Safety, tolerability, pharmacokinetics, and immunogenicity of an anti-SARS-CoV-2 monoclonal antibody HFB30132A after single dose intravenous administration in healthy Chinese subjects: a phase 1, randomized, double-blind, placebo-controlled study.

Objective: The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) still protracts worldwide. HFB30132A is an anti- SARS-CoV-2 monoclonal antibody purposely engineered for an extended half-life with neutralizing activity against majority of the virus variants identified so far. The aim of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of HFB30132A in healthy Chinese subjects. Methods: A phase 1, randomized, double-blind, placebo-controlled, single ascending dose clinical trial was designed. Twenty subjects were enrolled to Cohort 1 (1,000 mg dose level, 10 subjects) or Cohort 2 (2,000 mg dose level, 10 subjects). Subjects in each cohort were assigned randomly to receive a single intravenous (IV) dose of HFB30132A or placebo at a ratio of 8:2. Safety was assessed in terms of treatment emergent adverse events (TEAEs), vital signs, physical examination, laboratory tests, and ECG findings. PK parameters were measured and calculated appropriately. Anti-drug antibody (ADA) test was performed to detect anti-HFB30132A antibodies. Results: All subjects completed the study. Overall, 13 (65%) of the 20 subjects experienced TEAEs. The most common TEAEs were laboratory abnormalities (12 subjects [60%]), gastrointestinal disorders (6 subjects [30%]), and dizziness (4 subjects [20%]). All TEAEs were Grade 1 or Grade 2 in severity based on the criteria of Common Terminology Criteria for Adverse Events (CTCAE). Serum exposure (Cmax, AUC0-t, AUC0-∞) of HFB30132A increased with ascending dose. After single dose of 1,000 mg and 2000 mg HFB30132A, the mean Cmax was 570.18 µg/mL and 898.65 µg/mL, the mean AUC0-t value was 644,749.42 h*µg/mL and 1,046,209.06 h*µg/mL, and the mean AUC0-∞ value was 806,127.47 h*µg/mL and 1,299,190.74 h*µg/mL, respectively. HFB30132A showed low clearance ranging from 1.38 to 1.59 mL/h, and a long terminal elimination half-life (t½) of 89-107 days. ADA test did not detect any anti-HFB30132A antibodies Conclusion: HFB30132A was safe and generally well-tolerated after single IV dose of 1,000 mg or 2000 mg in healthy Chinese adults. HFB30132A did not induce immunogenic response in this study. Our data support further clinical development of HFB30132A. Clinical Trial Registration: https://clinicaltrials.gov, identifier: NCT05275660.

Integrative population pharmacokinetic/pharmacodynamic analysis of nemonoxacin capsule in Chinese patients with community-acquired pneumonia.

Introduction: Nemonoxacin is an innovative quinolone antibiotic for treatment of community-acquired pneumonia (CAP). As more data are available from clinical studies, it is necessary to perform an integrative pharmacokinetic/pharmacodynamic (PK/PD) analysis to support and justify the optimal dosing regimen of nemonoxacin in clinical practice. Methods and Results: We developed a population PK model using non-linear mixed effect model based on the data of 195 Chinese subjects receiving nemonoxacin in phase I to III clinical trials. The base model was a standard two-compartment PK model defined by clearance (12 L/h) and central volume of distribution (86 L). Covariates included creatinine clearance (CLcr), body weight (BW), sex, disease status and food. Compared to the subject with BW 60 kg, Cmax and A U C 0 - 24 , ss reduced by 24% and 19% in the subject with BW 80 kg, respectively. Compared to the subject with CLcr 150 ml/min, A U C 0 - 24 , ss and T1/2 increased by 28% and 24%, respectively in the subject with CLcr 30 ml/min. Compared to the fasted status, Tmax of nemonoxacin increased by 1.2 h in the subject with fed status. Effects of sex and disease status on PK parameters were small (change of PK parameters ≤19%). AUC0-24/MIC and %T > MIC were identified as the optimal PK/PD indices for predicting clinical efficacy. The AUC0-24/MIC target was 63.3, 97.8, and 115.7 against Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae, respectively. The %T > MIC target was 7.96% against Klebsiella pneumoniae. Monte Carlo simulation showed that treatment with nemonoxacin 500 mg q24 h could attain a PK/PD cutoff value higher than the MIC90 against S. pneumoniae and S. aureus. The corresponding cumulative fraction of response (CFR) was greater than 93%, while nemonoxacin 750 mg q24 h would provide higher PK/PD cutoff value against Haemophilus parainfluenzae, and higher CFR (83%) than 500 mg q24 h. Conclusion: Integrative PK/PD analysis justifies the reliable clinical and microbiological efficacy of nemonoxacin 500 mg q24 h in treating CAP caused by S. pneumoniae, S. aureus, and K. pneumoniae, irrespective of patient sex, mild renal impairment, empty stomach or not. However, nemonoxacin 750 mg q24 h would provide better efficacy than 500 mg q24 h for the CAP caused by H. parainfluenzae in terms of CFR.

