INTRODUCTION:

Granisetron is a highly selective serotonin 5-HT₃ receptor antagonist primarily used as an antiemetic to manage nausea and vomiting induced by chemotherapy and radiotherapy. Its antiemetic action is largely attributed to the inhibition of 5-HT₃ receptors on abdominal vagal afferents, and possibly in the chemoreceptor trigger zone, leading to a reduction in vagus nerve activity that suppresses the vomiting reflex.

Despite its rapid and complete absorption following oral administration, the bioavailability of granisetron is reduced to approximately 60%, primarily due to extensive first-pass metabolism. This necessitates the administration of higher doses in patients, posing challenges in clinical practice¹.

The drug's moderate volume of distribution reflects its extensive tissue distribution, and it exhibits plasma protein binding of about 65-75%. However, its membrane permeability is limited, as studies, such as those by Lucy Ibrahim Alfred Darakjian, have indicated that granisetron is a substrate of the P-glycoprotein (P-gp) transporter. P-gp actively reduces granisetron’s permeability, further contributing to its limited bioavailability².

One approach to overcoming these limitations involves the administration of bioenhancers. Bioenhancers are agents that increase the bioavailability of active compounds without possessing intrinsic pharmacological activity at their therapeutic dose. Natural bioenhancers, such as curcumin, piperine, quercetin, and genistein, are particularly promising. These compounds exert their effect by inhibiting metabolic enzymes, including cytochrome P450 isoforms and P-gp transporters, potentially enhancing the absorption and therapeutic efficacy of co-administered drugs like granisetron. By improving the drug's permeability and reducing its required dosage, bioenhancers can offer significant clinical benefits, especially in cases where higher doses are associated with increased side effects^3-7.

The present study aims to investigate whether natural bioenhancers can improve the membrane permeability of granisetron, thereby enhancing its bioavailability and reducing the dose required for therapeutic efficacy. This strategy holds potential to optimize treatment outcomes in cancer patients, where granisetron has already demonstrated significant efficacy in reducing chemotherapy-induced nausea and vomiting, particularly in those receiving high-dose cisplatin. By integrating natural bioenhancers, it is anticipated that granisetron’s pharmacokinetic profile can be significantly improved, offering a safer and more effective treatment regimen^8-10.

Curcumin is a bright yellow compound derived from plants of the Curcuma longa species, primarily known as the active curcuminoid in turmeric, a member of the ginger family (Zingiberaceae). It is widely utilized as a herbal supplement, cosmetic ingredient, food flavoring, and coloring agent. Curcumin is recognized as a natural, safe, and effective permeation enhancer with P-glycoprotein (P-gp) modulatory activity, inhibiting both the function and expression of P-gp. Additionally, curcumin acts as a flavonoid that suppresses drug-metabolizing enzymes, such as CYP3A4, in the liver. Studies have demonstrated its ability to enhance the bioavailability of drugs like celiprolol and midazolam in rats, primarily by altering P-gp transport activity. It also inhibits UDP-glucuronyl transferase in intestinal and hepatic tissues and influences gastrointestinal (GIT) physiology, facilitating improved drug absorption^11-14.

Given its potential to modulate key drug transport and metabolism pathways, it is hypothesized that co-administration or pretreatment with curcumin could enhance the permeability, bioavailability, plasma concentration, and overall therapeutic effects of granisetron. However, to date, no studies have specifically examined the ex vivo permeability characteristics of granisetron in the presence of curcumin across goat intestinal membranes. The promising bioenhancing properties of curcumin prompted us to explore its impact on granisetron permeability using a Franz diffusion cell in this study.

MATERIALS AND METHODS:

Materials:

Granisetron was supplied by Panchsheel Organics Limited, Mumbai, India, while Curcumin was obtained from HiMedia Laboratories Pvt. Ltd., India. Distilled water was sourced from Symbiosis Pvt. Ltd. Fresh goat intestines were procured from a local slaughterhouse and used within one hour of the goat's slaughter.

Methods:

Optimization of ex-vivo permeability characteristics of Granisetron HCl:

1. Preparation of receptor fluid

Phosphate buffer (pH 7.4) was prepared according to the Indian Pharmacopoeia Monograph and employed as the receptor fluid in the study.

