Guangji Wang

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.

Induction of cytochromes P450 1A1 and 1A2 by tanshinones in human HepG2 hepatoma cell line

Diterpenoid tanshinones including tanshinone IIA (TIIA), cryptotanshinone (CTS), tanshinone I (TI) and dihydrotanshinone I (DHTI) are the major bioactive components from Danshen. The major aim of our present study was to investigate the induction potential of these four main components of tanshinones (TIIA, CTS, TI, and DHTI) on the expression of CYP1A1 and CYP1A2 in HepG2 cells. Our results showed that all of these four tanshinones caused a significant time- and concentration-dependent increase in the amount of CYP1A1/2 expression in HepG2 cells. These induction effects were further characterized through transcriptional regulation: the induction of CYP1A1/2 mRNA level by tanshinones was completely blocked by the transcription inhibitor actinomycin D; the expression of CYP1A1/2 heterogeneous nuclear RNA was induced by tanshinone treatment; and CYP1A1 mRNA stability was not influenced by these tanshinones. Interestingly, tanshinones plus B[a]P produced additive/synergistic effect on CYP1A1/2 induction. In addition, the tanshinone-induced CYP1A1/2 expression was abolished by the aryl hydrocarbon receptor (AhR) antagonist resveratrol, suggesting an AhR dependent transcription mechanism. In the reporter gene assay, while TI and DHTI significantly induced AhR-dependent luciferase activity, TIIA and CTS failed to induce this activity. Collectively, the tanshinones could induce CYP1A1 and CYP1A2 expression through transcriptional activation mechanism and exert differential effects on activating AhR in HepG2 cells. Our findings suggest that rational administration of tanshinones should be considered with respect to their effect on AhR and CYP1A1/2 expression.

Metabonomic profiling in studying anti-osteoporosis effects of strontium fructose 1,6-diphosphate on estrogen deficiency-induced osteoporosis in rats by GC/TOF-MS

A novel strontium salt compound strontium fructose 1, 6-diphosphate (FDP-Sr) has been proved to have highly effective for bone loss via dual effects of stimulating bone formation and suppressing bone absorption. In the present study, metabolomic approach was used to identify and study potential biomarkers associated with the effect and safety of FDP-Sr. The metabolomic profiles of bone loss induced by estrogen deficiency in a rat model was described to attain a system-level map of the shift on the metabolic response in plasma using GC/TOF-MS, after FDP-Sr was orally administered at the dose of 110 mg/kg/day for the prevention and 220 mg/kg/day for the treatment. Meanwhile, bone turnover biomarkers and bone mineral density were investigated to identify the specific changes of potential anti-osteoporosis effects of FDP-Sr. The differences in metabolic profiles between osteoporosis rats and FDP-Sr treated rats were well observed by the partial least squares-discriminant analysis (PLS-DA) to the MS spectra. Some metabolites including homocysteine, arachidonic acid, alanine, and hydroxyproline, which significantly changed during osteoporosis progression could be effectively reversed after FDP-Sr therapy. Of course some metabolites such as uric acid, glyceric acid, octadecadienoic acid, docosahexaenoic acid, oleic acid, and hexadecanoic acid were not found to reverse significantly after FDP-Sr administration. These results delineated the FDP-Sr effects-related metabolic alterations in the bone loss rats, suggesting that metabonomic analysis could provide helpful information on the new potential biomarkers relating to the mechanism of anti-osteoporosis action and side effects of FDP-Sr against estrogen deficiency induced bone loss.

Pharmacokinetic properties of S-adenosylmethionine after oral and intravenous administration of its tosylate disulfate salt: A multiple-dose, open-label, parallel-group study in healthy Chinese volunteers