Pharmacokinetics of benapenem for injection in subjects with mild to moderate renal impairment.

OBJECTIVE: This study evaluated the pharmacokinetic (PK) characteristics of benapenem in subjects with mild to moderate renal impairment to provide a reference for benapenem dosing regimens in this patient population. METHODS: Eighteen subjects were enrolled in this study. Each subject received a single dose of benapenem intravenously (1.0 g in 100 ml of 0.9% saline) followed by blood and urine collection to measure the concentrations of benapenem and its major metabolite. PK analysis was performed to evaluate the effect of varying degrees of renal impairment on the PK characteristics of benapenem. The safety of benapenem was also evaluated. RESULTS: In subjects with normal renal function, mild renal impairment, and moderate renal impairment, the maximum plasma benapenem concentrations were 163 ± 6.58 mg/L, 138 ± 17.4 mg/L, and 134 ± 0.11 mg/L, respectively (15.3% and 17.8% lower in subjects with mild and moderate renal impairment, respectively, than in subjects with normal renal function). The areas under the plasma concentration-time curve (AUC0-inf) were 1153.67 ± 143.2 mg·h/L, 1129.17 ± 241.41 mg·h/L, and 1316.46 ± 229.83 mg·h/L, respectively (P > 0.05); the cumulative urinary excretion rates at 72 h after dosing were 52.61 ± 8.58%, 39.42 ± 8.35%, and 29.84 ± 9.15%, respectively; and the metabolic ratio (AUC0-inf_KBP-3331/AUC0-inf_benapenem) were 3.96 ± 0.35%, 5.56 ± 0.82%, and 8.24 ± 0.85%, respectively. No drug-related adverse events (AEs), serious AEs, or AEs leading to withdrawal occurred in this study. CONCLUSION: No adjustment to benapenem dosing is needed in patients with mild to moderate renal impairment. CLINICAL TRIAL REGISTRATION: Drug clinical trial registration and information publicity platform: http://www.chinadrugtrials.org.cn/index.html . REGISTRATION NUMBER: CTR20190760.

Pharmacokinetics and pharmacodynamics of levofloxacin in bronchial mucosa and lung tissue of patients undergoing pulmonary operation.

Levofloxacin is a major antimicrobial agent that is used for the treatment of community-acquired lower respiratory tract infections (LRTIs). The present study was designed to investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of levofloxacin in bronchial mucosa and lung tissue. A total of 32 patients undergoing pulmonary surgery were randomly assigned to one of four groups (8 subjects/group). All patients received a single dose of 500 mg levofloxacin orally prior to the operation. Blood, lung tissue and bronchial mucosa samples were collected prior to treatment and at 1.5, 4, 8, 12 and 24 h following treatment. The drug concentration was determined and PK and PD profiles were calculated using MATLAB software. The peak concentration of levofloxacin was 7.0±1.2 µg/g in lung tissues and 9.4±2.1 µg/g in bronchial mucosa. The corresponding area under the curve between 0 and 24 h (AUC0-24) was 85.7±8.5 and 137.3±19.4 µg h/g. The mean permeability of levofloxacin (ratio of concentration in tissue to that in plasma) was 2.4 in lung tissue and 4.4 in the bronchial mucosa. The PK profiles of levofloxacin in the plasma, lung and bronchial mucosa were described using an integrated one-compartment model. The probability of fAUC0-24/minimal inhibitory concentration (MIC) target attainment of levofloxacin against Streptococcus pneumoniae in the lung and bronchial mucosa was maintained at 100% when MIC ≤1 mg/l, while the cumulative fraction of fAUC0-24/MIC in the corresponding tissues was 94.4 and 98.1%, respectively. The present study demonstrated the high permeability of levofloxacin in the lung and bronchial mucosa of patients undergoing pulmonary surgery. In conclusion, treatment using 500 mg levofloxacin exhibits good clinical and microbiological efficacy for use in LRTIs that are caused by S. pneumoniae. This trial was registered retrospectively in the Chinese Clinical Trial Registry on January 13, 2020 (registration no. ChiCTR2000029096).

