Alteration of UDP-glucuronosyltransferase 1a1, 1a7 and P-glycoprotein expression in hepatic fibrosis rats and the impact on pharmacokinetics of puerarin.

BACKGROUND: Puerarin, derived from a traditional Chinese herb Pueraria lobata (Willd.) Ohwi which was distributed globally and planted in most parts of China, has been extensively applied in patients with cardiovascular diseases in China. Yet a considerable proportion of the patients were accompanied with liver illnesses simultaneously because of all sorts of reasons. HYPOTHESIS/PURPOSE: It had been implied by some previous research that the absorption and the metabolism of puerarin were susceptible to liver issues due to changed P-gp and Ugt1a level, but pharmacokinetics of puerarin under such conditions were few concerned. Our study aimed to make sure whether and how much the behavior of puerarin in vivo was affected by hepatic diseases, and to explore the potential mechanisms. METHODS: A CCl4 induced rat model of hepatic fibrosis (HF) was prepared and verified. Single low/high doses of oral and intravenous administration of puerarin to HF and normal rats were performed. Pharmacokinetics of puerarin were determined by a validated HPLC method. The expression of P-gp, Ugt1a1, and Ugt1a7 in both liver and intestines were determined by quantitative RT-PCR and Western blot analysis respectively. RESULTS: The systemic exposure of puerarin in HF rats of experimental groups were found decreased remarkably except for that of the high dose intravenous group. Moreover, the expression of P-gp, Ugt1a1, and Ugt1a7 in liver and intestines of HF rats were figured out increased. CONCLUSION: The results indicated that the HF originated overexpression of Ugt1a1, Ugt1a7, and P-gp level played important roles in pharmacokinetics of puerarin, suggested the clinical regimen of puerarin based on normal populations might be inappropriate for patients with chronic liver diseases. It was implied drugs whose absorption or elimination were related to P-gp, Ugt1a1, or Ugt1a7 might also be affected by hepatic illnesses.

Plasma Pharmacokinetic Determination of Canagliflozin and Its Metabolites in a Type 2 Diabetic Rat Model by UPLC-MS/MS.

Canagliflozin is a novel, orally selective inhibitor of sodium-dependent glucose co-transporter-2 (SGLT2) for the treatment of patients with type 2 diabetes mellitus. In this study, a sensitive and efficient UPLC-MS/MS method for the quantification of canagliflozin and its metabolites in rat plasma was established and applied to pharmacokinetics in a type 2 diabetic rat model. We firstly investigated the pharmacokinetic changes of canagliflozin and its metabolites in type 2 diabetic rats in order to use canagliflozin more safely, reasonably and effectively. We identified three types of O-glucuronide metabolites (M5, M7 and M17), two kinds of oxidation metabolites (M8 and M9) and one oxidation and glucuronide metabolite (M16) using API 5600 triple-TOF-MS/MS. Following liquid⁻liquid extraction by tert-butyl methyl ether, chromatographic separation of canagliflozin and its metabolites were performed on a Waters XBridge BEH C18 column (100 × 2.1 mm, 2.5 µm) using 0.1% acetonitrile⁻formic acid (75:15, v/v) as the mobile phase at a flow rate of 0.7 mL/min. Selected ion monitoring transitions of m/z 462.00→191.10, 451.20→153.10, 638.10→191.10 and 478.00→267.00 were chosen to quantify canagliflozin, empagliflozin (IS), O-glucuronide metabolites (M5, M7 and M17), and oxidation metabolites (M9) using an API 5500-triple-MS/MS in the positive electrospray ionization mode. The validation of the method was found to be of sufficient specificity, accuracy and precision. The pathological condition of diabetes could result in altered pharmacokinetic behaviors of canagliflozin and its metabolites. The pharmacokinetic parameters (AUC0⁻t, AUC0⁻∞, CLz/F, and Vz/F) of canagliflozin were significantly different between the CTRL and DM group rats (p < 0.05 or p < 0.01), which may subsequently cause different therapeutic effects.

Comparative pharmacokinetics study of sinomenine in rats after oral administration of sinomenine monomer and Sinomenium acutum extract.

Various products containing sinomenine monomer and extracts of Sinomenium acutum have been widely applied in clinical treatments. The goal of the present study was to compare the pharmacokinetics of sinomenine in rats after oral administration of sinomenine monomer and Sinomenium acutum extract, and to attempt to explore potential component-component interactions between the constituents of this traditional Chinese herbal medicine. A reliable and specific reversed phase high performance liquid chromatography method was developed to analyze sinomenine in rat plasma. Pharmacokinetic parameters for sinomenine were processed by non-compartmental analysis. The results showed that the maximum concentration, the area under the concentration-time curve, clearance and the apparent volume of distribution of sinomenine in the Sinomenium acutum extract statistically differed from those of sinomenine monomer (p < 0.05); however, the mean residence time, time of peak concentration, and half-life did not show significant differences between the two groups. These findings suggested that some additional components in the Sinomenium acutum extract may decrease the absorption of sinomenine. The complex interactions between sinomenine and other components of the herbal extract could result in the altered pharmacokinetic behavior of sinomenine, which may subsequently cause different therapeutic and detoxification effects.

