INTRODUCTION:

Herbal medicine/herbal preparation has been used in low-income countries, as well as in countries with high per capita income for a long time¹. The herbal product market is rapidly growing so fast, and developments in online sales technology facilitate easy transactions for people. Herbal medicines have been widely used in Africa, China, South America, Central America, the Pacific Islands, India, the United States, Peru, Suriname, and Ghana^2,3,4.

Pharmacological or clinical responses that arise due to the simultaneous use of traditional medicines and herbal products as well as pharmaceutical preparations are known as herbal-drug interactions⁵. The increasing incidence of herbal-drug interactions can be attributed to the frequent use of herbal and prescribed medicines together, especially for an extended period⁶. Herbal products are assumed to be natural, thereby making them safe for long-term consumption. In addition, herbal products are easily obtained and readily available at affordable prices on the market. This condition boosts the sales of herbal products^1,7. Herbal medicines contain many chemical compounds that, potentially affect the bioavailability of drugs if used simultaneously. This influence is attributed to the induction process of enzyme metabolization either in phase 1, phase 2, or both, which may influence the therapeutic effect of the drug. Several articles regarding herb-drug interactions, the possibility of side effects when using herbal medicines, and the effects of herbal medicines on the therapeutic effects of prescribed drugs have been published^8,9,10. A combination of effects that are mimicry, conflicting or synergistic effects is produced due to the concomitant use of herbal medicine with prescription drugs¹¹. Serious clinical effects can frequently be attributed to this interaction process^6,12.

However, published research regarding the herb-drug interaction of Eurycoma longifolia (ELO) is limited. Salman et al. (2010)¹³ reported the effect of ELO on the propanolol pharmacokinetic profile. They found that water extract reduced the AUC and C_max by 29% and 42%, respectively, and extended the T_max by 86%. Purwantiningsih et al. (2010 and 2012)^14,15 investigated the interaction between ELO extract and aminopyrine metabolism. They reported a significant increase in the metabolism of aminopyrine in female and male rat hepatocytes, due to the aforementioned product and found differences in its effects at the molecular level on the aminopyrine metabolism process in female rats compared with male rats. Studies on the effect of the rosiglitazone metabolism process have also been conducted, and the results revealed that ELO extract significantly increased the phase I metabolism process of rosiglitazone, especially in old male rats for normal and diabetic rats¹⁶.

Therefore, this herb drug interaction study is expected to provide key information on the safety of using herbal medicines¹.

MATERIALS AND METHODS:

Materials:

ELO extract was obtained, and a certificate of analysis was issued by Phytochemindo Reksa. Acetonitrile (ACN), ethyl acetate, and methanol (all at HPLC grade) were purchased from Merck (Germany). Rosiglitazone maleate (Wuhan Sunrise Technology, China), ketamine hydrochloride injection (Pfizer), hydrochloride acid (HCL, analytical grade; Fizer Scientific, UK), disodium hydrogen phosphate (R&M Chemicals, UK), polyethylene glycol-400 (PEG 400) (Sigma Chemicals Co., USA), potassium dihydrogen orthophosphate (Ajak Chemicals, Australia), and triethylamine (analytical grade; Across Organics USA) were also utilized in this study. The rosiglitazone concentration in the blood sample was analyzed using Waters HPLC system (Waters Corporation, USA).

Experimental animals:

Twenty-four rats of the Sprague Dawley strain, were used in this experiment, aged 20-24 months and weighing approximately 400±50g. Twenty-four test animals were induced with streptozotocin therefore the test animals experienced type I diabetes mellitus and were then divided into two groups for pharmacokinetic studies. All test animals were conditioned to get enough food and drink. Rats were given food (standard food pellets RadBio^® were purchased from PT. Citra Ina Feedmill, Jakarta, Indonesia) and water ad libitum. The cages contain 5 rats per cage, are cleaned every two days and get enough lighting, with dark-light circulation for 12hours each. The Ethics Committee approved this test protocol with Ref. Number 104/EC-FKH/Eks/2023, Faculty of Veterinary Medicine, Universitas Gadjah Mada.