[Accuracy of two thyroid imaging, reporting and data systems for differential diagnosis of benign and malignant thyroid nodules].

OBJECTIVE: To compare the accuracy of two widely used thyroid imaging, reporting and data systems (TI-RADS), namely ACR TI-RADS and Kwak TI-RADS, in the differential diagnosis of benign and malignant thyroid nodules. METHODS: We reviewed the data of 350 thyroid nodules with definite diagnoses by surgical histopathology (n=144, 41.14%) or fine needle aspiration (FNA) cytopathology (n=206, 58.86%). The nodules were graded using ACR TI-RADS and Kwak TI-RADS based on the ultrasound images, and the diagnostic accuracy of these two systems was evaluated by the area under the receiveroperating characteristic curve (AUC). RESULTS: The AUCs of ACR TI-RADS and Kwak TI-RADS were both 0.879. For a differential diagnosis of the thyroid nodules, ACR TI-RADS had a diagnostic sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, Youden's index and accuracy of 77.3%, 89.1%, 83.0%, 85.1%, 7.101, 0.255, 27.848, 0.664 and 0.843, respectively, with an optimal threshold of TR5, as compared with 84.8%, 84.0%, 78.3%, 89.0%, 5.283, 0.181, 29.265, 0.688 and 0.843, respectively, of Kwak TI-RADS, which had an optimal threshold of 4c. CONCLUSIONS: Both ACR TI-RADS and Kwak TI-RADS have good performance for differential diagnosis of thyroid nodules, but ACR TI-RADS has a higher specificity and a lower sensitivity compared with Kwak TI-RADS.

Identification of potential functional genes in papillary thyroid cancer by co-expression network analysis.

Interactions between multiple genes are involved in the development of complex diseases. However, there are few analyses of gene interactions associated with papillary thyroid cancer (PTC). Weighted gene co-expression network analysis (WGCNA) is a novel and powerful method that detects gene interactions according to their co-expression similarities. In the present study, WGCNA was performed in order to identify functional genes associated with PTC using R package. First, differential gene expression analysis was conducted in order to identify the differentially expressed genes (DEGs) between PTC and normal samples. Subsequently, co-expression networks of the DEGs were constructed for the two sample groups, respectively. The two networks were compared in order to identify a poorly preserved module. Concentrating on the significant module, validation analysis was performed to confirm the identified genes and combined functional enrichment analysis was conducted in order to identify more functional associations of these genes with PTC. As a result, 1062 DEGs were identified for network construction. A brown module containing 118 highly related genes was selected as it exhibited the lowest module preservation. After validation analysis, 61 genes in the module were confirmed to be associated with PTC. Following the enrichment analysis, two PTC-related pathways were identified: Wnt signal pathway and transcriptional misregulation in cancer. LRP4, KLK7, PRICKLE1, ETV4 and ETV5 were predicted to be candidate genes regulating the pathogenesis of PTC. These results provide novel insights into the etiology of PTC and the identification of potential functional genes.

Population Pharmacokinetics and Dosing Regimen Optimization of Meropenem in Cerebrospinal Fluid and Plasma in Patients with Meningitis after Neurosurgery.

