INTRODUCTION:

The bioavailability of administered drugs will be decided by the Cytochrome-P450 (CYP) enzymes present in human body. The chemical form of the administered drug may be changed due to metabolism by CYP enzymes. The converted forms may be active or inactive. Being the substrates for these CYP enzymes, most of the antidiabetic drugs are metabolized by these enzymes. The activity of CYP enzymes may be inhibited or induced by many phytoconstituents. These phytoconstituents affect the extent of metabolism of antidiabetic drugs which are metabolized by CYP enzymes. As a result, the pharmacokinetics of antidiabetic drugs will be affected¹. The major sources of these phytochemicals are dietary fruits, vegetables, some medicinal plants and some antidiabetic ayurvedic products. These phytoconstituents also show therapeutic activities.

If the phytoconstituents with antidiabetic activity are ingested along with synthetic antidiabetic drug, there will be synergistic effect leading to enhanced antidiabetic property (alteration of pharmacodynamics). If the phytoconstituents are ingested by a patient on antidiabetic drug therapy, there will be a chance of alteration of both pharmacokinetics and pharmacodynamics of administered drug. As a result, there will be alteration in final therapeutic efficacy of antidiabetic drug².

Capsaicin (trans-8-methyl-N-vanilly-6-nonenamide) is the active phytoconstituents present in the fruits of Capsicum annum (Solanaceae family). The hot pungent taste of chilli peppers is mainly caused by Capsaicin. Capsaicin constitutes as main ingredient in many spicy foods consumed throughout the world. It possesses antidiabetic activity and the activity of CYP enzymes like CYP2C9 and CYP 3A4 is inhibited by Capsaicin³. In the previous literature, it was reported that the bioavailability (there by pharmacokinetics and pharmacodynamics) of drugs such as simvastatin, galantamine and gliclazide was altered by Capsaicin^3-7. Nateglinide [N (trans-4-isopropylcyclohexylcarbonyl)-d-phenylalanine] is an oral antihyperglycemic agent used for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). It belongs to the meglitinide class of short-acting insulin secretagogues, which act by binding to β-cells of the pancreas to stimulate insulin release ⁸. Nateglinide is metabolized by CYP2C9 and CYP 3A4 enzymes^8,9.

As the spicy food with chilli peppers is a common food item for most of the people, diabetic patients unknowingly may consume the Capsaicin. There are many ayurvedic products containing Capsaicin as active ingredient for the treatment of diabetes. Many diabetic patients may consume these products along with prescribed synthetic drug like Nateglinide. When a diabetic patient on Nateglinide therapy is ingested with Capsaicin, the metabolism of the drug may be reduced leading to alteration of bioavailable fraction of active form of drug and also there is a chance of alteration of therapeutic activity of drug. So, there is a need to study the interaction between a phytoconstituent (which alter CYP enzymes activity) and an antidiabetic drug (which is metabolized by CYP enzymes). In this research, the interaction between Capsaicin and Nateglinide was studied using rats models and the changes in pharmacokinetics and pharmacodynamics of drug were reported.

MATERIALS AND METHODS:

Drugs and chemicals:

Nateglinide and Repaglinide (gifted from Glenmark Pharmaceuticals Limited, Mumbai), Capsaicin (purchased from Kshipra biotech pvt ltd.), Streptozotocin (purchased from Sisco Research Labs), Methanol HPLC grade, Citric acid, Sodium bicarbonate (purchased from Merck Labs).

Animals for in-vivo study:

Rat models were used in the study. In-vivo experimental protocol was presented in a meeting of IAEC (Institutional Animal Ethical committee), University College of Pharmaceutical Sciences, Kakatiya University, Warangal and got approval for in-vivo work with rats (approval no. IAEC/05/UCPSc/KU/2020). Male wistar rats weighing 230-260grams were procured from a registered vendor. Animals were hosted at controlled environment (12 hours light and 12 hours dark) in poly propylene cages as per CPCSEA guidelines and fed with standard rat pellet diet & water al bitum. Rats were fasted over night before starting the study⁹.

