Effect of Naringin Co-administration on Oral Bioavailability of Efavirenz in Rabbit


Mohammad Asif1*, Rakesh K. Patel2, Hardik Patel2, Sadaf Jamal Gilani3

1Department of Pharmacognosy, Lachoo Memorial College of Science and Technology, Jodhpur, India.

2Department of Pharmacognosy, S.K Patel College of Pharmaceutical Education and Research, Gujarat, India.

3Department of Basic Health Sciences, Preparatory Year, Princess Nourah Bint Adbulrahman University, Riyadh, Saudi Arabia.

*Corresponding Author E-mail: writemail2asif@gmail.com, plantlaboratory@gmail.com



Efavirenz is a first line anti-retroviral drug belonging to category of non-nucleoside reverse transcriptase inhibitor (NNRTIs), However, it has variable bioavailability due to its limited aqueous solubility. Naringin is a bioavailability enhancer which has been used to increase bioavailability of several drugs. Therefore, the purpose of this study was to investigate the possibility of improving the bioavailability of Efavirenz using Naringin in experimental rabbits. The experimental rabbits were divided into four groups. Group I received Efavirenz 9.33 mg/kg, p.o (which corresponded to 200mg of human dose), Group II received Efavirenz 9.33mg/kg, + Naringin 20.8mg/kg, p.o; Group III received Efavirenz 28mg/kg, p.o (which corresponded to 600mg of human dose); Group IV received Efavirenz 28mg/kg + Naringin 20.8mg/kg, p.o. Afterwards, plasma from each group of rabbits was extracted and at fixed time interval drug plasma concentration was estimated using HPLC.  Pharmacokinetic parameters of were determined for each group. Efavirenz (9.33mg/kg and 28mg/kg) - Naringin (20.8mg/kg) co-administration significantly increased absorption rate constant (Ka) and elimination rate constant (Kel), Cmax, T1/2, Tmax significantly. Efavirenz 9.33mg/kg - Naringin (20.8mg/kg) co-administration increased area under the curve significantly. The relative bioavailability of Efavirenz 9.33 mg/kg - Naringin (20.8mg/kg) co-administration and Efavirenz 28mg/kg - Naringin (20.8mg/kg) co-administration was found to be 113.77% and 106.75% respectively. Based on the results it can be concluded that Naringin co-administration increased the oral exposure of Efavirenz to some extent. Bioavailability of Efavirenz with Naringin was found to be higher than Efavirenz control.


KEYWORDS: Efavirenz, Naringin, HPLC, Area under the curve, Pharmacokinetic parameters.




The concept of bioavailability enhancers is derived from traditional system of Ayurveda. Bose in 1929 first documented the action of bioenhancers when long pepper led to enhanced anti-asthamatic activity of Adhatoda vasika.1 The bioavailability enhancer derived from natural origin are considered safe, lowers drug toxicity and drug resistance, reduce the cost and duration of treatment.2 Bioflavonoids, namely quercetin, genistein, and Naringin have been reported to enhance the activity of certain drugs.3


Naringin (7-[[2-O-(6-Deoxy-L-mannopyranosyl)-D-glucopyranosyl] oxy]-2,3-dihydro-5-hydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is naturally occurring flavonoid glycoside. It has been reported to exhibit various pharmacological effects viz., anti-oxidant, anti-ulcer, anti-allergic and anti-cancer activity and blood lipid lowering property. Additionally, it has been reported to inhibits Permeability glycoprotein (P-gp) and CYP3A4 thereby reducing the metabolism of several drugs leading to reduced drug dose and increased plasma concentration. Choi et al reported that absolute and relative bioavailability of paclitaxel was increased by 3.5-6.8% and 152-302% respectively when co-administered with Naringin compared to control group and the enhanced bioavailability was attributed to suppression of P-gp and CYP-450 in the gastrointestinal mucosa. In another study, Cmax and Area under the curve (AUC) of Diltiazem was significantly increased by two-fold, when the experimental rats were pre-treated with Naringin.4


