Matrine In Rats Research Articles

Pharmacokinetic characterization of oxymatrine and matrine in rats after oral administration of radix Sophorae tonkinensis extract and oxymatrine by sensitive and robust UPLC–MS/MS method

The purpose of this study is to systematically investigate the pharmacokinetic (PK) behaviors of radix Sophorae tonkinensis (S. tonkinensis) using oxymatrine (OMT) and matrine (MT) as the target markers (2mg/kg OMT and 1.3mg/kg MT, oral administration). The PK characteristics in radix S. tonkinensis extracts were also compared with those of pure OMT. A fast ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method was developed. OMT absorption was very fast, and no significant differences were observed (p>0.05) in tmax, CL, and t1/2 for both pure OMT and extracts. Cmax and AUC0→∞ of pure OMT were significantly higher than those of S. tonkinensis extracts (Cmax, 61.64±6.65 vs. 43.24±10.14ng/mL; AUC, 9894.48±2234.99 vs. 4730.30±3503.8minng/mL) (p<0.05). However, the absolute OMT bioavailability of pure OMT was higher than that of the compound in radix S. tonkinensis extracts (6.79±2.52% vs. 1.87±2.66%). By contrast, the bioavailability of total alkaloids (OMT+MT) after pure OMT administration was 81.14±8.83%, similar to that of radix S. tonkinensis extracts (69.36±17.37%) (p>0.05). It was presumed that OMT absorption has no effect on the bioavailability of the two alkaloids. Other constituents in radix S. tonkinensis extracts can influence the transformation of OMT to MT, which directly leads to variations in the PK behavior of OMT. In addition, the protein binding of OMT and MT in plasma was very low (4.80%–8.95% for OMT, 5.10–10.55% for MT). In conclusion, OMT in radix S. tonkinensis extracts exhibits different PK behaviors with pure OMT through the transformation of OMT to MT due to other complex ingredients.

Effect of ceftiofur hydrochloride on pharmacokinetics of matrine in rats

To investigate the effect of ceftiofur hydrochloride on the pharmacokinetics of matrine in rats. The rats were divided into two groups: one group was administrated with matrine only (control group) and the other was administrated with matrine in combination with ceftiofur hydrochloride. HPLC-UV method was used for determining the plasma concentration of matrine in both groups. The pharmacokinetic parameters were calculated from the plasma concentration-time data using the DAS 2. 1. 1 software program. The main pharmacokinetic parameters for the control group were C(max) = 21.113 9 mg x L(-1), T(max) = 0.75 h, t1/2alpha = 1.34 h, t1/2beta = 3.509 h, AUC(0-t) = 90.984 mg x h(-1) x L(-1) and AUC(0-inifinity) = 100.346 mg x h(-1) x L(-1), and the data for the combination group were C(max) = 11.707 mg x L(-1), T(max) = 0.917 h, t1/2alpha = 1.598 h, t1/2beta = 3.247 h, AUC(0-t) = 53.28 mg x h(-1) x L(-1) and AUC(0-inifinity) = 60.035 mg x h(-1) x L(-1). The plasma concentration of matrine and bioavailability in combination group were significantly lower than those of the control group. In combination group, matrine had a higher clearance and volume of distribution in the central compartments, as well as a lower volume of distribution in the peripheral compartments.

Preparation and evaluation of self-nanoemulsified drug delivery systems (SNEDDSs) of matrine based on drug–phospholipid complex technique

To enhance oral bioavailability of matrine, a dedicated and newly emerging drug system called self-nanoemulsifying drug delivery system (SNEDDSs) was developed. Phospholipid complex (MPC) was prepared using solvent-evaporation method to improve the liposolubility of matrine. Solubilization test, infrared spectroscopy (IR) and differential scanning calorimetry (DSC) analysis were employed to confirm the formation of MPC. A rational experimental design was adopted to optimize the properties of SNEDDSs. Eight SNEDDSs prototypes were obtained to form nanoemulsion spontaneously based on optimization experiments. Among them, MPC prepared exhibited excellent solubility. SNEDDSs 2 (composition: Lauroglycol FCC, Cremophor EL and Transcutol HP; ratio: 6:4:1) was selected as the optimal formulation, with a mean droplet size in the range of 65–80 nm and 8.34% of the leakage rate, exhibiting instantaneous emulsion formation with only one flask inversion. Media pH and dilution factor showed no effect on the droplet size. The oral absorption of matrine in rats via SNEDDSs delivery was investigated. C max was increased dramatically from 4.12 to 6.52 and 7.95 μg/mL in case of matrine, MPC and MPC-SNEDDS. In parallel to C max, prolonged T max from 0.39 to 0.50 h, and 3.00 h could be observed. AUC 0– t of MPC-SNEDDSs was significantly higher than other two counterparts. In conclusion, the absolute bioavailability of matrine drastically increased from 25% to 84.6% by the formation of MPC-SNEDDS, with an outstanding relative bioavailability of 338%, suggesting its great potential for clinical application.