Chromatographic estimation of Nateglinide:

A validated Ultra Fast Liquid Chromatography (UFLC) method coupled with photodiode array detection (Shimadzu Corporation, Japan) was used for the quantification of serum concentration of Nateglinide. This modified reverse phase HPLC system consisted of binary LC-20AD pumps with a micro gradient mixer. The stationary phase used in this technique was RP C18 column (250mm x 4.6mm, 5µm, Phenomenex Luna). The mobile phase used in the study consisted of a mixture of acetonitrile and 10 mM phosphate buffer (adjusted to pH 2.5) (in the ratio of 65:35, v/v). The flow rate was maintained at 1ml/min. The mobile phase was degassed using ultra sonicator and filtered through a 0.22µm membrane filter. The eluent was monitored at a wavelength of 210nm to detect the Nateglinide. Repaglinide was used as an internal standard. The sample run time for analysis was 10min. Lab solutions software was used for carrying out of all analysis operations and for interpretation of analyzed data^10,11.

Sample preparations for HPLC analysis:

The collected test serum (100µl) was mixed with 100µl of internal standard drug solution (Repaglinide solution with concentration of 10µg/ml) in a centrifuge tube. After shaking the mixture for 1 min, this mixture was added to 100µl of acetonitrile for precipitation. The resultant was vortexed for 1 min and centrifuged for 20 min at 3000rpm. Then the supernatant was collected and filtered. The collected filtrate (20µl) was injected in to HPLC system for analysis¹².

The developed HPLC method was tested for its precision and accuracy by analyzing quality control samples at three concentrations like 2, 10 and 100 µg/ml. Analysis was carried out in three replicates. Intra-day precision data was obtained by analyzing three sets of quality control samples in same day, whereas the samples were analyzed on three consecutive days to obtain inter day precision data. The developed HPLC method was found to have accuracy and precision. The Limit of Detection (LOD) and Limit of Quantification (LOQ) of the analysis were found to be 0.27478µg and 0.86533µg, respectively. These LOD and LOQ were found to be within the range of the analyzed levels in serum samples¹².

Experimental Design for In-vivo studies:

Pharmacokinetic Interaction study in Normal rats:

Rats were kept for overnight fasting and then rats were divided in to 3 groups (each group has 6 rats; n=6). Nateglinide was administered to rats in Group-1, whereas rats in Group-2 were administered with Capsaicin followed by Nateglinide (Single Dose Interaction Study). Rats in Group-3 were given with Capsaicin for 7 days consecutively and on 8^th day, administered with Capsaicin followed by Nateglinide (Multiple Dose Interaction Study). All the rats were received with Nateglinide at the dose of 20mg/kg. In each group, the blood samples were collected immediately after administration of Nateglinide. The blood samples were collected from retro orbital plexus using heparinised capillary tubes at particular predetermined time points like 0, 0.5, 1, 1.5, 2, 4, 8, 12 and 24 hours. After collection of blood sample, double the volume was replaced with normal saline. The collected blood samples were subjected to centrifugation in cooling centrifuge (Heraeus Biofuge Fresco centrifuge, Germany). Then serum was separated from centrifuged blood samples and separated serum samples were stored at -80^oC until analysis^12-16.

Pharmacokinetic Interaction study in Diabetic rats:

Induction of Diabetes in rats:

Freshly prepared streptozotocin in pH 4.5 citrate buffer was given to rats (after overnight fasting) through IP route at the dose of 55mg/kg. Rats were given with dextrose solution at different time points for avoiding sudden hypoglycemia. First rats were given with 20% v/v dextrose solution by IP route after 4-6 hours of streptozotocin injection and then rats were fed orally with 50% v/v dextrose solution up to 24 hours. Blood samples were collected from retro orbital plexus after 72 hours of streptozotocin injection. GOD-POD (Glucose oxidase-Peroxidase) method was used to estimate the serum glucose levels in collected blood samples. The rats having blood glucose levels more than 250 mg/dL were considered as diabetic and used for study¹².

After overnight fasting, the diabetic rats were grouped and treated with drug and phytochemical same as in study with normal rats. Here also the blood samples were collected and separated serum samples were stored at -80^oC until analysis.

The serum drug concentration values against time points of blood collection were generated. Then pharmacokinetic parameters like C_max, T_max, AUC_0-t, AUC_total, t_1/2, MRT, V_d and Cl_T were calculated using Kinetica software.

Pharmacodynamic Interaction study in Diabetic rats:

Diabetic rats (after overnight fasting) were divided into 3 groups (each consisting of 6 rats; n=6). Rats in Group-1 were administered with Nateglinide only. Single dose interaction (SDI) study was conducted in Group-2 by oral administration of Capsaicin followed by Nateglinide, whereas multi dose interaction (MDI) study was conducted in Group-3 which was administered with Capsaicin for 7 days and on 8^th day given with Capsaicin followed by Nateglinide. Blood samples were collected from retro orbital plexus at different time points. The blood glucose levels were estimated using GOD-POD method.

