mechanism, the effect of other herbal ingredients of APE on CXB and to predict the interaction in humans. The changes in pharmacokinetic parameters of ACF may be due to the interference of partial inhibition in the activity of esterase enzyme through CYP1A induction and CYP2C11 inhibition activity of AN and APE which needs to be confirmed. In addition, AN and APE might have occupied the distribution sites of ACF, thus ACF is eliminated faster and it might have not been available for further conversion into DCF.

The study concludes that AN and APE have definite interactions with the pharmacokinetics of CXB & ACF. Co-administration of APE or AN may lead to a reduction in the potency of CXB & ACF and hence pharmacodynamic study will be more helpful for further understanding. The study provides a base for the rational use of APE in the management of cold, fever and, inflammation along with CXB and ACF. Patients and medical practitioners using AP should have awareness about its herb–drug interaction with CXB and ACF.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author, upon reasonable request.



Andrographis Paniculata Nees




Andrographis Paniculata Nees Extract






Nonsteroidal Anti-inflammatory Drug


Dexketoprofen trometamol


Mefenamic acid


High Performance Liquid Chromatography


Committee for the Purpose of Control and Supervision of Experiments on Animals

p.o . :



Ethylenediaminetetraacetic acid


Quality control


Internal Standard


Relative standard deviation


The area under the concentration–time curve




Elimination rate constant




Maximum serum concentration


Time to maximum concentration


Mean residence time


Volume of distribution


Area under the first moment curve


Analysis of variance


  1. Iolascon G, Gimenez S, Mogyorosi D (2021) A review of aceclofenac: analgesic and anti-inflammatory effects on musculoskeletal disorders. J Pain Res 14:3651–3663

    Article  CAS  Google Scholar 

  2. Chen J, Zhu W, Zhang Z, Zhu L, Zhang W, Du Y (2015) Efficacy of celecoxib for acute pain management following total hip arthroplasty in elderly patient: a prospective, randomized, placebo-control trial. Exp Ther Med 10:737–742

    Article  Google Scholar 

  3. Hu X, Wu R, Logue M, Blondel C, Yuen L et al (2017) Andrographis paniculata (Chuān Xīn LiaÂn) for symptomatic relief of acute respiratory tract infections in adults and children: A systematic review and meta-analysis. PLoS ONE.

    Article  Google Scholar 

  4. Cheepsattayakorn A, Cheepsattayakorn R (2020) Andrographis paniculata (Green chiretta) may combat COVID-19. J Lung Pulm Respir Res 7:26.

    Article  Google Scholar 

  5. Zhang X, Zhang X, Wang X, Zhao M (2018) Influence of andrographolide on the pharmacokinetics of warfarin in rats. Pharm Biol 56:351–356

    Article  CAS  Google Scholar 

  6. Zeng B, Wei A, Zhou Q, Yuan M, Lei K, Liu Y, Song J, Guo L, Ye Q (2021) Andrographolide: a review of its pharmacology, pharmacokinetics, toxicity and clinical trials and pharmaceutical researches. Phytother Res 36:336–364

    Article  Google Scholar 

  7. Burgos RA, Alarcon P, Quiroga J, Manosalva C, Hancke J (2021) Andrographolide, an anti-inflammatory multitarget drug: all roads lead to cellular metabolism. Molecules 26:1–17

    Google Scholar 

  8. Jarukamjorn K, Nemoto N (2008) Pharmacological aspects of Andrographis paniculata on health and its major diterpenoid constituent andrographolide. J Health Sci 54:370–381

    Article  CAS  Google Scholar 

  9. Ooi JP, Kuroyanagi M, Sulaiman SF, Muhammad TST, Tan ML (2011) Andrographolide and 14-Deoxy-11, 12-Didehydroandrographolide inhibits cytochrome P450s in HepG2 hepatoma cells. Life Sci 88:447–454

    Article  CAS  Google Scholar 

  10. Qui F, Hou XL, Takahashi K, Chen LX, Azuma J, Kang N (2012) Andrographolide inhibits the expression and metabolic activity of cytochrome P4503A4 in the modified Caco-2 cells. J Ethnopharmacol 141:709–713

    Article  Google Scholar 

  11. Dhiman A, Goyal J, Sharma K, Nanda A, Dhiman S (2012) A review on medicinal prospective of Andrographis paniculata Nees. J Pharm Sci Innov 1:1–4

    CAS  Google Scholar 

  12. Paulson SK, Zhang JY, Breau AP, Hribar JD, Liu NWK, Jessen SM, Lawal YM, Cogburn JN, Gresk CJ, Markos CS, Maziasz TJ, Schoenhard GL, Burton EG (2000) Pharmacokinetics, tissue distribution, metabolism, and excretion of celecoxib in rats. Drug Metab Dispos 28:514–521