Induction of streptozotocin (STZ) to obtain the type I diabetes mellitus animal test:

Sprague Dawley rats were induced intravenously by streptozotocin (STZ) injection at a dose of 60mg/kg. A sodium chloride solution (NaCl_0.9%) was used to dissolve STZ and immediately injected into the tail vein of the test animal under ketamine anaesthesia. Three days after the STZ injection, the glucose level was checked. Rats with glucose levels of more than 15.6 mmol/L (280mg/dL) on the fasting condition were considered to be type I diabetic. This study did not use type II diabetic rats because obtaining rats that experienced type II diabetes mellitus is difficult.

Pharmacokinetic studies:

This pharmacokinetic study used 24 old male diabetic rats. The rats received treatment according to their group, namely intravenous and oral groups. Each group was further divided into two subgroups for administration of single rosiglitazone and a combination of rosiglitazone and ELO extract (n = 6).

a) Blood sampling:

ELO extract was prepared fresh in distilled water (25 mg/mL) and administered orally at 50mg/kg BW¹⁷. For oral and intravenous studies, the extract was initially administered 30min before the administration of rosiglitazone. Rosiglitazone solution was prepared by diluting the rosiglitazone stock solution in PEG-400 (10%) or in methanol for oral administration and diluting in distilled water for intravenous injection. The final methanol concentration was calculated to be no more than 1% (note: the LD50 of methanol was 2.3 mL/kg for intravenous administration). Rosiglitazone solution was intravenously and orally administered to the test animals at a dose of 10mg/kg BW¹⁸. A total of 0.5mL of blood was collected via the rat tail vein into a centrifuge tube containing 20μL of heparin at the specified time. For intravenous studies, sample collection was conducted at times 0 (predose), 0.25, 0.5, 1, 2, 3, 5, 8, and 12h and at 24h for oral studies. The sample was centrifuged for 10 min at a speed of 4,500 rpm, and the plasma was separated and stored in a 20 ºC refrigerator. Methods reported by Mamidi et al., (2003) was used to analyze rosiglitazone concentrations in blood samples¹⁹.

b) Chromatographic conditions:

The HPLC system consists of 3 main parts, namely an autosampler (Waters 717plus), controller (Waters 600 LC) and a Waters 474 scanning with fluorescence detector. The System used a Kromasil C18 HPLC column (KR100-5C18-250Å, 5µM, 4.6X250mm) (HiChrom, Fisher Scientific, UK). The mobile phase was set at a flow rate of 1.0mL/min, comprised 0.01M KH2PO4 buffer, acetonitrile, and methanol (40-50-10 [v/v/v], respectively), and then adjusted with triethylamine to obtain a pH of 6.5. The eluate with an excitation wavelength of 249nm and an emission wavelength of 364nm was monitored using a fluorescence detector.

c) Standard solution and standard curve for rosiglitazone:

Methanol solvents with a concentration of 1.0mg/mL each were used to prepare the standard solution of rosiglitazone and the internal standard (IS) of quinidine which were then stored at 4ºC during the experimental period. Serial concentrations ranging from 0.05µg/mL to 200µg/mL were created to prepare the rosiglitazone standard curve using the stock solution dilution method, whereas the IS solution was used without dilution from the stock.

d) Analytical procedure:

A plasma sample of 100µL was added to an IS solution equivalent to 10µg and vortexed for 15 s. Separation of the organic layer was realized by adding ethyl acetate (3 mL) to the mixture, which was vortexed again for 1min, and then centrifuged for 10min at 2000rpm. The mixture was evaporated to dryness using nitrogen gas. The remaining residue was dissolved in 750μL of mobile phase, and 50µL of this solution was removed and injected into the HPLC system¹⁹.

e) Method validation:

The determination of method validation considers the following three factors: accuracy (percentage deviation from the known concentration), precision (percentage coefficient of variation), and recovery values within and between days. Additional rosiglitazone to blank plasma facilitated the preparation of spiking samples, and the concentration was adjusted to 0.5, 5, 50, and 200µg/mL. Three replicate samples were processed for each concentration. Compared with the recovery of standard rosiglitazone, which was prepared without a plasma matrix and processed by the same method, the recovery values were determined from peak height of the drug chromatogram in the plasma sample.