The Mean blood glucose levels were estimated in each group and compared with each other. The percentage reduction in blood glucose was calculated by using following equation^13,14.

% Glucose reduction at t hour = [(G₀– G_t)/G₀] X 100

Where, G_{t =}Mean glucose level at t hour

G_{0 =}Mean glucose level at 0 hour

Statistical Analysis:

All the obtained results were expressed as mean ± SD. The statistical significance of obtained results was estimated using Graph Pad Prism 7.01 software in one way ANOVA (Bonferroni post test). The values with p˂0.05 were considered as statistically significant.

RESULTS:

1. Pharmacokinetic interaction study in normal rats:

All the pharmacokinetic parameters were calculated using Kinetica software. The values are represented in Table 1. There was an increase in C_maxby 14.45% (SDI) and 41.57% (MDI) in Capsaicin pretreated groups compared to control (Nateglinide alone treated) group. The increase in AUC_0-n was observed in SDI and MDI by 20.82% and 41.88% respectively. AUC_total also increased by 14.76% (SDI) and 36.91% (MDI) in Capsaicin pretreated groups compared to control group. T_maxwas observed at 1.5 hr after drug administration in to body. MRT and t_1/2 were also increased significantly in Capsaicin pretreated groups. The parameters like V_d and Cl_Twere decreased in pretreated groups.

The serum drug concentration profiles of three treated groups are represented in Table 2 as follows:

Table 2: Mean serum drug concentration profiles in Normal rats

Time (hr)	NTG	NTG + Capsaicin (SDI)	NTG + Capsaicin (MDI)
0.5	3.104 ± 0.18	3.846 ± 0.45	3.912 ± 0.24
1.0	4.654 ± 0.29	5.241 ± 0.55	5.436 ± 0.57*
1.5	6.241 ± 0.21	7.138 ± 0.23	8.861 ± 0.36**
2.0	5.438 ± 0.37	5.891 ± 0.34*	6.012 ± 0.59*
4.0	4.263 ± 0.44	4.864 ± 0.62*	5.525 ± 0.55*
8.0	3.212 ± 0.14	3.431 ± 0.49	4.032 ± 0.86**
12.0	2.137 ± 0.73	2.468 ± 0.53*	2.936 ± 0.39**
24.0	0.863 ± 0.43	0.912 ± 0.68*	1.003 ± 0.29**

All Values expressed as Mean ± SD; * Significant with p˂0.05; ** Significant with p˂0.01; NTG: Nateglinide; SDI: Single Dose Interaction; MDI: Multiple Dose Interaction.

Fig.1: Serum Drug Concentration versus Time Plots in Normal Rats

2. Pharmacokinetic interaction study in diabetic rats:

All the pharmacokinetic parameters were calculated using Kinetica software (Table 3). In SDI group, the C_maxwas significantly increased by 9.91%, whereas in MDI group it was increased by 30.03%. AUC_0-n was increased by 14.31% (SDI) and 27.17% (MDI) and AUC_total was also increased by 12.12% (SDI) and 23.48% (MDI) in Capsaicin pretreated groups compared to control group. After 1.5 hours (T_max) of administration of drug, C_max was observed in blood serum. MRT and t_1/2 were also increased significantly in Capsaicin pretreated groups. The parameters like V_d and Cl_Twere decreased in pretreated groups.

Table 3: Pharmacokinetic parameters of Nateglinide in Diabetic rats

PK parameter	NTG	NTG + Capsaicin (SDI)	NTG + Capsaicin (MDI)
C_max (µg/ml)	6.86 ± 0.42	7.54 ± 0.36*	8.92 ± 0.23**
T_max(hr)	1.5 ± 0	1.5 ± 0	1.5 ± 0
AUC_0-n(µg.hr/ml)	48.2 ± 1.37	55.1 ± 0.83	61.3 ± 1.23**
AUC_total(µg.hr/ml)	52.8 ± 0.45	59.2 ± 2.21*	65.2 ± 1.73**
t_1/2(hr)	1.68 ± 0.32	1.73 ± 0.67	2.14 ± 0.76*
MRT (hr)	6.84 ± 0.63	7.03 ± 1.45	7.74 ± 0.53**
V_d(ml)	86.4 ± 0.76	81.3 ± 2.17*	78.2 ± 0.73**
Cl_T (ml/min)	2.72 ± 0.54	2.33 ± 1.23*	1.91 ± 0.89**

All Values expressed as Mean ± SD; * Significant with p˂0.05; ** Significant with p˂0.01; NTG: Nateglinide; SDI: Single Dose Interaction; MDI: Multiple Dose Interaction.