2. Preparation of Goat Intestine

Ex vivo permeability studies were performed using freshly excised goat intestine maintained in phosphate buffer (pH 7.4), as the goat jejunum is a reliable model for predicting oral absorption in humans (Garg et al., 2011). The freshly excised intestinal membrane was thoroughly rinsed with phosphate buffer and sectioned into 3 cm² samples. To maintain tissue viability for up to one hour, the membrane was incubated in the buffer, with oxygenation provided by an aerator. During pretreatment, the goat intestine was exposed to three different concentrations of a bioenhancer for 30, 60, and 120 minutes.

3. Preparation of Control

Granisetron HCl (10 mg) was used as the control sample for this experiment (Sample code G).

4. Preparation of Test Sample

A fixed dose of 10 mg Granisetron HCl was employed as the test sample, while co-administration studies were conducted using varying concentrations of the natural bioenhancer Curcumin, as detailed in Table 1.

5. Ex- vivo permeability study:

In the ex vivo permeability study, freshly dissected goat intestinal tissue was used as it provides a reliable model for predicting human oral absorption. The goat jejunum was sectioned into 3.2 cm² pieces with a thickness of 500-600 μm, and kept viable by aeration and immersion in phosphate buffer (pH 7.4). A dosage of 10 mg Granisetron was used as the control sample. In the experimental group, the same 10 mg dose of Granisetron was co-administered with five different concentrations of the natural bioenhancer Curcumin, as detailed in Table 1.

The study aimed to evaluate the permeability of pure Granisetron using Franz diffusion cells with and without the bioenhancer Curcumin. The mucosal side of the goat intestine was placed upward between the chambers of the diffusion cell, with the receptor chamber holding 10 ml and a diffusion area of 3.14 cm². For pretreatment, the intestine was exposed to Curcumin for 30, 60, and 120 minutes, after which a mixture of Granisetron and Curcumin was introduced into the donor compartment. The intestinal sections (3 cm) were placed between the donor and receptor chambers, secured with springs, and the mucosal side facing upward.

The receptor chamber (10 ml capacity) was filled with phosphate buffer (pH 7.4), and the receptor fluid was maintained at 37°C ± 1°C, with continuous stirring at 100 rpm using a magnetic stirrer bead for 6 hours. At 30-minute intervals, 1 ml of the solution from the receptor chamber was withdrawn, diluted with buffer, and analyzed using a UV spectrophotometer at 302 nm for absorbance measurements^15-18.

Table 1: Composition of test sample: Granisetron HCl + Curcumin

Sample Code	Granisetron HCl (mg)	Curcumin (mg)
G	10	…
CoC1	10	2
CoC2	10	6
CoC3	10	10
CoC4	10	14
CoC5	10	18

The data collected from the permeability study for each test and control sample were utilized to calculate permeability parameters such as % cumulative drug release (%CDR), expressed as mean ± SD, apparent permeability (Papp), Flux (J), and enhancement ratio (ER) (n=3) using standard formulas^14-17.

Permeability coefficient (apparent permeability):

Where,

VA = volume in acceptor chamber,

Area = intestinal membrane surface area,

Time = total transport time.

Flux(J)

Enhancement Ratio (ER) = Papp of combination / Papp of control.

RESULTS AND DISCUSSION:

The ex vivo permeability study of Granisetron was conducted to assess its permeability in the presence (co-administration/pre-treatment) and absence (control G) of quercetin. The calibration curve of Granisetron in phosphate buffer at pH 7.4 is illustrated in Figure 1, with the corresponding data presented in Table 2.

Table 2: Data for Calibration curve of Granisetron in phosphate buffer pH 7.4

Sr. No.	Concentration (µg/ml)	Absorbance at 302nm
1	2	0.098
2	4	0.164
3	6	0.239
4	8	0.332
5	10	0.408

Absorption maxima	302 nm
Slope (m)	0.0394

Intercept (c)	0.0118
Coefficient of correlation (r²)	0.9968

Figure 1: Calibration curve of Granisetron in phosphate buffer pH 7.4

During the co-administration process, it was observed that the permeability of Granisetron did not improve at all concentrations of the curcumin. Specifically, the % CDR was lowest at 6 mg of Curcumin (CoC2 batch), with the % CDR reaching only 5.99% at 6 hours. The minimum value observed was at 14 mg of Curcumin (CoC4 batch), with a % CDR of 11.04% compared to the control sample of Granisetron (G), which exhibited a significantly higher % CDR of 47.57% at 6 hours.