Efavirenz is a first line anti-retroviral drug belonging to category of non-nucleoside reverse transcriptase inhibitor (NNRTIs) which acts against HIV-1 reverse transcriptase but lacks significant inhibitory activity on HIV-2 reverse transcriptase. Tmax of Efavirenz is approximately 3-5 hours. The Area under the curve (AUC) and Cmax ­increases proportionally with dose till 1600 mg, afterwards the absorption decreases with increase in dose. It is more than 99% protein bound.  Efavirenz is primarily metabolised in liver mainly by CYP3A4 and CYP2B6 to hydroxylated metabolite (inactive) and is reported to have oral bioavailability of 40-45%.5,6  Viral resistance to Efavirenz develops by point mutation and it also exhibit cross resistance with various NNRTIs.7 The drug’s bioavailability is determined by its absorption, metabolism, distribution, and excretion which are mostly mediated by nuclear-mediated detoxification system involving variety of CYPs. CYP enzyme carries out the metabolism of various chemicals including drugs, toxins, etc.8


Therefore, citing to low bioavailability of Efavirenz, the present study was undertaken to evaluate the effect of Naringin on pharmacokinetic parameters of Efavirenz in rabbit after oral administration of Efavirenz at two different doses with or without Naringin using HPLC as it is extensively used analytical technique9 for pharmacokinetic and bioequivalence studies.10




Efavirenz was received as gift sample from Al-Chem Pharmaceuticals, Diazepam was purchased from Santham Pharma Pvt. Ltd., Naringin (90%) was obtained from Sigma Aldrich (St. Louis, MO, USA).  Acetonitrile (HPLC grade) was obtained from S.D Fine ChemLtd., Water (HPLC grade), Methanol (AR) and potassium EDTA (AR), potassium dihydrogen phosphate (AR) and Tween 80 were obtained from Finar Chemicals Ltd., Ethyl acetate (AR) and hydrochloric acid (AR) were obtained from S.D Fine Chem Ltd., Ethanol (AR) was obtained from Baroda Chemical Industries Ltd.


Experimental animals:

Rabbits (2000-3500gm), were procured from Central Animal Facility, S.K. Patel College Education and Research, Kherva and housed under standard conditions of temperature (25±1°C), relative humidity (50±10 %), 12 hr of alternate light and dark cycle. Rabbits were fed with carrot, cauliflower, fresh leafs of vegetables. The care and the use of these animals were in accordance with the guidelines of the CPCSEA (Reg.no. 197/PO/Re/S/2000/CPCSEA).


Calculation of dose:

The dose to be given to experimental rabbits on the basis of surface area was extrapolated as per description of Paget et al.11 Based on which dose of Efavirenz to be administered to rabbit was calculated to be 9.33mg/kg (Dose corresponding to 200mg in humans) and 28 mg/kg of rabbit (Dose corresponding to 600 mg in humans); dose of Naringin to be administered was calculated to be 20.8mg/kg of rabbit (Dose corresponding to 8 mg in rats); The treatment was administered as suspension using Tween 80 as suspending agent.


Experimental design:

The experimental rabbits were divided into four group containing six rabbit in each group. Group I rabbits were administered with Efavirenz (9.33mg/kg); Group II rabbits were administered with Efavirenz+Naringin (9.33mg/kg+20.8mg/kg); Group III rabbits were Efavirenz (28mg/kg); Group IV rabbits were administered with Efavirenz+Naringin (28mg/kg+ 20.8mg/kg). All the group received single oral dose of above drug and blood was collected at 0, 0.5, 1, 2, 4, 6, 8, 10, 24 and 48 hours respectively from marginal ear vein of rabbit. Blood collected was subjected to plasma separation followed by series of extraction process and sample prepared was finally subjected to estimation of drug by using High Performance Liquid Chromatography.


HPLC assay:

Calibration curve preparation:

Standard stock solution preparation:

Pure Efavirenz was dissolved in methanol to form a stock solution (50mg/mL). Efavirenz from 5 to 20000ng of concentrations were prepared in rabbit plasma and served as working standards.12,13


Sample preparation of Efavirenz:

Plasma (250 µL) was added in microcentrifuge tube (2 ml) and spiked with internal standard Diazepam (100 ng). The following mixture was vortexed for 1 minute. Separate addition of Efavirenz standard stock of concentration 5, 25, 250, 500, 1000, 2500, 5000, 10000, 15000 and 20000ng was made. 1000 µL  ethyl acetate was added for plasma sample extraction, vortexed for 1 minute and centrifuged for 10 minutes at 12000rpm. In other micro centrifuge tube (2ml), supernatant organic solution was added and evaporated to dryness at 37C, under gentle nitrogen stream. The dried residue was reconstituted with mobile phase (200µL), vortexed for 1 minute and centrifuged for 10 minutes at 12000rpm in microcentrifuge (Eppendorf’s AG). The clear solution was subjected to HPLC analysis.12,13