    CAS  Google Scholar 

  13. Josa M, Urizar J, Rapado P, Itez J, Castaneda-Hernandez CD, Flores-Murrieta G, Renedo F, Maco J, Troconiz IF (2001) Pharmacokinetic/pharmacodynamic modeling of antipyretic and anti-inflammatory effects of naproxen in the rat. J Pharmacol Exp Ther 297:198–205

    CAS  Google Scholar 

  14. Aresta A, Palmisano F, Zambonin CG (2005) Determination of naproxen in human urine by solid-phase microextraction coupled to liquid chromatography. J Pharm Biomed Anal 39:643–647

    Article  CAS  Google Scholar 

  15. Dhondt L, Devreese M, Croubels S, Baere SD, Haesendonck R, Goessens T, Gehring R, Backer PD, Antonissen G (2017) Comparative population pharmacokinetics and absolute oral bioavailability of COX-2 selective inhibitors celecoxib, mavacoxib and meloxicam in cockatiels (Nymphicus hollandicus). Sci Rep 7:12043.

    Article  CAS  Google Scholar 

  16. Zheng X, Wen J, Liu T, Ou-yang Q, Cai J and Zhou H (2017) Genistein exposure interferes with pharmacokinetics of celecoxib in SD male rats by UPLC-MS/MS. Biochem Res Int.

  17. Park S, Park J, Park M, Yim S, Kim B (2018) Effects of Ojeok-san on the pharmacokinetics of celecoxib at steady-state in healthy volunteers. Basic Clin Pharmacol Toxicol 123:51–57

    Article  CAS  Google Scholar 

  18. Panossian A, Hovhannisyan A, Mamikonyan G, Abrahamian H, Hambardzum-yan E, Gabrielian E, Goukasova G, Wikman G, Wagner H (2000) Pharma-cokinetic and oral bioavailability of andrographolide from Andrographis paniculata fixed combination Kan Jang in rats and human. Phytomedicine 7:351–364

    Article  CAS  Google Scholar 

  19. Naidu SR, Ameer OZ, Salman IM, Venkatesh G, Sadikun A, Asmawi MZ (2009) Pharmacokinetic study of Andrographis paniculata chloroform extract in rats. Pharmacol Online 1:309–319

    Google Scholar 

  20. Chien CF, Wu YT, Lee WC, Lin LC, Tsai TH (2010) Herb–drug interaction of Andrographis paniculata extract and andrographolide on the pharmacokinetics of theophylline in rats. Chem Biol Interact 184:458–465

    Article  CAS  Google Scholar 

  21. Mutakin A, Megantara S, Larasati BA, Yogiyanto LJ, Ibrahim S (2020) The pharmacokinetic drug–drug interactions of Andrographis paniculata and ibuprofen in the plasma of healthy Oryctolagus cuniculus rabbits. Pharmacol Clin Pharm Res 5:40–47

    Article  Google Scholar 

  22. Balap A, Atre B, Lohidasan S, Sinnathambi A, Mahadik K (2016) Pharmacokinetic and pharmacodynamic herb–drug interaction of Andrographis paniculata (Nees) extract and andrographolide with etoricoxib after oral administration in rats. J Ethnopharmacol 183:9–17

    Article  CAS  Google Scholar 

  23. Balap A, Lohidasan S, Sinnathambi A, Mahadik K (2017) Herb–drug interaction of Andrographis (Nees) extract and andrographolide on pharmacokinetic and pharmacodynamic of naproxen in rats. J Ethnopharmacol 195:214–221

    Article  CAS  Google Scholar 

  24. Balap A, Lohidasan S, Sinnathambi A, Mahadik K (2016) Pharmacokinetic and pharmacodynamic interaction of andrographolide and standardized extract of Andrographis paniculata (Nees) with nabumetone in wistar rats. Phytother Res.

    Article  Google Scholar 

  25. Bothiraja C, Pawar AP, Shende VS, Joshi PP (2013) Acute and subacute toxicity study of andrographolide bioactive in rodents: evidence for the medicinal use as an alternative medicine. Comp Clin Path 22:1123–1128

    Article  CAS  Google Scholar 

  26. Worasuttayangkurn L, Nakareangrit W, Kwangjai J, Sritangos P, Pholphana N, Watcharasit P, Rangkadilok N, Thiantanawat A, Satayavivad J (2019) Acute oral toxicity evaluation of Andrographis paniculata-standardized first true leaf ethanolic extract. Toxicol Rep 6:426–430

    Article  CAS  Google Scholar 

  27. Guidance for Industry: Bioanalytical Method Validation, 2018. US Department of Health and Human Services, Food and Drug Administration Centre for Drug Evaluation and Research (CDER), Centre for Veterinary Medicine (CVM)