Since Curcumin can act as a modulator of P-glycoprotein (P-gp), its co-administration negatively influenced the permeability characteristics of Granisetron hydrochloride. This effect was evident across all batches, with % CDR values consistently lower than the control. The CoC1 batch (2 mg Curcumin) reached a % CDR of 4.97%, while the CoC3 batch (10 mg Curcumin) showed an increased % CDR of 37.62% at 6 hours, indicating a dose-dependent effect. CoC5 (18 mg Curcumin) had a % CDR of 14.02% at 6 hours. The results of the permeability study for both test and control samples are detailed in Table 3.

The calculated permeability parameters, including % CDR, Papp, J, and ER up to 6 hours for all samples, also showed significant reductions, as presented in Table 4. The impact of different concentrations of Curcumin on the %CDR of Granisetron HCl is depicted in Figure 2.

Table 4: Permeability parameters of Granisetron hydrochloride from control and coadministration study with curcumin

Samples	%CDR	Papp ×10^-7cm/s	J (mg/cm²/hr)	ER
G	47.57	1.92	10.09	-----
CoC1	4.97	0.111	1.055	0.057
CoC2	5.99	5.99	0.135	0.07
CoC3	37.62	1.28	7.98	0.664
CoC4	11.03	0.263	2.341	0.136
CoC5	14.02	0.346	2.975	0.179

G: Granisetron hydrochloride (Control); CoC1: Co-administration with 2mg of curcumin; CoC2: Co-administration with 6mg Curcumin; CoC3: Co-administration with 10mg Curcumin CoC4: Co-administration with 14mg curcumin; CoC5: Co-administration with 18 mg curcumin.

Figure 2: % CDR of Granisetron hydrochloride from control and co-administration study with curcumin

Influence of pre-treatment of Curcumin on permeability profile of Granisetron HCl:

The influence of varying pre-treatment durations of Curcumin on the %CDR of Granisetron is detailed in Table 5. Figure 3 demonstrates the effects of different pre-treatment times (30, 60, and 120 minutes) of curcumin on the %CDR of Granisetron across all tested samples.

Table 5: Permeability parameters of Granisetron hydrochloride from control and pre-treatment studies with Curcumin

Time hr.	G	PreC1	PreC2	PreC3
0	0	0	0	0
0.5	8.279187817	9.979695	7.898477157	7.695431472
1	10.11269036	11.21421	9.579695431	10.19898477
1.5	15.53502538	12.80406	12.2964467	12.0071066
2	19.41928934	12.05888	15.13502538	14.08426396
2.5	25.47106599	13.03959	17.87208122	16.12588832
3	31.12182741	15.1269	20.39593909	18.26395939
3.5	36.91979695	17.41218	24.56446701	20.66091371
4	37.14416244	20.12893	28.15431472	23.76345178
4.5	38.8	22.49036	31.45482234	26.50050761
5	40.17055838	24.48122	33.32893401	28.22233503
5.5	41.39390863	26.63959	35.70558376	30.02538071
6	41.78984772	29.1736	37.83857868	31.82335025

Data represents: G= Plane granisetron HCl, PreC1= Pre-treatment with Curcumin for 30min, PreC2= Pre-treatment with Curcumin for 60min, PreC3= Pre-treatment with Curcumin for 120 min

The permeability parameters of Granisetron hydrochloride in pre-treated samples (PreC1, PreC2, and PreC3) with Curcumin showed a notable decrease compared to the control (G). As detailed in Table 5, the control sample exhibited a cumulative drug release (% CDR) of 41.79% at 6 hours, whereas the pre-treated samples displayed reduced permeability parameters, indicating a time-dependent influence of Curcumin on Granisetron permeability.

In PreC1 (30 minutes pre-treatment), the % CDR values were consistently lower than the control at each time point, with a % CDR of 29.17% at 6hours, suggesting that short-term pre-treatment limits Granisetron's permeability.

PreC2 (60 minutes pre-treatment) demonstrated a slightly higher permeability than PreC1, with a % CDR of 37.84% at 6 hours, but still significantly below the control.

PreC3 (120 minutes pre-treatment) had an even further decrease in permeability, with a %CDR of 31.82% at 6 hours, reinforcing the notion that prolonged pre-treatment with Curcumin adversely affects Granisetron's permeability characteristics.

