Bioequivalence Analysis of Ondansetron Hydrochloride Tablets in Healthy Chinese Subjects: A Randomized, Open-Label, Two-Period Crossover Phase I Study.

BACKGROUND: Ondansetron is a highly selective 5-HT3 receptor antagonist that alleviates nausea and vomiting. Bioequivalence evaluation ensures that the efficacy of generic drugs is consistent with that of the original drug. OBJECTIVE: The objective of this study was to evaluate the bioequivalence of ondansetron hydrochloride (HCl) tablets taken in single doses under fasting and postprandial conditions in healthy subjects. METHODS: In this randomized, open-label, two-cycle, crossover phase I study, liquid chromatography‒tandem mass spectrometry (LC‒MS/MS) was used to determine the ondansetron concentration in dipotassium-ethylenediaminetetraacetate (K2-EDTA) plasma after the subjects received a single 8 mg of ondansetron and reference formulation. Twenty-six healthy subjects received one tablet of ondansetron under fasting conditions and 28 subjects received one under postprandial conditions. Bioequivalence was established if the 90% confidence interval (CI) was 80.00-125.00%. The pharmacokinetic parameters were calculated via WinNonLin 8.1 software and the bioequivalence data were evaluated via Phoenix WinNonlin 8.1 statistics software. RESULTS: The geometric mean ratio (GMR) of the maximum observed concentration (Cmax), the area under the plasma concentration‒time curve (AUC) from time zero to the last sampling time (AUC0-t), and the AUC from time zero to infinity (AUC0-∞) from the test/reference formulation under fasting conditions were 90.50, 90.43, and 90.25, respectively. The 90% CIs were 83.75-97.79, 82.64-98.95, and 82.25-99.03, respectively. The GMRs of Cmax, AUC0-t, and AUC0-∞ after a high-fat meal were 96.85, 93.57, and 93.77, respectively; the 90% CIs were 88.43-106.07, 87.35-100.24, and 87.35-100.68, respectively. CONCLUSION: The test and reference formulations of ondansetron HCl have bioequivalence for healthy adult subjects under fasting and postprandial conditions.

Pharmacokinetics and Bioequivalence of Apremilast Tablets in Chinese Healthy Subjects Under Fasting and Postprandial States.

Objective: This study compared the pharmacokinetics, safety and bioequivalence (BE) of generic and original apremilast tablets in healthy Chinese subjects under fasting and postprandial conditions, providing sufficient evidence for abbreviated new drug application. Methods: A randomized, open-label, two-formulation, single-dose, two-period crossover pharmacokinetic study was performed. Thirty-two eligible healthy Chinese subjects were enrolled in fasting and postprandial studies, respectively. In each trial, subjects received a single 30-mg dose of the test or reference apremilast tablet, followed by a 7-day washout interval between periods. Serial blood samples were obtained for up to 48 h post-intake in each period, and the plasma concentrations of apremilast were determined by a validated method. The primary pharmacokinetic (PK) parameters, including the maximum plasma concentration (Cmax), the areas under the plasma concentration-time curve (AUC0-t, AUC0-∞), were calculated using the non-compartmental method. The geometric mean ratios of the two formulations and the corresponding 90% confidence intervals (CIs) were acquired for bioequivalence analysis. The safety of both formulations was also evaluated. Results: Under fasting and postprandial states, the PK parameters of the test drug were similar to those of the reference drug. The 90% CIs of the geometric mean ratios of the test to reference formulations were 94.09-103.44% for Cmax, 94.05-103.51% for AUC0-t, and 94.56-103.86% for AUC0-∞ under fasting conditions, and 99.18-112.48% for Cmax, 98.79-106.02% for AUC0-t, and 98.95-105.89% for AUC0-∞ under postprandial conditions, all of which were within the bioequivalence range of 80.00-125.00%. Both formulations were well tolerated, and no serious adverse events occurred during the study. Conclusion: The trial confirmed that the PK parameters of the generic and original apremilast tablets were bioequivalent in healthy Chinese subjects under fasting and postprandial states, which met the predetermined regulatory standards. Both formulations were safe and well tolerated. Clinical Trial Registration: chinaDrugtrials.org.cn, identifier CTR20191056 (July 30, 2019); chictr.org.cn, identifier ChiCTR2300076806 (October 19, 2023).