BACKGROUND S-adenosylmethionine (SAMe) is an endogenous molecule that plays an important role in cellular metabolism. Despite being widely used as a dietary supplement with claimed benefits for numerous conditions, there is little information about the pharmacokinetic properties of exogenous SAMe. OBJECTIVES One aim of this study was to characterize the pharmacokinetic properties of SAMe after administration of single and multiple doses of orally and intravenously administered SAMe tosylate disulfate (STD) in healthy male and female Chinese volunteers. Because men have higher erythrocyte levels of endogenous SAMe than do women, we also assessed the effects of sex on the disposition of SAMe. METHODS A simple and sensitive assay for SAMe based on liquid chromatography-mass spectrometry using selected-ion monitoring of analyte and acyclovir as internal standard was developed and validated. The assay was used to study the pharmacokinetic properties of SAMe. STD was administered as single and multiple doses of enteric-coated tablets and IV infusion of STD to groups of healthy native Chinese volunteers. After an overnight fast, male and female Chinese volunteers were assigned to receive STD 1000 mg for 5 days, either in enteric-coated tablet formulation or as a 250-mL IV infusion. Blood samples were collected 24 hours after the first and last dose and used for determining plasma SAMe concentrations and pharmacokinetic parameters. For the oral formulation, SAMe concentrations were corrected for concentrations of endogenous SAMe. Pharmacokinetic parameters were calculated for men and women separately and for the total group of volunteers. Adverse events were monitored using a physician during blood collection and by spontaneous reporting. RESULTS Twenty healthy volunteers were enrolled (oral formulation: 5 men, 5 women; mean [SD] age, 24.1 [4.7] years [range, 21-37 years]; mean [SD] weight, 59.9 [4.8] kg [range, 54-70 kg]; IV formulation: 5 men, 5 women; mean [SD] age, 22.6 [1.8] years [range, 21-27 years]; mean [SD] weight, 59.5 [5.4] kg [range, 53-67 kg]). None of the between-sex differences in SAMe pharmacokinetic properties were significant. The (mean [SD]) pharmacokinetic properties of singledose oral SAMe in men and women, respectively, were as follows: C(max), 2.37 (1.58) and 2.50 (1.83) micromol/L; T(max), 5.40 (1.14) and 5.20 (1.48) hours; AUC(0-24), 8.56 (5.16) and 10.3 (8.0) micromol/L/h; and t(1/2beta), 6.06 (1.80) and 6.28 (2.60) hours. Corresponding values with the single-dose IV formulation were: C(max), 127 (49) and 211 (94) micromol/L; T(max), 1.90 (0.22) and 1.60 (0.22) hours; AUC(0-24), 329 (84) and 480 (176) micromol/L/h; and t(1/2beta), 4.34 (0.57) and 3.83 (0.78) hours. The single-dose oral:IV ratios of AUC(0-24) in men and women, respectively, were 2.60% and 2.14% (degrees of fluctuation: 4.96 [1.77] and 9.49 [0.91]). The pharmacokinetic properties of multiple-dose oral and IV SAMe were not significantly different from those with single-dose administration. None of the volunteers reported any adverse events during the study. CONCLUSIONS In this small study in healthy Chinese volunteers, there were no significant differences in the pharmacokinetic parameters of SAMe between men and women or between single- and multiple-dose administration of STD 1000 mg administered orally or intravenously. No evidence of accumulation of SAMe in plasma was found on multiple dosing. Both enteric-coated tablets and the IV infusion were well tolerated in these volunteers.

Simultaneous Determination and Pharmacokinetic Study of Metformin and Pioglitazone in Dog Plasma by LC–MS-MS

A high-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of metformin (MET) and pioglitazone (PIO) in dogs. To increase the reliability of the method, moroxydine (IS-1) and rosiglitazone (IS-2) were used as internal standards for MET and PIO, respectively. The analytes were extracted from beagle dog plasma by a one-step protein precipitation. Chromatographic separation was performed on a Phenomenex Synergi POLAR-RP 80A column (250 × 4.6 mm, 4 µm). The total chromatographic run time was 8.0 min, with retention times of 3.0 and 2.9 min for MET and IS-1, respectively, and 6.1 and 4.9 min for PIO and IS-2. The lower limit of quantitation values were 2 and 1 ng/mL for MET and PIO, respectively. The recoveries ranged from 96.4 to 112.8% for MET and 102.1 to 104.5% for PIO.

Bioequivalence and Pharmacokinetic Comparison of a Single 200-mg Dose of Meclofenoxate Hydrochloride Capsule and Tablet Formulations in Healthy Chinese Adult Male Volunteers: A Randomized Sequence, Open-Label, Two-Period Crossover Study

BACKGROUND Meclofenoxate hydrochloride is a psychostimulant in the nootropic agent group available in capsule and tablet formulations approved for traumatic cataphora, alcoholic poisoning, anoxia neonatorum, and childrens enuresis in China. Although these 2 generic formulations are marketed in China, information regarding their pharmacokinetics and bioequivalence in humans has not been published. OBJECTIVE The aim of this study was to compare the pharmacokinetic properties and bioequivalence of the capsule (test) and tablet (reference) formulations of meclofenoxate hydrochloride 200 mg in healthy Chinese volunteers. METHODS This single-dose, randomized-sequence, open-label, 2-period crossover study was performed at the Nanjing First Hospital of Nanjing Medical University, Nanjing, China. Eligible subjects were healthy male volunteers who were randomly assigned at 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. As a prodrug, meclofenoxate is hydrolyzed into 4-chlorophenoxyacetic acid and is not detected in plasma. The active metabolite of meclofenoxate, chlorophenoxyacetic acid, was assayed using a high-performance liquid chromatography method. For analysis of pharmacokinetic properties, including Cmax, AUC0-24, and AUC0-infinity, blood samples were obtained at 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 14, and 24 hours after administration. The formulations were considered bioequivalent if the log-transformed ratios of Cmax and AUC were within the predetermined equivalence range (80%-125%) as established by the US Food and Drug Administration (FDA). Subjects were interviewed concerning the occurrence of adverse events including excitement, insomnia, lassitude, and headache. Tolerability was assessed at baseline (before administration) and at 1, 2, 6, and 12 hours after administration by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis). RESULTS Twenty-four Chinese male subjects (mean [range]age,23.5[22-30]years;weight,63.3[56-68]kg; height, 171 [165-184] cm) were enrolled; all completed the study. No period or sequence effect was observed. The 90% CIs for the log-transformed ratios of chlorophenoxyacetic acid Cmax, AUC0-24, and AUC0-infinity were 95.7 to 122.9, 97.6 to 111.9, and 97.8 to 111.7, respectively (all, P>0.05). Similar results were found for the data without log-transformation. No adverse events were reported or observed during this single-dose study. CONCLUSIONS In this small study in healthy Chinese adult male volunteers, a single 200-mg dose of the capsule formulation was found to be bioequivalent to a single 200-mg dose of the tablet formulation based on the US FDAs regulatory definition (rate and extent of absorption). Both formulations were well tolerated.