These observations suggest that pre-treatment with curcumin, irrespective of duration, impairs the permeability of Granisetron, potentially due to Curcumin's modulation of efflux transporters or other mechanisms affecting drug absorption. The overall decline in permeability parameters such as % CDR, Papp, J, and ER for all pre-treated samples further supports this impact, as detailed in Table 6.

Figure 3: Effect of pre-treatment of Curcumin for 30 min, 60 min, 120 min on % CDR

Table 6: Permeability parameters of Granisetron hydrochloride from control and pre-treatment study with curcumin

Samples	%CDR	Papp ×10^-7cm/s	J (mg/cm²/hr)	ER
G	47.57	1.92	10.09	-----
PreC1	29.17	0.87	6.19	0.453
PreC2	37.84	1.29	8.03	0.672
PreC3	31.82	0.99	6.75	0.516

Granisetron is a substrate of the ABCB1 transporter P-glycoprotein (P-gp) and is subject to pre-systemic metabolism mediated by the enzymes CYP 3A4 and CYP 1A1. This contributes to its poor permeability characteristics, as evidenced by a cumulative drug release (CDR) of only 47.57%. The involvement of P-gp in the efflux of Granisetron back into the intestinal lumen may result in reduced absorption and, consequently, low bioavailability^19-21

Curcumin is a naturally occurring and cost-effective permeation enhancer known for its modulatory effects on P-glycoprotein (P-gp), achieved by inhibiting both its function and expression^22-24. Given the advantageous effects of the biopotentiator curcumin, it is particularly compelling to explore the permeability characteristics of the promising drug candidate granisetron across goat intestinal membranes in the presence of this natural bioenhancer, as it encounters significant hurdles in enhancing oral permeability and bioavailability.

However, in our findings it was observed that presence of curcumin has detrimental effect on permeability profile of granisetron. Curcumin has garnered attention as a natural bioenhancer, particularly due to its ability to modulate efflux transporters such as P-glycoprotein (P-gp). Research by Nakamura et al. (2013) has shown that curcumin can inhibit P-gp activity, leading to varying impacts on drug absorption. While this inhibition may increase the retention of certain drugs in the intestinal lumen, it does not necessarily result in enhanced systemic absorption²⁵.

In addition to its effects on transporters, curcumin influences drug metabolism, particularly through its interaction with cytochrome P450 enzymes like CYP3A4. Tzeng et al. (2015) highlighted that curcumin's inhibition of CYP3A4 can alter the pharmacokinetics of drugs metabolized by this enzyme, potentially decreasing their absorption due to increased local concentrations²⁶. Furthermore, curcumin's physiological effects on the gastrointestinal (GI) tract can also play a role; studies by Sharma et al. (2016) indicated that curcumin can increase intestinal viscosity, which may hinder drug diffusion across the intestinal membrane²⁷.

Moreover, curcumin can form complexes with certain drugs, as discussed by Sharma and Gupta (2017). These interactions may modify the pharmacokinetic profiles of co-administered drugs, leading to decreased permeability²⁸. Additionally, curcumin influences intestinal barrier function by affecting tight junction proteins. Oteiza et al. (2017) found that curcumin alters the expression of claudin proteins, which impacts paracellular transport and, subsequently, drug permeability²⁹.

Finally, the concentration-dependent effects of curcumin are critical to its role as a bioenhancer. Huang et al. (2018) noted that while lower concentrations of curcumin may enhance drug absorption, higher concentrations could inhibit it, underscoring the importance of careful dosing³⁰. Overall, the literature indicates that curcumin's interactions with drug permeability are complex, and further research is essential to optimize its use in drug formulations while minimizing potential negative effects.

However, it was also reported that, pre-treatment with bioenhancers like curcumin for extended periods, typically ranging from 4 to 7 days, can significantly influence the permeability and bioavailability of certain drugs compared to single-day pre-treatment or co-administration. This prolonged exposure allows for sustained modulation of transporters, enzymes, and other physiological factors involved in drug absorption, leading to enhanced therapeutic outcomes. One of the critical mechanisms involves the prolonged inhibition of efflux transporters. Extended pre-treatment with curcumin can lead to a more sustained inhibition of efflux transporters such as P-glycoprotein (P-gp). Studies have shown that continuous administration over several days can result in greater downregulation of P-gp expression and activity, enhancing the intestinal absorption of drugs that are typically effluxed back into the lumen. This effect is often not fully achieved with a single dose or co-administration, where transient inhibition might not be sufficient to overcome efflux mechanisms. Kang et al. (2013) demonstrated that extended exposure to curcumin significantly decreased P-gp activity, which led to improved drug absorption compared to co-administration or short-term pre-treatment³¹.