Effect of High-Fat Meal on the Pharmacokinetics and Safety of Valsartan/Amlodipine Fixed Dose Combination Tablets in Healthy Subjects.

Background: The objective of this study was to evaluate the effect of a high-fat meal on the pharmacokinetics and safety of 80/5 mg valsartan/amlodipine tablets in healthy subjects. Subjects and Methods: These results were derived from a bioequivalence trial where subjects were randomly assigned to take valsartan/amlodipine 80/5mg under fed conditions or after a high-fat meal contained 978.6 kilocalories (54.6% from fat). The blood samples were collected and plasma concentrations of valsartan/amlodipine were measured using high-performance liquid chromatography-mass spectrometry. The non-compartmental module of Phoenix WinNonlin Version 8.2 was used to calculate pharmacokinetic parameters. The BE module of WinNonLin was used to analyze the statistics of the maximum plasma concentration (Cmax), the area under the concentration-time curve from zero to the last quantifiable time point (AUC0-t), and the area under the concentration-time curve from zero to infinity(AUC0-∞) in plasma. 88 healthy subjects were enrolled and divided into in a fasted group and a fed group. Results: The Cmax, AUC0-t, and AUC0-∞ of valsartan in plasma under fed conditions were 51%, 56%, and 57% lower, respectively, than those under fasted conditions, and the 90% confidence interval (90% CI) were outside the 80.00-125.00% range. All the pharmacokinetic parameters for amlodipine under fed conditions were similar to those observed under fasted conditions, and the 90% CIs were within the 80.00-125.00% range. The incidence of treatment emergent adverse events (TEAE) was similar between the fasted group and the fed group, while adverse drug reaction (ADR) was more frequent in the fasted group which may be related to the higher blood concentrations of valsartan, but all were mild. Conclusion: The result indicated that the high-fat meal had a significant effect on the pharmacokinetics of valsartan, but no effect on amlodipine. All treatments were safe and well tolerated in healthy subjects under fed and fasted conditions.

Selenium-enriched crude polysaccharide from Rosa roxburghii Tratt ameliorates cadmium-induced acute kidney injury in mice by modulating intestinal microorganisms.

Cadmium is a toxic heavy metal that can cause serious damage to the body. It can trigger the oxidative stress response and damage various organs of the body (kidney, liver, brain, lung, testis, etc.). Selenium polysaccharides are considered to possess better antioxidant, immune regulation, and heavy metal removal activities than other polysaccharides, But few reports focused on Selenium Polysaccharides in Rosa roxburghii Tratt. The purpose of this study was to isolate crude polysaccharides (RRP), and crude Selenium polysaccharides (SeRRP) from Rosa roxburghii Tratt fruit and determine their structure, antioxidant activity, and protective effects on cadmium-exposed mice (PONY-2020-FL-62). Results showed that SeRRP had lower half-maximal inhibitory concentration (IC50) and higher superoxide dismutase (SOD) activity. The intake of food and body weight decreased, while the kidney index and liver index increased significantly after acute cadmium exposure. Most significantly, SeRRP ameliorates kidney injury by improving the kidney index. Furthermore, changes in the gut microbiota may be related to SeRRP or RRP. SeRRP and RRP decreased the Firmicutes/Bacteroidetes ratio, and increased the abundance of beneficial bacteria (Lachnospiraceae, Muribaculaceae, and Ruminococcaceae, etc.). These findings indicate that SeRRP and RRP have the potential to be functional food against oxidant and heavy metal exposure.

Bioequivalence Study of Vortioxetine Hydrobromide Tablets in Healthy Chinese Subjects Under Fasting and Fed Conditions.