Sample preparation for Group I-IV:

Healthy rabbits were fasted overnight with free access and were administered single oral dose of respective treatment. After 0, 0.5, 1, 2, 3, 4, 5, 6, 10, 24 and 48 hours of drug administration, blood sample (1.5mL) were collected in anticoagulant treated micro centrifuge tube. The samples were centrifuged for 10 minutes at 12000rpm to separate plasma. Ethyl acetate (1000µL) was added for plasma sample extraction, vortexed for 1 minute and centrifuged for 10 minutes at 12000rpm. In other micro centrifuge tube (2ml), supernatant organic solution was added and evaporated to dryness at 37C, under gentle nitrogen stream. The dried residue was reconstituted with mobile phase (200µL), vortexed for 1 minute and centrifuged for 10 minutes at 12000rpm. The clear solution was subjected to HPLC analysis.12,13


HPLC system (Shimadzu Corporation, Kyoto, Japan) consisted of two pumps (LC 20 AD), diode array detector (SPD M20A) and degasser (DGU-20A5). A rheodyne manual injector (7725i) (Rheodyne, Cotati, USA) attached with sample loop (20µL) was used for loading the sample by syringe (25µL, Hamilton, Bonaduz, Switzerland). Class VP LC workstation was utilized for data collection and acquisition. The analytical column was Kromasil C18, 250 x 4.6mm ID, 5µ, 100 Ĺ particle size (Phenomenex, CA, USA). The mobile phase constituted of 10mM phosphate buffer, pH 2.4 and acetonitrile (55:45, v/v). Wavelength was set at 247nm. The time run of chromatogram was 25 minutes with flow rate of 2.4ml/min at 25°C.


Pharmacokinetic analysis:

Pharmacokinetic parameters were calculated as per one compartment open model and trapezoidal rule was used to calculate the area under the plasma concentration-time curve (AUC). Determination of maximum plasma concentration (Cmax) and time to reach Cmax (Tmax) was done by a visual inspection of experimental data. The terminal phase rate constant (Kel) was estimated as the negative of the slope of the log linear terminal portion of the plasma concentration versus time curve using least square regression analysis. Formula 0.693/Kel was used to calculate terminal phase half-life (T˝). Residual method was used to calculate the absorption rate constant (Ka). The relative bioavailability of Efavirenz was calculated as follows:14,15


                                              AUC coadmin

Relative bioavailability= ----------------------------- × 100

                                              AUC contorl

Statistical analysis:

Data are presented as Mean ± standard deviation (S.D) and analysed using one way ANOVA, followed by a posterior testing with Dunnett’s correction.



The mean plasma concentration – time profile of Efavirenz at dose 9.33 and 28mg/kg with and without Naringin was characterized in rabbit and illustrated in Figure 1 and 2.  Area under the curve (AUC) at different concentration and time has been detailed in table 1 and 2. HPLC chromatogram at 1 hour from Group I, II, III and IV is depicted in figure 3, 4, 5, and 6 respectively. The pharmacokinetic parameters of Efavirenz (9.33 mg/kg and 28mg/kg), and Naringin co-administration have been detailed in Table 3.


Figure 1: Plasma concentration of Efavirenz control 9.33mg/kg, and Efavirenz 9.33mg/kg+Naringin 20.8mg/kg at different time intervals.


Figure 2: Plasma concentration of Efavirenz control 28 mg/kg, and Efavirenz 28mg/kg+Naringin 20.8mg/kg at different time intervals.


Table 1: AUC of group I and II at different concentration and time.

S. No

Time (h)

Efavirenz (9.33mg/kg)

Efavirenz  (9.33 mg/kg) + Naringin  (20.8 mg/kg)

Conc. (µg/ml)


Conc. (µg/ml)























1.472625± 0.1934








































Table 2: AUC of  group III and IV at different concentration and time.

S. No



Efavirenz (28 mg/kg)

Efavirenz  (28 mg/kg)+ Naringin   (20.8 mg/kg)

Conc. (µg/ml)


Conc. (µg/ml)













0.979575±0. 2778



















































Figure 3: Chromatogram showing Efavirenz at 1 hour for Group I (Efavirenz control 9.33 mg/kg).