Meropenem is used to manage postneurosurgical meningitis, but its population pharmacokinetics (PPK) in plasma and cerebrospinal fluid (CSF) in this patient group are not well-known. Our aims were to (i) characterize meropenem PPK in plasma and CSF and (ii) recommend favorable dosing regimens in postneurosurgical meningitis patients. Eighty-two patients were enrolled to receive meropenem infusions of 2 g every 8 h (q8h), 1 g q8h, or 1 g q6h for at least 3 days. Serial blood and CSF samples were collected, and concentrations were determined and analyzed via population modeling. Probabilities of target attainment (PTA) were predicted via Monte Carlo simulations, using the target of unbound meropenem concentrations above the MICs for at least 40% of dosing intervals in plasma and at least of 50% or 100% of dosing intervals in CSF. A two-compartment model plus another CSF compartment best described the data. The central, intercentral/peripheral, and intercentral/CSF compartment clearances were 22.2 liters/h, 1.79 liters/h, and 0.01 liter/h, respectively. Distribution volumes of the central and peripheral compartments were 17.9 liters and 3.84 liters, respectively. The CSF compartment volume was fixed at 0.13 liter, with its clearance calculated by the observed drainage amount. The multiplier for the transfer from the central to the CSF compartment was 0.172. Simulation results show that the PTAs increase as infusion is prolonged and as the daily CSF drainage volume decreases. A 4-hour infusion of 2 g q8h with CSF drainage of less than 150 ml/day, which provides a PTA of >90% for MICs of ≤8 mg/liter in blood and of ≤0.5 mg/liter or 0.25 mg/liter in CSF, is recommended. (This study has been registered at ClinicalTrials.gov under identifier NCT02506686.).

High incidence of severe neutropenia after gemcitabine-based chemotherapy in Chinese cancer patients with CDA 79A>C mutation.

Cytidine deaminase (CDA) is a crucial enzyme in gemcitabine inactivation. Mutations in CDA gene have been found to influence the activity of CDA enzyme, which might lead to altered pharmacokinetics profile and clinical outcome of gemcitabine. In this study, the screening for the presence of CDA 79A>C and CDA 208G>A was performed by allele-specific PCR and restriction fragment length polymorphism, respectively. No difference in CDA allele frequencies was found between Chinese cancer patients and healthy volunteers. The frequencies for CDA 79A>C and 208G>A in the studied population were 12.2% and 1.0%, respectively. While a high incidence of grade 3-4 neutropenia was noted as 5 out of 8 (62.5%) patients heterozygous or homozygous for CDA 79A>C mutation developed it, in patients homozygous for the wild-type allele, the incidence was only 17.2% (5 out of 29) (p=0.021). Our study suggests that CDA 79A>C mutation might be a potential risk factor of gemcitabine-induced neutropenia toxicity.

Relative imbalances in the expression of catechol-O-methyltransferase and cytochrome P450 in breast cancer tissue and their association with breast carcinoma.

OBJECTIVE: To investigate the expression levels of genes encoding phase I and phase II estradiol-metabolizing enzymes, and their association with breast cancer risk in Chinese women. METHODS: The mRNA expression levels of cytochrome P450 (CYP) 1A1, 1B1 and 3A4 and catechol-O-methyltransferase (COMT) were examined in the breast tumor tissues, matched adjacent non-tumor tissues and the tissues with benign breast disease (BBD) by fluorescent quantitative real-time PCR. RESULTS: Compared to BBD tissue, the mRNA expression of CYP1A1, CYP1B1 and CYP3A4 significantly reduced by 81.8%, 77.5%, and 85.6%, respectively, in the breast tumor tissue and by 27.2%, 38.8%, and 51.3%, respectively, in the adjacent non-tumor tissue in average (p<0.0001). COMT mRNA was 6.9 and 6.4 fold higher in the breast tumor and match non-tumor tissue (p<0.0001) than in the BBD, respectively. The level of COMT detected in pre-menopausal group and lymph nodal stage N1-N2 group was lower than that in post-menopausal group (p=0.0292) and N0 group (p=0.0389), respectively. CONCLUSION: Significantly deceased expression of estradiol-metabolizing enzymes might result in the excess exposure of intratumoural E2, which could be one of the important risk factors for breast cancer. Significantly elevated COMT expression suggested that COMT could play a key role in breast tumor formation.

Cellular pharmacokinetic mechanisms of adriamycin resistance and its modulation by 20(S)-ginsenoside Rh2 in MCF-7/Adr cells.