  28. Han D, Kwak J, Seo S, Kim J, Yoo J, Jung Y, Lee Y, Kim M, Jung Y, Yun H, Yoon I (2019) Pharmacokinetic evaluation of metabolic drug interactions between repaglinide and celecoxib by a bioanalytical HPLC method for their simultaneous determination with fluorescence detection. Pharmaceutics 11:382

    Article  Google Scholar 

  29. He J, Fang P, Zheng X, Wang C, Liu T, Zhang B, Wen J, Xu R (2018) Inhibitory effect of celecoxib on agomelatine metabolism in vitro and in vivo. Drug Des Devel Ther 12:513–519

    Article  CAS  Google Scholar 

  30. Pekthong D, Martin H, Abadie C, Bonet A, Heyd B, Mantion G, Richert L (2008) Differential inhibition of rat and human hepatic cytochrome P450 by Andrographis paniculata extract and andrographolide. J Ethnopharmacol 115:432–440

    Article  CAS  Google Scholar 

  31. Jaruchotikamol A, Jarukamjorn K, Sirisangtrakul W, Sakuma T, Kawasaki Y, Nemoto N (2007) Strong synergistic induction of CYP1A1 expression by andrographolide plus typical CYP1A inducers in mouse hepatocytes. Toxicol Appl Pharmacol 224:156–162

    Article  CAS  Google Scholar 

  32. Tang C, Shou M, Mei Q, Rushmore TH, Rodrigues AD (2000) Major role of human liver microsomal cytochrome P450 2C9 (CYP2C9) in the oxidative metabolism of celecoxib, a novel cyclooxygenase-II inhibitor. J Pharmacol Exp Ther 293:453–459

    CAS  Google Scholar 

  33. Karjalainen MJ, Neuvonen PJ, Backman JT (2008) Celecoxib is a CYP1A2 inhibitor in vitro but not in vivo. Eur J Clin Pharmacol 64:511–519

    Article  CAS  Google Scholar 

  34. Bort R, Pondosa X, Carrasco E, Gomez-Lechon MJ, Castell JV (1996) Metabolism of aceclofenac in humans. Drug Metab Dispos 24:834–841

    CAS  Google Scholar 

  35. Bort R, Pondosa X, Carrasco E, Gomez-Lechon MJ, Castell JV (1996) Comparative metabolism of the nonsteroidal antiinflammatory drugs, aceclofenac, in the rat, monkey and humans. Drug Metab Dispos 24:969–975

    CAS  Google Scholar 

  36. Stacey L, Polsky-Fisher CH, Lu P, Gibson C (2006) Effect of cytochromes P450 chemical inhibitors and monoclonal antibodies on human liver microsomal esterase activity. Drug Metab Dispos 34:1361–1366

    Article  Google Scholar 

  37. Weizhu Z, Li S, He Z, Lynn M, Edward L, Bingfang Y (1999) Dexamethasone differentially regulates expression of carboxylesterase genes in humans and rats. Drug Metab Dispos 28:186–191

    Google Scholar 

Download references


The authors are thankful to the Principal, BVDU’s Poona College of Pharmacy, Pune for providing instrumental and infrastructure facility to carry out the research work.


This research work has not received any funding.

Author information

Authors and Affiliations



S. J. More: Investigation S. S. Tandulwadkar: Investigation A. R. Balap: Visualization, Writing—Original Draft S. Lohidasan: Conceptualization and Supervision A. Sinnathambi: Methodology K. R. Mahadik: Supervision. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Aishwarya R. Balap.

Ethics declarations

Ethics approval and consent to participate

All applicable international, national, and institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (1701/PO1C/12/CPCSEA & 1702/PO1C/12/CPCSEA).

Consent for publication

The authors declare no conflict of interest.

Competing interests

The authors declare that they have no competing interests.

Plant extract

Andrographis paniculata extract; Source or Supplier: Natural Remedies Pvt. Ltd. Bangalore.

Batch no

FAPEX/2013110012; All the quality control tests like identification, moisture, acid insoluble ash, bulk density, tapped bulk density heavy metals, microbiology test, residual solvent analysis, pesticide residue analysis and phytochemical analysis were within limits; Phytochemical analysis performed by HPLC with stating ≈30% w/w andrographolide in the extract.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

More, S.J., Tandulwadkar, S.S., Balap, A.R. et al. Effect of Andrographis paniculata extract and Andrographolide on the pharmacokinetics of Aceclofenac and Celecoxib in rats. Futur J Pharm Sci 9, 1 (2023).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI:


  • Celecoxib
  • Aceclofenac
  • Andrographis Paniculata Nees
  • Andrographolide
  • Pharmacokinetics
  • Herb drug Interaction