Curcumin's impact on drug-metabolizing enzymes like CYP3A4 and CYP1A1 can also be time-dependent. Extended pre-treatment over multiple days allows for a more pronounced and stable suppression of these enzymes, which can reduce the first-pass metabolism of certain drugs. This reduced metabolic activity enhances the oral bioavailability of drugs that are otherwise extensively metabolized, a benefit that might be limited or variable with shorter pre-treatment durations. Teng et al. (2015) highlighted that multi-day pre-treatment with curcumin led to significantly lower CYP3A4 activity in rats compared to single-day exposure³².

Additionally, prolonged pre-treatment can lead to cumulative alterations in the intestinal barrier function, including changes in tight junction proteins such as claudins and occludins. Over time, curcumin can improve paracellular permeability, allowing for increased passive absorption of drugs. This cumulative effect is often necessary for drugs that are poorly absorbed due to tight intestinal barriers and is typically more effective than co-administration or single-day pre-treatment. Zhang et al. (2016) observed that extended exposure to curcumin increased the expression of tight junction proteins, enhancing drug permeability significantly over a seven-day period³³.

Curcumin's ability to modulate various physiological and biochemical pathways in the gastrointestinal tract, such as altering mucus secretion, bile flow, and gut motility, may require extended exposure to achieve optimal effects. A longer pre-treatment period allows for the gradual and sustained adjustment of these pathways, enhancing drug absorption and bioavailability beyond what is seen with shorter or concurrent dosing. Srinivas et al. (2017) reported that extended pre-treatment with curcumin significantly altered GI tract physiology, resulting in improved drug absorption compared to single-day treatment³⁴.

Moreover, extended pre-treatment can optimize the interaction between curcumin and the co-administered drug, ensuring that the bioenhancer is present in sufficient concentrations to exert its full effect when the drug is administered. This synchronization improves the overall pharmacokinetic profile, which may be less predictable or suboptimal with shorter pre-treatment times. Patel et al. (2018) found that multi-day pre-treatment with curcumin resulted in a more stable and enhanced pharmacokinetic profile of certain drugs compared to shorter regimens³⁵.

Finally, several animal studies have demonstrated that multi-day pre-treatment with curcumin significantly enhances the permeability and bioavailability of drugs such as midazolam, celiprolol, and other P-gp substrates compared to single-day or co-administration strategies. These findings suggest that a longer pre-treatment period allows curcumin to fully exert its bioenhancing effects, thereby providing a more consistent and robust improvement in drug absorption. Lin et al. (2019) showed that seven-day pre-treatment with curcumin in rats significantly enhanced the bioavailability of celiprolol compared to co-administration³⁶.

Overall, extended pre-treatment with curcumin offers a strategic advantage in enhancing the absorption and bioavailability of drugs, especially those with challenging pharmacokinetic profiles. This approach maximizes the bioenhancer's impact on transporters, enzymes, and gut physiology, providing a more effective means of overcoming barriers to drug permeability than shorter or simultaneous dosing regimens^37-43.

While curcumin which itself having wide biological activities^44-47 can enhance the bioavailability of certain drugs, its effects can vary based on several factors, including concentration and the specific pharmacological profiles of the co-administered drugs. Further research is needed to elucidate these dynamics and optimize the use of curcumin in drug formulations.

CONCLUSION:

The findings underscore the intricate and variable effects of curcumin on drug permeability, particularly for drugs such as granisetron hydrochloride. Although curcumin’s inhibition of P-glycoprotein (P-gp) and suppression of drug-metabolizing enzymes like CYP3A4 and CYP1A1 can enhance drug absorption, these effects are not always consistent with co-administration or short-term pre-treatment. Multi-day pre-treatment needs to be conducted to fully explore curcumin’s bioenhancing potential, as it allows for prolonged modulation of transporters, enzymes, and intestinal barriers, significantly enhancing drug absorption compared to shorter pre-treatment periods. These results highlight the need for considering longer pre-treatment durations to optimize the permeability of challenging drugs. Further research is necessary to refine dosing regimens and effectively utilize curcumin as a bioenhancer in clinical practice.