f) Data analysis:

The STRIPE software was used for data analysis²⁰. The obtained data were used to calculate the pharmacokinetic parameters for the intravenous (i.v.) and oral studies. For intravenous administration, the volume of distribution (V_d), area under the curve (AUC_0--∞), elimination rate constant (k_e), clearance (CL) and elimination half-life (t_1/2) were all estimated. Meanwhile, AUC_0--∞ and k_e were estimated for the oral data. The actual data following oral administration were used to obtain the maximum concentration (C_max) and time to reach the maximum concentration (T_max). Additionally, Equation 1 was used to calculate the absolute bioavailability (F) of rosiglitazone (this calculation used the same doses for oral and i.v. experiments). T_1/2was calculated using the equation t_1/2= ln 2/k_e,whereasthe slope of the drug plasma concentration versus time curve was used to calculate k_e.Vd, was calculated from the equation V_d = dose/k_e.AUC_0--∞,and the AUC_0--∞ was computed by adding all the areas under the curve using the trapezoidal method. CL was determined from the following equation: CL = dose/AUC_0--∞²¹. Data were presented as mean and standard deviation (mean ± SD). The differences between the two datasets were analyzed using the T-test and the P level was set at P <0.05.

Equation-1

RESULT:

Validation Method:

Table 1 presents the validation method results. The percentage of accuracy error values and coefficient of variation values within the intraday and interday periods do not exceed 14%. In relation to precision and accuracy, Mamidi et al. (2003)¹⁹ required an acceptable limit of quantification (LOQ) value of approximately 20%. The intraday and interday recovery ranges were 89.20% - 96.70% and 86.20% - 97.28% respectively. A linear regression, Y = 55.99X + 52.11, with a correlation coefficient of R² = 0.999, was observed in the calibration curve for rosiglitazone determination and the LOQ was 5ng/mL. Figure 1 shows the chromatograms for the blank plasma and the baseline separation between quinidine and rosiglitazone under the chromatographic conditions.

Table 1. Accuracy and precision calculation results for intraday and interday (n = 6) values of the analysis method

Rosiglitazone concentration in spiked plasma (µg/mL)	Intraday		Interday
Rosiglitazone concentration in spiked plasma (µg/mL)	Accuracy (% error)	Precision (CV, %)	Accuracy (% error)	Precision (CV, %)
0.5	3.58	0.86	10.09	1.74
5	10.36	3.95	11.75	1.35
50	10.78	2.17	13.79	1.69
200	3.29	0.34	2.72	0.80

Effect of E. longifolia extract (ELO) on the pharmacokinetic profile of rosiglitazone:

Figure 2 shows the rosiglitazone plasma concentration versus sampling time curve in the oral study. Similar rosiglitazone concentrations were observed in the early stages. The rosiglitazone concentrations in the second group (treated with rosiglitazone combined with ELO) slightly decreased compared with those in the first group (administered with rosiglitazone only). Table 2 shows a decrease in some pharmacokinetic parameters, namely AUC_0--∞ (8.01%), C_max(12.95%), T_1/2(7.23%), and F (5.71%), and an increase in the parameters K_el(13.04%), T_max (15.52%), Vd (46.38%), and CL (43.30%). Significant changes were only found in the Vd and CL parameters (P < 0.05) based on the statistical results test.

Figure 2. Rosiglitazone plasma concentrations on a logarithmic scale (mean ± SD; n = 6) versus sampling time after oral administration. Closed point = rosiglitazone group (R); Opened point= rosiglitazone combined with ELO (R + ELO)

Table 2. Calculation results of pharmacokinetic parameters for single rosiglitazone and combination groups in oral studies

Pharmacokinetic parameters	Group of Single Rosiglitazone (Mean ± SD; n = 6)	Group of Rosiglitazone + ELO (Mean ± SD; n = 6)
AUC _0--∞(µg.h/mL)	73.02 ± 4.68	67.17 ± 41.30
C_max(µg/mL)	22.08 ± 6.07	19.22 ± 6.90
T_max (hour)	0.58 ± 0.20	0.67 ± 0.26
K_el (min^-1)	0.18 ± 0.04	0.20 ± 0.05
t_1/2(hour)	4.01 ± 1.09	3.72 ± 1.03
Vd (mL/kg)	528.32 ± 118.96	773.34 ± 193.18*
CL (mL/hour/kg)	137.43 ± 9.03	196.94 ± 97.99*
F (%)	65.76	60.05