Figure 4: Chromatogram showing Efavirenz at 1 hour for Group II. (Efavirenz 9.33 mg/kg + Naringin 20.8 mg/kg)


Figure 5: Chromatogram showing Efavirenz at 1 hour for Group III (Efavirenz control 28 mg/kg).


Figure 6: Chromatogram showing Efavirenz at 1 hour for Group IV (Efavirenz 28  mg/kg + Naringin 20.8 mg/kg)


Table 3: Pharmacokinetic parameters of various groups.


Efavirenz control (9.33mg/kg)

Efavirenz (9.33 mg/kg) – Naringin Co-admin

Efavirenz control

(28 mg/kg)

Efavirenz (28 mg/kg) - Naringin












AUC 0-48 (µg/ml/ hr)

22.65± 4.65

25.77± 5.47*

55.68± 7.69

59.44± 8.46#

Cmax (µg/ml)

1.75± 0.45

2.32 ± 0.68*

4.86 ± 0.81

6.87± 1.21**

Tmax (h)





T1/2 (h)

2.089± 0.55

2.786± 0.73*

1.349± 0.38

3.343± 0. 84**






Mean :±S.D. (n = 6), Ka: Absorption rate constant, Kel: Elimination rate constant, AUC0–48 Area under the plasma concentration–time curve from 0 to 48 hours, Cmax: Peak concentration, Tmax: Time to reach peak concentration, t1/2: Terminal half-life,  RB: Relative bioavailability AUC rate compared to AUC control. * p < 0.05 compared to control, **p < 0.01 compared to control, ***p < 0.001 compared to control #=Not significant compared to control.


Efavirenz (9.33mg/kg) with Naringin co-administration significantly increased absorption rate constant (Ka) and elimination rate constant (Kel) at p<0.01; area under the curve at p<0.05; Cmax at p<0.05; T1/2 at p<0.05 compared to Efavirenz control. The relative bioavailability of Naringin co-administration was increased by 113.77% compared to Efavirenz control. Tmax of Efavirenz- Naringin co-administration was found to be 2 hours, higher than Efavirenz control (Tmax = 1 hr).


Efavirenz (28mg/kg) with Naringin co-administration significantly increased absorption rate constant (Ka) and elimination rate constant (Kel) at p<0.01; Cmax at p<0.01; T1/2 at p<0.01 compared to Efavirenz control. However, no significant increase in area under the curve was found with Efavirenz-Naringin co-administration compared to Efavirenz control. The relative bioavailability of Efavirenz-Naringin co-administration was increased by 106.75% compared to Efavirenz control. Tmax of Efavirenz- Naringin co-administration was found to be 2 hours, higher than Efavirenz control (Tmax = 1 hr).



The present study deals with the effect of Naringin co-administration with Efavirenz on various pharmacokinetic parameters. Anti-retroviral drugs usually have narrow therapeutic index16 due to which clear plasma drug level monitoring is required in order to ensure that the does lies within the recommended therapeutic range.17 It also allows that fulfilment of minimum therapeutic concentration at therapy initiation and ascertains maximum therapeutic concentration is not exceeded during dose escalation phase.18 Efavirenz, alike other NNRTIs is associated with many adverse effects such as hepatotoxicity, rash, vivid dreams, hallucinations, insomnia, psychosis, etc. It is also reported to have teratogenicity in newborn.19 Hence, agents which are capable of increasing the bioavailability of Efavirenz leading to decrease in its dose is of great significance. Additionally, metabolism of Efavirenz can also be altered. Efavirenz is primarily metabolised by polymorphic enzyme CYP 450.20 On that account, any agent that retards the metabolism of Efavirenz may also be useful in increasing its bioavailability and decreasing its dose. In our study, we have used Naringin as bioenhancer to evaluate its effects on Efavirenz pharmacokinetic as Naringin has been reported to enhance bioavailability of many drugs such as diltiazem, paclitaxel, verapamil, tamoxifen in experimental animals via inhibition of CYP mediated metabolism and/or P-gp mediated membrane permeability.21