Objective: This study compared the pharmacokinetic and safety profiles of generic and original vortioxetine hydrobromide tablets under fasting and fed conditions, and evaluated the bioequivalence of two vortioxetine formulations to obtain sufficient evidence for abbreviated new drug application. Methods: A randomized, open-label, two-formulation, single-dose, two-period crossover bioequivalence study was conducted under fasting and fed conditions (n = 32 per study). Eligible healthy Chinese subjects received a single 10-mg dose of the test or reference vortioxetine hydrobromide tablet, followed by a 28-day washout interval between periods. Serial blood samples were collected up to 72 h after administration in each period, and the plasma concentrations of vortioxetine were detected using a validated method. The primary pharmacokinetic (PK) parameters were calculated using the non-compartmental method. The geometric mean ratios for the PK parameters of the test drug to the reference drug and the corresponding 90% confidence intervals were acquired for bioequivalence analysis. A safety evaluation was performed throughout the study. Results: Under fasting and fed conditions, the PK parameters of the test drug were similar to those of the reference drug. The 90% confidence intervals (CIs) of the geometric mean ratios of the test to reference formulations were 96.44-105.81% for peak concentration (Cmax), 97.94-105.05% for the area under the curve truncated at 72 hours (AUC0-72 h) under fasting conditions, 93.92-104.15% for Cmax, and 96.67-102.55% for AUC0-72 h under fed conditions, all of which were within the accepted bioequivalence range of 80.00-125.00%. Both the test and reference formulations were well-tolerated, and no serious adverse events related to the study drug were reported during the study. Conclusion: The PK bioequivalence of the test and reference vortioxetine hydrobromide tablets in healthy Chinese subjects was established under fasting and fed conditions, which met the predetermined regulatory criteria. Both formulations were safe and well tolerated.

Determination of vericiguat in rat plasma by UPLC-MS/MS and its application to drug interaction.

Vericiguat (VER) is a novel soluble guanylate cyclase stimulator treating symptomatic chronic heart failure (HF), and it is a substrate of both transporters P-glycoprotein and breast cancer resistance protein (BCRP). Astragaloside IV (ASIV) is the main active ingredient in Radix Astragali (Huangqi), a traditional Chinese medicine widely used for HF treatment in China. ASIV's effect on the protein expression of P-glycoprotein and BCRP has been observed, its impact on VER metabolism remain uncertain. In the present study, male Sprague-Dawley rats were administered with 20 mg/kg ASIV and 1 mg/kg VER to study their pharmacokinetics. Blood samples were subject to liquid-liquid extraction, and riociguat was employed as the internal standard (IS). The analytical method involved a C18 column (XSelect® HSS T3 column, 2.1 × 100 mm, 2.5 µm) with a mobile phase of 0.1% formic acid and acetonitrile for gradient elution. The flow rate of the mobile phase was set at 0.2 mL/min, and 5 µL of the sample was used for analysis. The positive ion multi-response monitoring mode was utilized with a transition of m/z 427.4→109.1 for VER and m/z 423.3→109.1 for the IS. The method exhibited good linearity within the concentration range of 0.1 to 300 ng/mL (r = 0.9987), and all the validation processes were conducted in accordance with the requirements of biological analysis. The pharmacokinetic results revealed that ASIV did not significantly alter the main parameters of VER, except for Cmax, which decreased by 33.2% (P < 0.05). Overall, our study successfully established a selective, sensitive and repeatable ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis for detecting VER in rat plasma.

In vivo assessment of the pharmacokinetic interactions between donafenib and dapagliflozin, donafenib and canagliflozin in rats.

Donafenib (DONA), a deuterium derivative of sorafenib, is used for advanced hepatocellular carcinoma (HCC). Dapagliflozin (DAPA) and canagliflozin (CANA) are sodium-glucose co-transporter 2 (SGLT2) inhibitors used for T2DM, which is frequently comorbid with HCC. Three drugs are substrates of UGT1A9 isoenzyme. This study aimed to evaluate donafenib-dapagliflozin and donafenib-canagliflozin pharmacokinetic interactions and explore the potential mechanisms. Rats were divided into seven groups (n = 6) that received donafenib (1), dapagliflozin (2), canagliflozin (3), dapagliflozin and donafenib (4), canagliflozin and donafenib (5), donafenib and dapagliflozin (6), donafenib and canagliflozin (7). The concentrations of drugs were determined by an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. The messenger RNA (mRNA) expressions were measured by quantitative RT-PCR. Multiple doses of dapagliflozin caused donafenib maximum plasma concentration (Cmax) to increase 37.01%. Canagliflozin increased donafenib Cmax 1.77-fold and the area under the plasma concentration-time curves (AUC0-t and AUCinf) 1.39- and 1.41-fold, respectively, while reducing the apparent clearance (CLz) 28.38%. Multiple doses of donafenib increased dapagliflozin AUC0-t 1.61-fold, AUCinf 1.77-fold, whereas its CLz reduced 40.50%. Furthermore, donafenib caused similar changes in canagliflozin pharmacokinetics. The PCR results demonstrated that dapagliflozin inhibited the mRNA expression of Ugt1a7 in liver and donafenib decreased the expression of Ugt1a7 mRNA in liver and intestine. Increased exposure to these drugs may be due to their metabolism inhibition mediated by Ugt1a7. These pharmacokinetic interactions observed in this study may be of clinical significance, which may help adjust dose properly and avoid toxicity effects in patients with HCC and T2DM.