BACKGROUND AND PURPOSE: Intracellular pharmacokinetics of anticancer drugs in multi-drug resistance (MDR) cancer cells is hugely important in the evaluation and improvement of drug efficacy. By using adriamycin as a probe drug in MDR cancer cells, we developed a cellular pharmacokinetic-pharmacodynamic (PK-PD) model to reveal the correlation between cellular pharmacokinetic properties and drug resistance. In addition, the ability of 20(S)-ginsenoside Rh2 (20(S)-Rh2) to reverse MDR was further investigated. EXPERIMENTAL APPROACH: The cellular pharmacokinetics of adriamycin were analysed visually and quantitatively in human breast cancer cells MCF-7 and in adriamycin-resistant MCF-7 (MCF-7/Adr) cells. Mitochondria membrane potential was assayed to evaluate the apoptotic effect of adriamycin. Subsequently, a PK-PD model was developed via MATLAB. KEY RESULTS: Visual and quantitative data of the dynamic subcellular distribution of adriamycin revealed that it accumulated in cells, especially nuclei, to a lesser and slower extent in MCF-7/Adr than in MCF-7 cells. 20(S)-Rh2 increased the rate and amount of adriamycin entering cellular/subcellular compartments in MCF-7/Adr cells through inhibition of P-glycoprotein (P-gp) activity, in turn augmenting adriamycin-induced apoptosis. The integrated PK-PD model mathematically revealed the pharmacokinetic mechanisms of adriamycin resistance in MCF-7/Adr cells and its reversal by 20(S)-Rh2. CONCLUSIONS AND IMPLICATIONS: P-gp, which is overexpressed and functionally active at cellular/subcellular membranes, influences the cellular pharmacokinetic and pharmacological properties of adriamycin in MCF-7/Adr cells. Inhibition of P-gp activity represents a key mechanism by which 20(S)-Rh2 attenuates adriamycin resistance. Even more importantly, our findings provide a new strategy to explore the in-depth mechanisms of MDR and evaluate the efficacy of MDR modulators.

Using neural networks to determine the contribution of danshensu to its multiple cardiovascular activities in acute myocardial infarction rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Danshensu is an active water-soluble component from Salvia Miltiorrhiza, which has been demonstrated holding multiple mechanisms for the regulation of cardiovascular system. However, the relative contribution of danshensu to its multiple cardiovascular activities remains largely unknown. AIM OF THE STUDY: To develop an artificial neural network (NN) model simultaneously characterizing danshensu pharmacokinetics and multiple cardiovascular activities in acute myocardial infarction (AMI) rats. The relationship between danshensu pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated using contribution values. MATERIALS AND METHODS: Danshensu was intraperitoneally injected at a single dose of 20mg/kg to AMI rats induced by coronary artery ligation. Plasma levels of danshensu, cardiac troponin T (cTnT), total homocysteine (Hcy) and reduced glutathione (GSH) were quantified. A back-propagation NN model was developed to characterize the PK and PD profiles of danshensu, in which the input variables contained time, area under plasma concentration-time curve (AUC) of danshensu and rat weights (covariate). Relative contribution of input variable to the output neurons was evaluated using neuron connection weights according to Garson's algorithm. The kinetics of contribution values was also compared and was validated using bootstrap resampling method. RESULTS: Danshensu exerted significant cTnT-lowering, Hcy- and GSH-elevating effect, and these marker profiles were well captured by the trained NN model. The calculation of relative contributions revealed that the effect of danshensu on the PD marker could be ranked as cTnT>GSH>Hcy, while the effect of AMI disease on the PD marker could be ranked in the following order: cTnT>Hcy>GSH. The activity of transsulfuration pathway was quite obvious under the AMI state. CONCLUSION: NN is a powerful tool linking PK and PD profiles of danshensu with multiple cardioprotective mechanisms, it provides a simple method for identifying and ranking relative contribution to the multiple therapeutic effects of the drug.

Mechanism-based pharmacokinetic-pharmacodynamic modeling of the estrogen-like effect of ginsenoside Rb1 on neural 5-HT in ovariectomized mice.