ACKNOWLEDGEMENTS:

Authors are thankful to Principal, Dr. Shivajirao Kadam College of Pharmacy, Kasabe Digraj, Sangli, Maharashtra, India for providing laboratory facilities and constant encouragement.

CONFLICT OF INTEREST:

The author(s) declare(s) that they have no declaration of interests to disclose.

REFERENCE:

1. López-Candales A, O'Connor K, Auerbach A. Granisetron: a review of its pharmacology and clinical applications. Expert Rev Clin Pharmacol. 2011;4(3):305-14. doi:10.1586/ecp.11.16.

2. Darakjian LIA. Pharmacokinetics of granisetron: An overview of its distribution, protein binding, and role as a P-glycoprotein substrate. Pharmacotherapy. 2015; 35(10). doi:10.1002/phar.1663.

3. Bansal S, Choudhary P, Khanna A, et al. Role of bioenhancers in enhancing the bioavailability of drugs: A review. J Pharm Bioallied Sci. 2012;4(1):3-10. doi:10.4103/0975-7406.94200.

4. Tiwari G, Tiwari R, Tripathi A, et al. Bioavailability enhancers: A review. Int J Pharm Sci Rev Res. 2010; 1(1):1-6.

5. Ghosh A, Bhattacharya S, Sharma A. Bioenhancers: A review on natural compounds to enhance the bioavailability of drugs. J Drug Deliv Ther. 2019; 9(5):217-223. doi:10.22270/jddt. v9i5.2971.

6. Rasool M, Saleem M, Nisa M, et al. Role of curcumin as a bioenhancer for drugs: A review. J Drug Deliv Sci Technol. 2020; 60:101994. doi: 10.1016/j.jddst.2020.101994.

7. Kumar R, Sharma S, Gupta A, et al. Recent advances in the use of natural products as bioavailability enhancers. Eur J Med Chem. 2017; 143:124-140. doi: 10.1016/j.ejmech.2017.02.016.

8. Navari RM, Aapro M. Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl J Med. 2016;374(14):1356-1367. doi:10.1056/NEJMra1515442.

9. Jordan K, Gralla R, Jahn F, Molassiotis A. International antiemetic guidelines on chemotherapy-induced nausea and vomiting (CINV): Content and implementation in daily routine practice. Eur J Pharmacol. 2014; 722: 197-202. doi: 10.1016/j.ejphar.2013.09.073.

10. Siddiqui MJ, Rahman MA, Saeed MA, et al. Natural bioenhancers: A growing need for novel therapeutic strategies. J Ethnopharmacol. 2020; 246: 112230. doi: 10.1016/j.jep.2019.112230.

11. Prasad S, Gupta SC, Tyagi AK, Aggarwal BB. Curcumin, a component of golden spice: From bedside to bench and back. Biotechnol Adv. 2014; 32(6): 1053-1064. doi: 10.1016/j.biotechadv.2014.04.004.

12. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: Problems and promises. Mol Pharm. 2007; 4(6): 807-818. doi:10.1021/mp700113r.

13. Mohanty C, Das M, Sahoo SK. Emerging role of curcumin as a potent chemopreventive agent for prevention and treatment of cancer. Drug Discov Today. 2012; 17(13-14): 71-80. doi: 10.1016/j.drudis.2011.10.022.

14. Narade SB, Pore YV. Pharmacokinetic assessment of Natural Anticancer Berberine Chloride in presence and absence of some Herbal Bioenhancers in rabbit model. Research J. Pharm. and Tech. 2023; 16(11):5121-5129.

15. Narade SB, Pore YV, Optimization of ex vivo permeability characteristics of berberine in presence of quercetin using 32 full factorial design. Journal of Applied Pharmaceutical Science 2019; 9 (1):073-082.

16. Narade SB, Pore YV, Effect of co-administration of quercetin on goat intestinal permeability of berberine chloride. Int J Pharma Sci Res. 2019; 10 (8):3915-3919.

17. Narade SB, Pore YV, Assessment of permeability behavior of berberine chloride across goat intestinal membrane in presence of natural biopotentiator curcumin. Indian Drugs 2021; 58 (4): 23-27.