Pharmacokinetic Interactions between Canagliflozin and Sorafenib or Lenvatinib in Rats.

Hepatocellular carcinoma (HCC) and type 2 diabetes mellitus (T2DM) are common clinical conditions, and T2DM is an independent risk factor for HCC. Sorafenib and lenvatinib, two multi-targeted tyrosine kinase inhibitors, are first-line therapies for advanced HCC, while canagliflozin, a sodium-glucose co-transporter 2 inhibitor, is widely used in the treatment of T2DM. Here, we developed an ultra-performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of canagliflozin, sorafenib, and lenvatinib, and investigated the pharmacokinetic drug interactions between canagliflozin and sorafenib or lenvatinib in rats. The animals were randomly divided into five groups. Groups I-III were gavage administrated with sorafenib, lenvatinib, and canagliflozin, respectively. Group IV received sorafenib and canagliflozin; while Group V received lenvatinib and canagliflozin. The area under the plasma concentration-time curves (AUC) and maximum plasma concentrations (Cmax) of canagliflozin increased by 37.6% and 32.8%, respectively, while the apparent volume of distribution (Vz/F) and apparent clearance (CLz/F) of canagliflozin significantly decreased (30.6% and 28.6%, respectively) in the presence of sorafenib. Canagliflozin caused a significant increase in AUC and Cmax of lenvatinib by 28.9% and 36.2%, respectively, and a significant decrease in Vz/F and CLz/F of lenvatinib by 52.9% and 22.7%, respectively. In conclusion, drug interactions exist between canagliflozin and sorafenib or lenvatinib, and these findings provide a reference for the use of these drugs in patients with HCC and T2DM.

Determination of Osimertinib, Aumolertinib, and Furmonertinib in Human Plasma for Therapeutic Drug Monitoring by UPLC-MS/MS.

The third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), osimertinib, aumolertinib, and furmonertinib represent a new treatment option for patients with EGFR p.Thr790 Met (T790 M)-mutated non-small cell lung cancer (NSCLC). Currently, there are no studies reporting the simultaneous quantification of these three drugs. A simple ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous quantitative determination of osimertinib, aumolertinib, and furmonertinib concentrations in human plasma, and it was applied for therapeutic drug monitoring (TDM). Plasma samples were processed using the protein precipitation method (acetonitrile). A positive ion monitoring mode was used for detecting analytes. D3-Sorafenib was utilized as the internal standard (IS), and the mobile phases were acetonitrile (containing 0.1% formic acid) and water with gradient elution on an XSelect HSS XP column (2.1 mm × 100.0 mm, 2.5 µm, Waters, Milford, MA, USA) at a flow rate of 0.5 mL·min-1. The method's selectivity, precision (coefficient of variation of intra-day and inter-day ≤ 6.1%), accuracy (95.8-105.2%), matrix effect (92.3-106.0%), extraction recovery, and stability results were acceptable according to the guidelines. The linear ranges were 5-500 ng·mL-1, 2-500 ng·mL-1, and 0.5-200 ng·mL-1 for osimertinib, aumolertinib, and furmonertinib, respectively. The results show that the method was sensitive, reliable, and simple and that it could be successfully applied to simultaneously determine the osimertinib, aumolertinib, and furmonertinib blood concentrations in patients. These findings support using the method for TDM, potentially reducing the incidence of dosing blindness and adverse effects due to empirical dosing and inter-patient differences.