We sought to develop a mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model to characterize the effects of ginsenoside Rb1 (Rb1) and estradiol (E(2)) on neural 5-hydroxytryptamine (5-HT) concentration in ovariectomized mice. PK data of Rb1 and E(2) were obtained in plasma and brain. Brain levels of 5-HT, tryptophan (TRP), 5-hydroxytryptophan (5-HTP), and 5-hydroxyindoleacetic acid (5-HIAA) were determined after a single intravenous injection of Rb1 (20mg/kg) and E(2) (0.2mg/kg) in ovariectomized mice. The activities of tryptophan hydroxylase (TPH), aromatic amino acid decarboxylase (AAAD), and monoamine oxidase (MAO) were also evaluated. Rb1 and E(2) elevated neural 5-HT levels via TPH activation and MAO inhibition, respectively. Effects were well described by the mechanism-based PK-PD model. The net effect of increased 5-HT induced by MAO inhibition is greater than TPH activation. The increased brain levels of 5-HT induced by Rb1 and E(2) were well described by the present PK-PD model, suggesting the use and further development of this mechanism-based model for the effects of ginsenoside on brain 5-HT levels.

Intracranial clear cell meningioma: a clinicopathologic study of 15 cases.

OBJECT: Clear cell meningioma (CCM) is a rare histological variant of meningioma. CCM has a high recurrence rate and aggressiveness. In this study, we reviewed our experience in the treatment of the lesion. METHODS: Here we present a series of 15 patients with intracranial CCM. The clinical data were retrieved from the records of our Neurosurgery Department and the patients' prognoses were attained by clinic service and telephone. Immunohistochemistry for epithelial membrane antigen (EMA), vimentin, glial fibrillary acidic protein (GFAP), CD10, and S-100 was done, and the MIB-1 labeling index was calculated in all cases. RESULTS: The 15 patients included eight males and seven females; the mean age was 34.8 years. The most frequent initial symptoms were headache and hearing loss. The most common location was the cerebellopontine angle (CPA) zone. Eleven patients had total removal and four patients underwent subtotal removal. Histological features of atypia were present in different proportions, from 6.7% to 100%, and six cases accorded with atypia. Three tumors showed brain invasion. EMA and vimentin were 100% positive, and CD10 was 100% negative. GFAP was 87% negative and S-100 was 93% negative. The mean follow-up period was 36.7 months. Three patients with brain invasion all recurred and five cases with atypia recurred. In 11 patients with total removal, six patients recurred. In four patients with subtotal removal, three patients recurred. Kaplan-Maier analysis showed that incomplete surgical resection was significantly associated with recurrence (p = 0.001). The MIB-1 labeling index for recurrence was 5.7 ± 2.7% versus 2.8 ± 1.5% for no recurrence (p = 0.036). CONCLUSIONS: CCM is a rare subtype of meningioma, with a tendency to present in younger patients and a propensity to recur. Immunohistochemistry plays a vital role in differentiating CCM from other tumors. Brain invasion, atypia and MIB-1 labeling index are likely to predict the recurrence. The extent of resection might be connected with the prognosis.

Mechanism-based pharmacokinetic-pharmacodynamic modeling of bidirectional effect of danshensu on plasma homocysteine in rats.

PURPOSE: To develop a mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model to characterize and predict the bidirectional effect of danshensu on plasma total homocysteine (tHcy) in rats described in our previous paper. METHODS: The effect of danshensu on tHcy was assessed in rats after simultaneously methionine loading. Danshensu, its methylated metabolite and tHcy were all quantified after single intravenous injection of 20 mg/kg danshensu. The bidirectional effect, of which, elevated by danshensu methylation and decreased via transsulfuration promotion, was characterized by a PK-PD model, where direct stimulatory sigmoidal function and time-dependent transduction function were introduced for the two effects description, respectively. RESULTS: Modeling and simulations reveals that: (1) the elevated effect by methylation occurs before the decreased effect via transsulfuration promotion, and the decreased effect is more profoundly dose-dependent than the elevated effect; (2) two steps are simplified to describe the delayed stimulatory effect on the transsulfuration in the model; (3) long term administration of danshensu dose not affect tHcy in normal rats, while it significantly reduces tHcy in rats treated with methionine. This is in consistent with previous report. CONCLUSIONS: The profiles were well-described by our PK-PD model, which constitutes a basis for the future development of mechanism-based model for polyphenols on Hcy in this paradigm.