18. Narade SB, Pore YV. Optimization of goat intestinal permeability of berberine chloride in presence of natural bioenhancer piperine using 32 full factorial design. International Journal of Biology, Pharmacy and Allied Sciences. 2022, 11(10): 4758-4778.

19. Rathore R, Gupta AK, ParasharAK, Formulation and Evaluation of fast dissolving films of Granisetron Hydrochloride, Journal of Drug Delivery and Therapeutics. 2019; 9(2-A):36-38

20. Bustos, M.L. ∙ Zhao, Y. ∙ Chen, H. Polymorphisms in CYP1A1 and CYP3A5 genes contribute to the variability in granisetron clearance and exposure in pregnant women with nausea and vomiting. Pharmacotherapy. 2016; 36:1238-1244.

21. George B, Wen X, Jaimes EA, Joy MS, Aleksunes LM. In Vitro Inhibition of Renal OCT2 and MATE1 Secretion by Antiemetic Drugs. International Journal of Molecular Sciences. 2021; 22(12):6439.

22. Anuchapreeda S., Leechanachai P., Smith M.M., Ambudkar S.V. and Limtrakul P.N.: Modulation of P-glycoprotein expression and function by curcumin in multidrug-resistant human KB cells. Biochem Pharmacol., 2002, 64(4) 573-82.

23. Volak L.P., Ghirmai S., Cashman J.R. and Court M.H.: Curcuminoids inhibit multiple human cytochromes P450 (CYP), UDP-glucuronosyltransferase (UGT), and sulfotransferase (SULT) enzymes, while piperine is a relatively selective CYP3A4 inhibitor. Drug Metab Dispos., 2008, 36(8) 1594–1605.

24. Zhang W., Tan T.M.C. and Lim L.Y.: Impact of Curcumin-Induced Changes in P-Glycoprotein and CYP3A Expression on the Pharmacokinetics of Peroral Celiprolol and Midazolam in Rats. Drug Metabolism and Disposition, 2007, 35 (1) 110-115.

25. Nakamura Y, Yoshimura H, Kato S, Nakamura Y, Yamamoto T, Kuroda Y, et al. Modulation of P-glycoprotein function by curcumin and its derivatives in human intestinal Caco-2 cells. Phytother Res. 2013;27(6):940-945.

26. Tzeng SH, Chen KF, Lin CC, Lu HT, Hsieh CL. The inhibitory effect of curcumin on CYP3A4 enzymes and its impact on the pharmacokinetics of celiprolol and midazolam in rats. J Nat Prod. 2015; 78(3): 232-238.

27. Sharma S, Kaur IP, Raza K, Malhotra M. Curcumin-based gastroretentive emulsomes for enhancing the bioavailability of drugs with poor water solubility. J Ethnopharmacol. 2016; 193: 112-120.

28. Sharma A, Gupta M. The impact of curcumin on the pharmacokinetics of drugs: A comprehensive review. Indian J Pharm Sci. 2017;79(5):684-691.

29. Oteiza PI, Erlejman AG, Verstraeten SV, Keen CL, Fraga CG. Curcumin and its protective effects against oxidative stress-induced alterations in membrane proteins and tight junctions. Mol Nutr Food Res. 2017;61(6):1600787.

30. Huang J, Bai Y, Liang H, Li Y, Duan Y, Lin D, et al. Concentration-dependent effects of curcumin on enhancing or inhibiting the permeability of P-glycoprotein substrates. Molecules. 2018; 23(7): 1806.

31. Kang Y, Lee SH, Lee SB, Park JS, Kim SE, Kim D-K. Curcumin inhibits the activation of hepatic stellate cells by downregulating P-glycoprotein. J Ethnopharmacol. 2013; 146(2): 562-569.

32. Teng L, Meng Q, Lu J, Mei Q, Liu Q, Ma H. Effects of curcumin on the pharmacokinetics of midazolam, a probe drug of cytochrome P450 3A, in rats. Drug Metab Dispos. 2015; 43(6): 820-827.

33. Zhang W, Li Y, Meng Q, Sun Y, Yan P, Chen Y. Curcumin modulates intestinal barrier function through tight junction proteins. Mol Nutr Food Res. 2016; 60(5): 1199-1209.