The serum drug concentration profiles of three treated diabetic groups are represented in Table 4 as follows:

Table 4: Mean serum drug concentration profiles in Diabetic rats

Time (hr)	NTG	NTG + Capsaicin (SDI)	NTG + Capsaicin (MDI)
0.5	3.567 ± 0.53	3.879 ± 0.58	3.956 ± 0.34
1.0	4.946 ± 0.27	5.012 ± 0.43*	5.412 ± 0.54**
1.5	6.831 ± 0.72	7.492 ± 0.31*	8.934 ± 0.28**
2.0	5.462 ± 0.51	5.912 ± 0.64	6.424 ± 0.54**
4.0	4.963 ± 0.29	5.113 ± 0.36*	5.645 ± 0.46*
8.0	4.013 ± 0.22	4.916 ± 0.75*	5.312 ± 0.27**
12.0	2.217 ± 0.78	2.916 ± 0.63	3.112 ± 0.24*
24.0	0.711 ± 0.43	0.894 ± 0.44*	1.024 ± 0.94*

All Values expressed as Mean ± SD; * Significant with p˂0.05; ** Significant with p˂0.01; NTG: Nateglinide; SDI: Single Dose Interaction; MDI: Multiple Dose Interaction.

Fig.2: Serum Drug Concentration versus Time Plots in Diabetic Rats

3. Pharmacodynamic interaction study in diabetic rats:

The percentage glucose reduction at each time point was calculated in comparison with mean glucose level at zero time point. The more glucose reduction was observed in rats of multi dose interaction study compared to other two groups (Table 5 and Fig. 3). After MDI group, more glucose reduction was observed in SDI group compared to control group. The maximum glucose reduction (36.87±1.68%) was observed after 8 hours of drug administration in Group-3. In Group-2 and Group-1, the glucose reduction was 32.47±0.74% and 22.42±1.47% respectively after 8 hours. Maximum glucose reduction was observed after 12 hours of drug administration in Group-2, whereas it was observed after 24 hours in Group-1.

Table 5: Pharmacodynamic parameters in Diabetic rats

Time (hr)	NTG		NTG + Capsaicin (SDI)		NTG + Capsaicin (MDI)
Time (hr)	Mean Glucose Level (mg/dL)	%Glucose Reduction	Mean Glucose Level (mg/dL)	% Glucose Reduction	Mean Glucose Level (mg/dL)	%Glucose Reduction
0	279.65 ± 1.64	0	284.24 ± 1.85	0	281.36 ± 0.83	0
0.5	274.73 ± 1.34	1.76 ± 0.87	273.24 ± 1.39	3.87 ± 1.21*	269.46 ± 1.37	4.23 ± 0.58*
1	267.96 ± 0.81	4.18 ± 1.76	266.13 ± 1.81	6.37 ± 0.92*	248.55 ± 2.54	11.66 ± 1.23**
1.5	258.48 ± 0.74	7.57 ± 1.32	253.17 ± 2.24	10.93 ± 1.42	233.89 ± 2.64	16.87 ± 0.98**
2	247.01 ± 1.52	11.67 ± 1.34	243.22 ± 1.94	14.43 ± 1.54*	221.23 ± 0.94	21.37 ± 1.45
4	234.74 ± 1.43	16.06 ± 0.98	212.81 ± 2.96	25.13 ± 2.14*	191.38 ± 1.34	31.98 ± 0.69**
8	216.95 ± 1.06	22.42 ± 1.47	191.95 ± 1.27	32.47 ± 0.74*	177.62 ± 0.82	36.87 ± 1.68**
12	212.90 ± 0.84	23.87 ± 1.65	182.94 ± 0.76	35.64 ± 1.19	179.73 ± 1.88	36.12 ± 1.92
24	212.62 ± 2.11	23.97 ± 1.97	184.64 ± 1.68	35.04 ± 1.78*	180.18 ± 1.34	35.96 ± 2.01

All Values expressed as Mean±SD; *Significant with p˂0.05; **Significant with p˂0.01; NTG: Nateglinide; SDI: Single Dose Interaction; MDI: Multiple Dose Interaction.