Pentraxin 3 depletion (PTX3 KD) inhibited myocardial fibrosis in heart failure after myocardial infarction.

BACKGROUND: HF is a common complication of MI. The underlying mechanisms of myocardial fibrosis in HF after MI are incompletely defined. Here, this study aims to investigate the role of PTX3 KD in HF after MI. METHODS: Bioinformatics analysis based on GSE86569 dataset was performed to explore the potential role of PTX3 in HF. Male C57/BL6J mice were administered with lentiviral vector encoding PTX3 KD or empty vector, and then underwent either coronary ligation or sham surgery. Echocardiography, Masson staining, and immunofluorescence counterstaining were conducted to evaluate the cardiac function and fibrosis. Cardiac fibroblasts were isolated and transfected with lentiviral vector encoding PTX3 KD in vitro to verify the in vivo findings. RESULTS: Bioinformatics analysis based on GSE86569 revealed the aberrant expression of PTX3 in HF patients. Echocardiography showed that PTX3 KD reversed the HF-induced cardiac dysfunction with better cardiac function parameters. Masson staining demonstrated that the obvious infarct and high fibrosis ratio in HF mice were remarkably improved after PTX3 KD. Immunofluorescence staining indicated that the HF-induced increase expression of α-SMA was significantly suppressed by PTX3 KD. Additionally, both in vivo and in vitro results confirmed that PTX3 KD decreased the fibrosis-related up-regulation of collagen I, collagen III, and p-STAT3. However, the result was opposite after IL-6 treatment. CONCLUSIONS: PTX3 KD protects the cardiac function and counteracts the myocardial fibrosis by down-regulating IL-6/STAT3 pathway in HF.

Wuzhi capsule increased systemic exposure to methotrexate by inhibiting the expression of OAT1/3 and P-gp.

BACKGROUND: Methotrexate (MTX) is an important anticancer agent and immunosuppressant with a narrow therapeutic window. Wuzhi capsule (WZC) is an extract of Schisandra which is widely used to treat liver diseases. Co-administration of MTX and WZC is common in the clinical setting, but research on the interaction between WZC and MTX is limited. This study aimed to investigate the effects of WZC on the pharmacokinetics of MTX in rats and to explore the role of membrane transport proteins OAT1/3 and P-gp in the interaction of these drugs. METHODS: Plasma MTX concentration was detected by ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS), and the messenger RNA (mRNA) and protein expression of OAT1/3 and P-gp was evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting analyses, respectively. RESULTS: The study results revealed that co-administration of WZC decreased the CLz/F and Vz/F of MTX, increased the Cmax and area under the curve [(AUC)0-24 h] of MTX, and inhibited OAT1/3 expression in the kidney and P-gp expression in the small intestine. CONCLUSIONS: The findings suggested that there is a drug interaction between WZC and MTX and that OAT1/3 in the kidney and P-gp in the small intestine may be the main targets mediating the drug interaction, and attention should be paid when they are used in combination.

Application of hollow fiber centrifugal ultrafiltrate purification as the pretreatment technology for traditional Chinese medicine: its application for analysis of honokiol and magnolol in TCM preparations containing Cortex Magnoliae Officinalis.

BACKGROUND: Traditional Chinese medicine (TCM) preparations are very complex mixtures, and the content of bioactive components is usually very low. Therefore, before final analysis, the preparation of an appropriate sample is necessary. Sample preparation is the most time-consuming and error-prone part of the analytical procedure, and the choice of purification technology greatly influences the reliability of the final analysis. METHODS: In the present study, we evaluated the feasibility of hollow fiber centrifugal ultrafiltrate (HFCF-UF) as a purification technology for the analysis of bioactive components in TCM preparations. The HFCF-UF technology was applied to analyze honokiol and magnolol in TCM preparations containing Cortex Magnoliae Officinalis (Hou Po in Chinese Pinyin). A mini centrifugal device based on hollow fiber was employed to remove the macromolecule components. A single step of simple centrifugation was required before the filtrate could be directly injected into an existing high performance liquid chromatography (HPLC) system without any further clean-up step or use of special columns. This greatly simplified the pretreatment steps, and improved the accuracy of analytic methods. The separation was achieved on a Diamonsil C18 column (i.d. 5 µm, 150 mm × 4.6 mm) with V (methanol):V (acetonitrile):V (0.5% acetic acid solution) =44:22:34 as the mobile phase at a flow rate of 1.0 mL/min. RESULTS: It had good linear relationship between the peak areas of honokiol and magnolol and their concentrations at 6.40-205 and 3.15-101 µg/mL (r=0.9999), respectively. The method recovery was over 92.6% with a relative standard deviation (RSD) of less than 3.0%. The average recovery of honokiol was 97.7% with an RSD of 3.0%, and that of magnolol was 96.8% with RSD of 2.8%. CONCLUSIONS: The application of HFCF-UF in TCM preparations could assist in making the quality control of TCM simple, rapid, and accurate. The HFCF-UF purification procedure can be used as an alternative means for analyzing bioactive components in TCM preparations.