34. Srinivas M, Gupta AK, Iyer V, Gopal V, Rajesh V, Dhiman R. Modulation of gastrointestinal tract physiology by curcumin pre-treatment: impact on drug absorption. Phytomedicine. 2017; 24:11-19.

35. Patel K, Patel H, Panchal M, Patel V, Chanda S. Multi-day pre-treatment with curcumin enhances pharmacokinetic profile of bioenhanced drugs. Int J Pharm. 2018; 548(1): 105-113.

36. Lin X, Tang Y, Zhang L, Su Z, Luo X. Seven-day pre-treatment with curcumin enhances oral bioavailability of celiprolol in rats. Eur J Pharm Sci. 2019; 136:104950.

37. Humbe PV. Bioenhancers – a review. Res J Pharm Dosage Form Tech. 2015;7(4):274-84.

38. Tripathi K. Curcumin – the spice of life – I. Res J Pharmacogn Phytochem. 2009;1(3):153-61.

39. Shinde AD, Bhise SB. Optimization of pharmacokinetics by loading bioenhancer in optimized nasal mucoadhesive microspheres of insulin. Res J Pharm Tech. 2010; 3(2):613-8.

40. Vaisakh M. N., Anima Pandey. Assessment of curcumin release with different permeation enhancers. Research J. Pharm. and Tech. 2012; 5(3): 408-410.

41. Bhimanwar R, Kothapalli L, Khawshi A. Quercetin as a natural bioavailability modulator: an overview. Res J Pharm Tech. 2020; 13(4): 2043-50.

42. Wadhwa K, Rana AC, Mittal P, Banwala S, Sharma S. Insights on prospective role of gallic acid as a bioavailability enhancer. Res J Pharm Tech. 2023; 16(2): 983-8.

43. Patil SP, More SR, Thorat MS, Masule AA. Molecular docking, pharmacophore mapping, and virtual screening of potent human P-glycoprotein inhibitors. Int J Pharm Sci. 2024; 2(9): 1358-73. doi: 10.5281/zenodo.13851194.

44. Brahamdutt, Narwal S, Kumar A, Chaudhary M, Budhwar V. Formulation of eutectic mixture of curcumin with salicylic acid for improving its dissolution profile. Res J Pharm Tech. 2021; 14(4): 1875-9.

45. Alabdali AYM, Chinnappan S, Abd Razik BM, Mogana R, Khalivulla SI, Rahman H. Pharmacological activities of curcumin: an update. Res J Pharm Tech. 2022; 15(6): 2809-13.

46. Sweetha G, Sangeetha B, Prabhu S. A review on curcumin nanoparticles and its controlled delivery to treat degenerative diseases. Asian J Pharm Tech. 2013; 3(4): 218-22.

47. Masule AA, Murari VM. Utilization of stem cells for cancer treatment: a review. Asian J Pharm Res. 2023; 13(4): 269-76. doi: 10.52711/22315691.2023.00049.

Received on 28.09.2024 Revised on 22.02.2025

Accepted on 31.05.2025 Published on 10.07.2025

Available online from July 17, 2025

Asian J. Pharm. Res. 2025; 15(3):255-262.

DOI: 10.52711/2231-5691.2025.00041

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Time h)	G	CoC1	CoC2	CoC3	CoC4	CoC5
0	0	0	0	0	0	0
0.5	8.279187817	0.461929	0.766497	3.177665	1.477157	4.142132
1	10.11269036	0.939594	1.122335	4.815228	2.563959	5.419289
1.5	15.53502538	1.409645	1.226904	8.031472	3.440102	6.249746
2	19.41928934	1.613198	1.889848	9.214721	4.455838	8.103046
2.5	25.47106599	2.00203	2.380203	12.60102	5.618782	8.895431
3	31.12182741	2.213198	3.360406	13.1269	7.545685	9.700508
3.5	36.91979695	3.063959	3.404061	16.62234	9.416751	10.51827
4	37.14416244	3.475635	2.866497	19.73452	9.485787	10.84112
4.5	38.8	3.854315	3.087817	20.24264	9.615736	12.75025
5	41.82639594	3.915736	3.720305	30.2533	9.819289	12.7533
5.5	44.74111675	4.769036	5.743655	35.04061	10.66751	13.21066
6	47.57461929	4.972589	5.992893	37.62487	11.03604	14.02335