Note: * P < 0.05 (significantly different compared to single rosiglitazone group)

Figure 3 shows the effect of ELO on the plasma concentration of rosiglitazone after intravenous injection, while Table 3 presents the pharmacokinetic parameters for the two groups. The AUC_0--∞, K_el, and T_1/2decreased by 31.49%, 3.03%, and 3.85%, respectively, after injection. By contrast, the Vd and CL increased by 37.63% and 15.50%, respectively. No significant changes (P>0.05) were observed in the pharmacokinetic parameters in this intravenous study.

Table 3. Calculation results of pharmacokinetic parameters for single rosiglitazone and combination groups in the intravenous study

Pharmacokinetic parameters	Group of Single Rosiglitazone (Mean ± SD; n = 6)	Group of Rosiglitazone + ELO (Mean ± SD; n = 6)
AUC _0--∞(µg.h/mL)	111.83 ± 53.43	76.64 ± 18.51
K_el (min^-1)	0.33 ± 0.11	0.32 ± 0.06
t_1/2(hour)	2.34 ± 0.81	2.25 ± 0.53
Vd (mL/kg)	210.69 ± 120.59	289.72 ± 97.30
CL (mL/hour/kg)	117.38 ± 72.08	135.57 ± 25.75

Note: All changes were not significantly different (P > 0.05)

Figure 3. Rosiglitazone plasma concentrations on a logarithmic scale (mean±SD; n = 6) versus sampling time in the intravenous studies. Closed_point = rosiglitazone group (R); Opened_point = rosiglitazone combined with ELO (R+ELO)

DISCUSSION:

In this study, streptozotocin was used as an inducer to obtain diabetic model rat before being treated. The use of streptozotocin is common and widely used in various studies related to experiment that using diabetic rat as a model test animal^22-23.

Good validation was demonstrated by the analytical method for assaying the plasma level of rosiglitazone. The linearity with a coefficient of correlation of R² = 0.999, was satisfactory. The intraday and interday precisions range from 0.34% to 3.95% and from 0.80% to 1.74%, respectively. These values remained within the range of previous studies with celecoxib as IS¹⁹. Compared with those in a previous report of 82% - 89%, the absolute recoveries ranged from 86.20% to 97.28%¹⁹. The retention time of quinidine is at 3.5min, while rosiglitazone is at 10min. In two similar studies using fluorescent detectors with slight differences in the mobile phase and stationary phase, rosiglitazone had retention times of 9min and 7.9min²⁴. Analysis of rosiglitazone in dosage forms, such as tablets or other forms, requires a more sensitive method such as the RP-HPLC or HPTLC method. This may be related to the small dose of rosiglitazone used^25-29.

In modern pharmacology, herbal-drug interactions are categorized into two groups: pharmacokinetic and pharmacodynamic interactions^30-32. Alterations in the effect of the drug by an interfering herb led to the emergence of pharmacodynamic herb-drug interactions. Ather than an alteration in plasma concentration, these interactions can be attributed to the net effect of the drug. Pharmacokinetic herb-drug interactions affect the absorption and distribution process, as well as drug metabolism or excretion. The underlying mechanism of frequent changes in drug concentrations due to the concomitant use of herbal products can involved the inhibition or induction of drug metabolizing enzymes in the intestine and liver, especially cytochrome (CYP) P-450 and drug transporters such as P-glycoprotein (PgP)^33,34.