Association between pharmacokinetics of lenvatinib in healthy subjects and genetic polymorphisms of ABCB1 3435C>T and ABCB1 2677G>T/A.

The aim of this study was to evaluate the impact of genetic polymorphisms in the pharmacokinetics of metabolism and transportation of lenvatinib in the Chinese population.Sixty-three healthy Chinese individuals were recruited and administered with a single dose of 4 mg lenvatinib. Allelic discriminations for 10 SNPs of CYP3A4 (20230 G>A(*1G)), CYP3A5 (6986 A>G(*3)), ABCB1 (1236 C>T, 2677 G>T/A, 3435 C>T), ABCG2 (421 C>A, 34 G>A), ABCC2 (-24 C>T, 1249 G>A, 3972 C>T) were performed. The concentrations of lenvatinib in the plasma were determined by UPLC-MS/MS.Under the fasting condition, individuals carrying of ABCB1 3435 C>T genotype presented lower Cmax (p < 0.01) and λz (p < 0.05), but higher t1/2 (p < 0.05) than those carrying C/C and T/T genotypes. For ABCB1 2677 G>T/A variant, individuals with the G/T and A/G genotype showed higher AUC (p < 0.05) and t1/2 (p < 0.01), but lower λz (p < 0.05) than those carrying G/G genotypes. Individuals with the A/T, A/A and T/T genotype had higher AUC, but no significant differences (p > 0.05) were observed. They also had higher t1/2 (p < 0.01) and lower λz (p < 0.01) than those carrying G/G genotypes.Under the fed condition, no difference in any pharmacokinetic parameters were observed with any polymorphisms in the 10 fragments.Data in this paper had demonstrated that polymorphisms ABCB1 3435 C>T and ABCB1 2677 G>T/A were associated with the pharmacokinetic variability of lenvatinib.

Comparative pharmacokinetics of seven bioactive components in normal, sham-operated, and myocardial ischemia-reperfusion injury rats after oral administration of the Salvia Miltiorrhiza-Moutan Cortex herb pair.

Recently the Salvia Miltiorrhiza-Moutan Cortex (SM-MC) herb pair is considered as a promising Chinese medicinal mixture exhibiting a range of pharmacological activities, including treating cardiovascular disease due to its unique composition. In this study, we conducted the comparative pharmacokinetic analysis of seven main bioactive components of SM-MC in a different model rat. A straightforward ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) strategy that could simultaneously evaluate the levels of seven compounds was used to ensure the reliability of these pharmacokinetic analyses in rat plasma. The rat plasma samples were collected from normal, sham-operated, and myocardial ischemia-reperfusion injury (MIRI) groups at predetermined time points after the administration of SM-MC. The main pharmacokinetic parameters were detected and calculated. We successfully assessed the maximum concentration (Cmax ), time to Cmax (Tmax ), the elimination rate constant (λz ), total half-life (t1/2 ), total body clearance (CL), and the area under the concentration-time curve from 0 to last sampling time (AUC0-t ) and extrapolated to infinity (AUC0-∞ ). To sum up, an optimized UPLC-MS/MS approach that could be used to rapidly, simultaneously, and sensitively detect seven bioactive compounds derived from SM-MC extract preparations was successfully developed, which may offer a pharmacokinetic basis for preclinical and clinical studies of SM-MC herb pair for treating MIRI.