Fig.3: Glucose Reduction profile in diabetic rats

DISCUSSION:

In both normal and diabetic groups (Group-2 and Group-3), there was an increase in C_max and AUC values. It has clearly indicated that the bioavailability of Saxagliptin was increased in Capsaicin pretreated rats. It may be because of inhibition of CYP 2C9 and CYP 3A4 activity by Capsaicin, which resulted in decreased metabolism of Nateglinide^3-5. The metabolism of Nateglinide is mainly catalyzed by these two CYP enzymes (CYP 2C9 and CYP 3A4). So, the inhibition of activity of these two enzymes has suppressed the drug metabolism. It clearly understood that there was an increase in fraction of active bioavailable drug due to the fall in drug metabolism. There was no alteration in t_max value in all 3 groups, which indicated that the rate of drug absorption was not affected in the presence of Capsaicin. The t_1/2 and MRT were slightly increased in Capsaicin pretreated rats compared to control group. It may be due to decreased drug metabolism which enhanced the drug amount in body fluids there by extending the drug residence period in body^17-19. There was a decrease in volume of distribution and total body clearance in Capsaicin pretreated groups. It indicated that Capsaicin could affect the protein binding of drug with body fluid proteins. Nateglinide has more protein binding capacity. When there was an increase in available drug fraction in body fluids (due to Capsaicin effect), the bound fraction of drug has also increased. This reduced the free drug fraction which affected drug distribution and drug clearance^20-22. The alterations in pharmacokinetic parameters were more significant in multiple dose Capsaicin pretreated (MDI) groups in both normal and diabetic rats.

The hikes in glucose reductions were observed in Capsaicin pretreated rats. This may be because of increased pharmacokinetic parameters of Nateglinide^{12- 14}. It clearly understood that there was a reduction in metabolism of drug which resulted in more availability of drug at tissue receptors to elicit the therapeutic activity. This caused to the enhancement of antihyperglycemic activity of Nateglinide. Capsaicin itself is an antidiabetic agent. When Capsaicin was administered along with Nateglinide, it resulted in synergistic antidiabetic activity. So, there were enhanced glucose reductions in Group-2 and Group-3. The effect of Capsaicin on antidiabetic property of Nateglinide was more significant in multiple dose interaction (MDI) group compared to single dose interaction group (SDI).

CONCLUSION:

The pharmacokinetic and pharmacodynamic parameters of Nateglinide were greatly affected by a phytochemical like Capsaicin. Being as an inhibitor of CYP 2C9 and CYP 3A4, Capsaicin was responsible for decreased metabolism of Nateglinide thereby enhancing drug’s bioavailable fraction. The antidiabetic activity of Nateglinide has been greatly increased due to increase of C_max and AUC of drug in the presence of Capsaicin. From the results of this research it could be concluded that the Capsaicin has shown significant interaction with Nateglinide and altered its therapeutic activity. So it is advised to be away from taking vegetables, fruits and ayurvedic products containing Capsaicin while patient is on antidiabetic therapy with Nateglinide. This research reveals the importance of dose adjustment of Nateglinide, if it is to be administered along with Capsaicin.

ACKNOWLEDGEMENT:

The authors are thankful to the Glenmark Pharmaceuticals Limited, Mumbai for supplying of required drug samples for research work.

CONFLICT OF INTEREST:

All the authors involved in this research work declare no conflict of interest for the results of study and publication of the manuscript.

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Received on 02.09.2020 Modified on 18.12.2020

Research J. Pharm. and Tech 2023; 16(3):991-996.

DOI: 10.52711/0974-360X.2023.00165

PK parameter	NTG	NTG + Capsaicin (SDI)	NTG + Capsaicin (MDI)
C_max (µg/ml)	6.23 ± 0.31	7.13 ± 0.42	8.82 ± 0.27
T_max(hr)	1.5 ± 0	1.5 ± 0	1.5 ± 0
AUC_0-n(µg.hr/ml)	41.3 ± 1.42	49.9 ± 1.32*	58.6 ± 0.86**
AUC_total(µg.hr/ml)	44.7 ± 0.73	51.3 ± 1.13*	61.2 ± 0.73**
t_1/2(hr)	1.63 ± 1.09	1.83 ± 0.76*	2.02 ± 1.13**
MRT (hr)	5.82 ± 0.87	6.08 ± 1.06*	6.74 ± 0.54**
V_d(ml)	89.4 ± 0.82	82.3 ± 1.37*	79.2 ± 0.83**
Cl_T (ml/min)	2.86 ± 0.58	2.73 ± 2.21	2.43 ± 0.87*