Pharmacokinetic properties and bioequivalence of two formulations of arbidol: an open-label, single-dose, randomized-sequence, two-period crossover study in healthy Chinese male volunteers.

BACKGROUND: Arbidol is an antiviral drug indicated for the prevention and treatment of all types of influenza infection and some other kinds of acute respiratory infections, specifically against influenza groups A and B, and severe acute respiratory syndrome. It is used to help prevent influenza infection as long as necessary with little risk for influenza mutation rendering it less effective. OBJECTIVE: The aim of this study was to compare the pharmacokinetic properties and tolerability, and to determine bioequivalence, of a newly developed generic dispersible tablet formulation (test) and a branded capsule formulation (reference) of arbidol 200 mg in healthy Chinese fasted male volunteers. METHODS: This open-label, single-dose, randomized-sequence, 2-period crossover study was conducted in healthy native Chinese male volunteers. Eligible subjects were randomly assigned in a 1:1 ratio to receive a single 200-mg dose of the test or reference formulation, followed by a 1-week washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. After the study drug administration, serial blood samples were collected for 72 hours after administration. Plasma drug concentrations were determined using high-performance liquid chromatography coupled with tandem mass spectrometry. Several pharmacokinetic pararameters, including C(max), T(max), t((1/2)), AUC(0-t), and AUC(0-infinity), were determined from the plasma concentrations of the 2 formulations of arbidol using noncompartmental analysis. The formulations were to be considered bioequivalent if the log-transformed ratios of C(max) and AUC were within the predetermined bioequivalence range of 80% to 125% established by the State Food and Drug Administration (SFDA) of the People's Republic of China. Tolerability was assessed by monitoring vital signs (blood pressure, heart rate, temperature, and electrocardiography), laboratory analysis (hematology, blood biochemistry, hepatic function, and urinalysis), and subject interview on adverse events. RESULTS: Twenty subjects were enrolled and completed the study (mean [SD] age, 21.1 [1.1] years; weight, 64.7 [5.1] kg; and height, 172.3 [3.1] cm). Neither period nor sequence effect was observed. The main pharmacokinetic properties with the test and reference formulations were as follows: C(max), 417.4 (107.6) and 414.8 (95.1) ng/mL, respectively (P = NS); median (range) T(max), 0.63 (0.25-1.0) and 0.75 (0.5-1.5) hours (P = 0.035); AUC(0-t), 2033.6 (564.9) and 1992.0 (483.3) ng/mL/h (P = NS); AUC(0-infinity), 2285.4 (597.7) and 2215.2 (604.0) ng/mL/h (P = NS); and t(1/2), 6.9 (4.2) and 6.1 (5.2) hours (P = NS). The 90% CIs for the log-transformed ratios of C(max), AUC(0-t), and AUC(0-infinity) were 91.7% to 109.7%, 91.0% to 112.8%, and 92.0% to 116.3%, respectively (all, P < 0.05), which were within the predetermined range for bioequivalence. No adverse events were found on analysis of vital signs or laboratory tests or reported by subjects in this study. CONCLUSION: In this study in healthy Chinese male volunteers, the dispersible tablet formulation and the 200-mg capsule formulation of arbidol met the SFDA's regulatory definition of bioequivalence based on the rate and extent of absorption.

Pharmacokinetics of single-dose and multiple-dose memantine in healthy chinese volunteers using an analytic method of liquid chromatography-tandem mass spectrometry.