Different pharmacokinetic parameters were determined to evaluate the effect of Naringin co-administration with Efavirenz. Elimination rate constant depicts the fraction of xenobiotics eliminated from the body during a course of time. For instance, a xenobiotics with elimination rate constant of 0.25/hour represents that approximately 25% of amount remaining in the body is excreted each hour.17 The elimination rate constant of Efavirenz control (9.33 mg/kg and 28mg/kg) was found to be higher than that of Efavirenz-Naringin co-administration which depicts that larger fraction of Efavirenz is eliminated compared to that with Naringin co-administration. Area under the curve represents the amount of xenobiotics effectively reaching the systemic circulation and it is influenced by degree of bioavailability and by rate of xenobiotic removal from the body. It is considered as good indicator of the internal exposure of dose in the body as it takes; blood concentration of xenobiotic as well as time a xenobiotic is present in the blood.17 The area under the curve of Efavirenz (9.33mg/kg) -Naringin co-administration was significantly higher than Efavirenz control, signifying that the former is reaching systemic circulation more effectively than later. However, this is not the case with Efavirenz (28mg/kg) – Naringin co-administration, when the increase in area under the curve is not significant. T1/2 represent a time period during which blood concentration of xenobiotics falls to half of its original value. The xenobiotics having smaller T1/2 values are rapidly cleared from the body but those with higher T1/2 are cleared more slowly.22 Herewith, Efavirenz-Naringin co-administration,the T1/2 was significantly increased for both the doses. The relative bioavailability of Efavirenz-Naringin co-administartion was also increased to some extent.


This study revealed that Efavirenz co-administration with Naringin led to sifnificant increase in plasma drug concentration which may be attributed to retardation of Efavirenz metabolising enzyme CYP3A4 and membrane dynamic alteration resulting in increased bioavailability of Efavirenz to some extent. The study suggests, that Naringin co-administration with Efavirenz may impart benefit by increasing oral exposure and hence, reducing the dose required to be administered. However, there is need of further studies to ascertain its clinical significance.



Naringin co-administartion with Efavirenz enhanced the oral exposure of the former in the rabbits. Futhermore, oral Efavirenz with Naringin (bioenhancer) could be developed to ascertain therapeutic benefits with low dose, low cost, reduced adverse effects and improved patient compliance.



The authors have no conflicts of interest regarding this investigation.



1.      Kesarwani K, Gupta R, Mukerjee A. Bioavailability enhancers of herbal origin: an overview. Asian Pacific Journal of Tropical Biomedicine. 2013 Apr; 3(4):253-66. doi:10.1016/S2221-1691(13)60060-X

2.      Rachana Bhimanwar, Lata Kothapalli, Akshay Khawshi. Quercetin as Natural Bioavailability Modulator: An Overview. Research Journal of Pharmacy and Technology. 2020 Apr; 13(4):2043-50. doi: 10.5958/0974-360X.2020.00368.6

3.      Randhawa GK, Kullar JS, Rajkumar. Bioenhancers from mother nature and their applicability in modern medicine. International Journal of Applied Basic Medical Research. 2011 Jan;1(1):5-10. doi:10.4103/2229-516X.81972

4.      Ajazuddin, Alexander A, Qureshi A, Kumari L, Vaishnav P, Sharma M, Saraf S, Saraf S. Role of herbal bioactives as a potential bioavailability enhancer for Active Pharmaceutical Ingredients. Fitoterapia. 2014 Sep; 97:1-14. doi: 10.1016/j.fitote.2014.05.005.

5.      Gaur PK, Mishra S, Bajpai M, Mishra A. Enhanced oral bioavailability of Efavirenz by solid lipid nanoparticles: in vitro drug release and pharmacokinetic studies. Biomed Research International 2014; 2014:363404. doi:10.1155/2014/363404

6.      Usach I, Melis V, Peris JE. Non-nucleoside reverse transcriptase inhibitors: a review on pharmacokinetic, pharmacodynamics, safety and tolerability. Journal of International AIDS Society. 2013 Sep 4; 16(1):1-14. doi:10.7448/IAS.16.1.18567

7.      Mohd. Yaqub Khan, Maryada Roy, Imtiyaz Ahmad, Irfan Aziz, Manju Panday. Formulation and Evaluation of Efavirenz 600 mg Tablet. Asian Journal Research in Pharmaceutical Sciences. 2015 July-Sept; 5(3): Page 153-67. doi: 10.5958/2231-5659.2015.00024.7