Considering their absorption, distribution, metabolism, and elimination the consequences of drugs in the body can be predicted by performing pharmacokinetic studies. The obtained results are not necessarily consistent with the actual use in humans because this study was performed in rats. Different from humans, rats have a distinct enzyme system. The effect of ELO extract on rosiglitazone pharmacokinetics and its bioavailability in Sprague-Dawley male rats was observed in oral and intravenous studies. After pretreatment of old male rats with ELO, some pharmacokinetic parameters decreased, whereas others increased. However, only in the Vd and CL parameters in the oral study demonstrated significant changes. Vd and CL parameter are the primary parameters for distribution and elimination process, respectively. These parameters are independent of each other; therefore, the distribution volume may be maintained despite changes in the clearance, and vice versa, a change in clearance will not influence the volume of distribution³⁵. Disease or physiological changes may account for variations in the distribution and clearance of a drug³⁶. Drug interactions with body components influence drug distribution, whereas drug physicochemical properties (such as molecular weight, degree of ionization, pK_a_,and lipid solubility) and physiological parameters (such as pH, plasma protein binding, blood flow, membrane permeability, and nature of the tissue) affect distribution patterns³⁷. All elimination processes indicate the concept of clearance. Drugs may be eliminated either unchanged through the excretion process or converted to metabolites by biotransformation reactions. Genetic variation, environmental determinants and disease factors may alter the biotransformation of drugs. The kidney is the most important excretory organ; therefore, the process is affected by renal blood flow, tubular secretion, glomerular filtration, and tubular reabsorption³⁷. ELO extract is known for its capacity to increase testosterone levels^10,38. High levels of plasma testosterone may increase blood flow in the body and kidneys and lead to increases in the volume of distribution and renal clearance.

Previous studies reported that in humans, rosiglitazone is rapidly absorbed and essentially completely absorbed. The absolute bioavailability of rosiglitazone reaches 99% and 95% after administration of oral tablets and oral solution, respectively, and is excreted mainly as metabolites. N-demethylation (as N-desmethylrosiglitazone) and hydroxylation pathways are the main routes of rosiglitazone metabolism^39,40. The absolute bioavailability of rosiglitazone was 63% and 60% in the single rosiglitazone and rosiglitazone + ELO groups, respectively. In the first group, this finding may be caused by the low absorption of rosiglitazone in rats so the results cannot be extrapolated directly to humans. In the second group, this finding may be influenced by ELO, thus requiring another experiment to confirm the results, for example, a pharmacokinetic study of rosiglitazone after ELO administration for a long-term period. On the other hand, the effect of ELO extract on rosiglitazone absorption can be seen from the decrease in the average AUC 0--∞ value which was originally 118.83 µg.h/mL to 76.64 µg.h/mL, although statistically there was no significant difference. Salman et al. (2010)¹³ stated that ELO extract can induce intestinal P-gP and may affect drug absorption. CYP3A4 and intestinal PgP play important roles in influencing the bioavailability of various drugs. Modulation of intestinal PgP and CYP3A processes are important mechanism that may either increase or decrease the bioavailability of concomitant medications^11,41,42.

Salman et al. (2010)¹³ studied interaction and found a 29% and 40% reduction in propanolol bioavailability and C_max, respectively, in healthy nonsmoking young males due to E. longifolia water extract. T_max was significantly increased by 86%, but no significant changes were observed in the elimination half-life. Based on their results, rather than its metabolism, the water E. longifolia herb extract affected propanolol absorption. Rational usage of herbal remedies can be encouraged by evaluating herb drug interactions and conducting studies on herbal pharmacokinetics. Numerous studies on herb drug interactions and clinical pharmacokinetics have been conducted^43,44. However, most clinical studies have focused on popular herbs due to the complex composition of herbal remedies and limited knowledge of their active constituents, and pharmacokinetic studies have been restricted to certain constituents ¹.

CONCLUSION:

The intravenous study results revealed that ELO had no effect on the rosiglitazone pharmacokinetic profile. In the oral study, ELO did not significantly reduce rosiglitazone bioavailability but significantly increased the CL and Vd parameters.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors would like to thank the 2023 Academic Excellence Grant program, Universitas Gadjah Mada, which provided financial support for this research project.

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Received on 10.06.2024 Revised on 17.10.2024

Accepted on 27.12.2024 Published on 02.05.2025

Available online from May 07, 2025

Research J. Pharmacy and Technology. 2025;18(5):2356-2362.

DOI: 10.52711/0974-360X.2025.00337

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