OBJECTIVE: This study consisted of 2 phases: development of a liquid chromatography-tandem mass spectrometry (LC/MS) method for determination of memantine in human plasma and characterization of single-dose and multiple-dose pharmacokinetic profiles of memantine in healthy Chinese volunteers using the LC/MS method. METHODS: An analytic method of LC/MS for determination of memantine in human plasma was developed and validated and was applied to this single-center, open-label, single-dose and multiple-dose pharmacokinetic study conducted in healthy native Chinese volunteers. Subjects were randomized to receive a single dose of 5, 10, or 20 mg of memantine to study the linear characteristics of pharmacokinetics, or a multiple dose of 5 mg once daily for 14 days to study the drug accumulation. The pharmacokinetic parameters calculated included C(max), T(max), AUC, t(1/2),mean residence time (MRT), maximum steady-state plasma concentration (C(ssmax)), minimum steady-state plasma concentration ((ssmin)), average steady-state plasma concentration (C(ssav)), and fluctuation percentage (DF). All values were expressed as mean (SD). Sequential blood samples were collected from 0 to 360 hours for single-dose pharmacokinetic determinations after the dose on day 1; in the multiple-dose pharmacokinetic arm, the sequential blood samples were also obtained from 0 to 360 hours on day 14 after collecting the predose samples at 0 hour on days 11, 12, and 13. Memantine concentrations in plasma were determined by LC/MS method. A calibration curve was constructed by 7 memantine concentrations and processed by least-squares linear regression analysis (w=1/x(2)). Safety assessments, including adverse events (AEs), were performed at all study visits. RESULTS: The LC/MS method for determination of memantine in human plasma was developed and validated. The standard calibration curve for spiked human plasma containing memantine was linear in the concentration range of 0.2 to 200.0 ng/mL. The correlation coefficient was greater than 0.9960 (n = 6). The lower limit of quantification for memantine in human plasma was 0.2 ng/mL, and the intraday and interday coefficients of variation were all lower than 15%. The mean recoveries of the 0.4, 20.0, and 180.0 ng/mL levels were 78.87%, 81.55%, and 81.98%, respectively. The coefficients of variation were all lower than 15% after being treated at room temperature for 24 hours, for 45 days at -40 degrees , and within 3 freeze-and-thaw cycles in plasma samples. Forty native Chinese subjects (10 [5 men, 5 women] subjects per group; mean [SD] age, 21.6 [1.6] [range, 19-27] years; weight, 63.0 [7.7] [range, 52-82] kg; height, 170.0 [7.0] [range, 155-185] cm) were enrolled in the study. After single-dose oral administration, the main pharmacokinetic parameters found for memantine at doses of 5, 10, and 20 mg were as follows: C(max), 6.20 (0.75), 11.60 (1.95), and 25.34 (8.34) ng/mL, respectively; T(max), 5.70 (1.64), 6.00 (1.33), and 6.89 (1.41) h; AUC(0-t), 486.19 (80.00), 889.32 (239.49), and 1772.91 (784.07) ng x h/mL; AUC(0-infinity), 540.05 (89.68), 932.07 (230.82), and 1853.29 (776.85) ng x h/mL; t(1/2), 66.86 (11.75), 63.57 (12.58), and 62.06 (9.26) h; and MRT, 99.37 (16.96), 91.73 (18.16), and 89.56 (13.77) h. The main pharmacokinetic parameters found for memantine at doses of 5 mg once daily for 14 days were as follows: T(max), 6.80 (2.46) h; C(ssmax), 19.69 (2.00) ng/mL; C(ssmin), 12.76 (2.80) ng/mL; C(ssav), 16.10 (2.46) ng/mL; t(1/2), 64.57 (15.78) h; MRT, 93.17 (23.38) h; AUC(ss),386.37 (59.00) ng x h/mL; and DF, 44.47% (15.27%). One female subject withdrew from the study after a single 20-mg dose due to an AE (dizziness and vomiting); no other subjects experienced an AE. CONCLUSIONS: In these healthy Chinese subjects, the t(1/2) and MRT values were fixed and did not increase following the increased dose, and the AUC(infinity) and C(max) values increased following the increasing dosage of memantine. Linear pharmacokinetics was found at doses from 5 to 20 mg. The multiple-dose pharmacokinetic parameters (other than C(max)) were nearly similar compared with the single-dose administration. The maximum plasma concentration of memantine after multiple-dose administration was greater than that after a single-dose administration, suggesting memantine accumulation with multiple-dose administration of 5 mg and requiring further confirmation in larger studies.

Interaction of water-soluble cationic porphyrin with anionic surfactant.

The interaction of a cationic water-soluble porphyrin, 5,10,15,20-tetrakis [4-(3-pyridiniumpropoxy)phenyl]porphyrin tetrakisbromide (TPPOC3Py), with anionic surfactant, sodium dodecyl sulfate (SDS), in aqueous solution has been studied by means of UV-vis, (1)H NMR, fluorescence, circular dichroism (CD) spectra and dynamic laser light scattering (DLLS), and it reveals that TPPOC3Py forms porphyrin-surfactant complexes (aggregates), including ordered structures J- and H-aggregates, induced by association with surfactant monomers below the SDS critical micelle concentration (cmc), and forms micellized monomer upon the cmc, respectively. The position of TPPOC3Py in the micelle is determined, which is not in the micelle core instead of intercalated among the SDS chains, most likely with the pyridinium group extending into the polar headgroup region of the micelle.

Study on the inclusion behavior between meso-tetrakis[4-(3-pyridiniumpropoxy)phenyl]prophyrin tetrakisbromide and beta-cyclodextrin derivatives in aqueous solution.

The interaction of a cationic water-soluble porphyrin, 5,10,15,20-tetrakis[4-(3-pyridiniumpropoxy)phenyl]prophyrin tetrakisbromide (TPPOC3Py), with beta-CD and HP-beta-CD in aqueous solution has been studied by UV-vis, 1H NMR, 2D-NOESY and MALDI-TOF MS, and it reveals that a stable 1:1 inclusion complex between TPPOC3Py and HP-beta-CD or beta-CD has formed, in which one of the meso substituents of porphyrin ring has deeply penetrated through the cavity of HP-beta-CD from secondary face. The inclusion constants of the complexes of TPPOC3Py-beta-CD and TPPOC3Py-HP-beta-CD are (1.6+/-0.2)x10(3) M-1 and (8.9+/-0.4)x10(4) M-1, respectively.