8.      Samir Shah, Kintu Patel, Mohsin Pathan. Evaluation of the Effect of Piperine on Bioavailability and Pharmacokinetics of Macrolides in Rats. Asian Journal Research in Pharmaceutical Sciences. 2018 Apr-Jun; 8(2):61-67. doi: 10.5958/2231-5659.2018.00013.9

9.      Rohini S. Koli, Aslam S. Patel, Kamlesh N. Chaudhari, Khushbu R. Patil. A Review on HPLC and Its New Trends. Asian Journal of Pharmaceutical Analysis . 2018 Oct-Dec; 8(4): 233-36. doi: 10.5958/2231-5675.2018.00042.X

10.   Hamid Khan, Javed Ali. UHPLC: Applications in Pharmaceutical Analysis. Asian Journal of Pharmaceutical Analysis.  2017; 7(2): 124-31. doi: 10.5958/2231-5675.2017.00020.5

11.   Paget GE. And. Barnes JM. Toxicity tests. Evaluation of Drug Activities. In Pharmacometrics, Edited by Lawrence DR and Bacharach A L. Academic Press, London. 1964; pp. 140–161.

12.   Hiwale AR, Dhuley JN, Naik SR. Effect of co-administration of piperine on pharmacokinetic of beta-lactam antibiotics in rats. Indian Journal of Experimental Biology. 2002 Mar; 40(3):277-281.

13.   Ramachandran G, Kumar AK, Swaminathan S, Venkatesan P, Kumaraswami V, Greenblatt DJ. Simple and rapid liquid chromatography method for determination of Efavirenz in plasma. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2006 May 1; 835(1-2):131-135. doi:10.1016/j.jchromb.2006.03.014

14.   Choi JS, Shin SC. Enhanced paclitaxel bioavailability after oral coadministration of paclitaxel prodrug with Naringin to rats. International Journal of Pharmaceutics. 2005 Mar 23; 292(1-2):149-156. doi:10.1016/j.ijpharm.2004.11.031

15.   Choi JS, Han HK. Enhanced oral exposure of diltiazem by the concomitant use of Naringin in rats. International Journal of Pharmaceutics. 2005 Nov 23;305(1-2):122-128. doi:10.1016/j.ijpharm.2005.09.004

16.   Soldin OP, Elin RJ, Soldin SJ. Therapeutic drug monitoring in human immunodeficiency virus/acquired immunodeficiency syndrome. Quo vadis?. Archives of Pathology & Laboratory Medicine. 2003 Jan; 127(1):102-105. doi:10.5858/2003-127-102-TDMIHI

17.   Kang JS, Lee MH. Overview of therapeutic drug monitoring. Korean J Intern Med. 2009; 24(1):1-10. doi:10.3904/kjim.2009.24.1.1

18.   Tamargo J, Le Heuzey JY, Mabo P. Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide. European Journal of Clinical Pharmacology,. 2015 May; 71(5):549-567. doi:10.1007/s00228-015-1832-0

19.   Tsibris AMN. And. Hirsch MS. Antiretroviral Therapy for Human Immunodeficiency Virus Infection. In Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, Edited by Bennett JE, Dolim R, Blaser MJ. W.B. Saunders. 2015; pp. 1622-1641.

20.   Bumpus NN, Kent UM, Hollenberg PF. Metabolism of Efavirenz and 8-hydroxyEfavirenz by P450 2B6 leads to inactivation by two distinct mechanisms. The Journal of Pharmacology and Experimental Therapeutics. 2006 July; 318(1):345-351. doi:10.1124/jpet.106.102525

21.   Venkatesh S, Pagilla B, Chiluka R, Alvala R, Pola RK, Mullangi R. Bioenhancing effects of Naringin on atrovastatin. ADMET and DMPK. 2019 Jun 6; 7(3):174–182. doi:10.5599/admet.647

22.   P. Hinderliter P, S.A. Saghir SA. Pharmacokinetic. In Encyclopedia of Toxicology, Edited by Wexler P. Academic Press; 2014; 3rd ed: pp.849-855.





Received on 22.07.2021                Modified on 08.09.2021

Accepted on 19.11.2021               © RJPT All right reserved

Research J. Pharm.and Tech 2022; 15(4):1641-1647.

DOI: 10.52711/0974-360X.2022.00274