Biopharmaceutical and pharmacokinetic characterization of matrine as determined by a sensitive and robust UPLC–MS/MS method

The purpose of this research was to develop a sensitive and reproducible UPLC–MS/MS method to analyze matrine, an anticancer compound, and to use it to investigate its biopharmaceutical and pharmacokinetic behaviors in rats. A sensitive and fast UPLC–MS/MS method was successfully applied to determine matrine in rat plasma, intestinal perfusate, bile, microsomes, and cell incubation media. The absolute oral bioavailability of matrine is 17.1 ± 5.4% at a dose of 2 mg/kg matrine. Matrine at 10 μM was shown to have good permeability (42.5 × 10 −6 cm/s) across the Caco-2 cell monolayer, and the ratio of P A–B to P B–A was approximately equal to 1 at two different concentrations (1 and 10 μM). Perfusion study showed that matrine displayed significant differences ( P < 0.05) in permeability at different intestinal regions. The rank order of permeability was ileum (highest, P w = 6.18), followed by colon ( P w = 2.07), duodenum ( P w = 0.61) and jejunum ( P w = 0.52). Rat liver microsome studies showed that CYP and UGTs were not involved in matrine metabolism. In conclusion, a sensitive and reliable method capable of measuring matrine in a variety of matrixes was developed and successfully used to determine absolute oral bioavailability of matrine in rats, transport across Caco-2 cell monolayers, absorption in rat intestine, and metabolism in rat liver microsomes.

Physiologically Based Pharmacokinetics of Matrine in the Rat after Oral Administration of Pure Chemical and ACAPHA

ACAPHA, a botanical drug for the treatment of human esophageal cancer in China, is under investigation as a lung cancer chemoprevention agent at the BC Cancer Agency (Vancouver, BC, Canada). Little or no information is available on the pharmacokinetics of ACAPHA in animals. The objectives of this study were as follows: to examine the disposition kinetics of matrine, a bioactive marker of ACAPHA in the rat; to develop a physiologically based pharmacokinetic (PBPK) model for pure matrine; and to characterize the absorption and clearance of crude matrine in ACAPHA-treated rats using the PBPK model. Pure matrine (15 mg/kg) or crude matrine in the form of ACAPHA (0.38 or 3.8 g/kg) was administered to the rat by gavages. The rats were sacrificed at different time points postdosing. Blood and major organs were removed from the rat, extracted with toluene/butanol, and quantified for matrine using gas chromatography-mass spectrometry. An 11-compartment, flow-limited PBPK model of matrine was developed. The PBPK model was able to simulate closely the empirical data of rats treated with pure matrine. Because the absorption and clearance of crude matrine in ACAPHA-treated rats could not be parameterized a priori, they were estimated by fitting the experimental data to the PBPK model. Results of the study show that pure matrine is absorbed and eliminated by the rat at faster rates than crude matrine. Moreover, the ACAPHA matrix may change the pharmacokinetics of matrine in the rat significantly. The PBPK model is a valuable tool to gain insights into the disposition kinetics of a botanical drug.

Molecular properties and intracellular localization of rat liver nuclear scaffold protein P130

We examined the molecular basis of rat P130, a nuclear scaffold protein, and its functions. P130 comprising 845 amino acid residues possesses several functional domains and yields an electrophoretically distinctive isoform, P123, by altering its phosphorylation status in association with translocation across the nuclear membrane and from the digitonin-extractable fraction of the nucleus to the nuclear scaffold. The functional domains, NLS, NES, and zinc-finger bearing DNA-binding domains, ZF1 and ZF2, aid these translocations. P130 binds RNA through two RNA-binding domains (RB1 and RB2) similar to those of hnRNPs I and L. Microsome- and polysome-localized P130 and P123 were found in rat liver and Ac2F hepatoma cells. This localization required prior entry of P130 to the nucleus, but did not require RB1 and RB2. Thus, P130 initially purified from rat liver nuclear scaffold has the potential to play a variety of roles in biological events not only in the nuclear scaffold but also in various subcellular compartments. P130 (AB205483) is identical to matrin 3 (M63485 and BC062231), although the primary structure of rat matrin 3 has been revised, since it was first published.

Cloning and genomic mapping of the mouse matrin 3 gene and its pseudogenes

Matrin 3 forms a family of nuclear proteins together with NP220s. Using cDNA sequences encoding rat matrin 3 as a probe, we isolated genomic clones of mouse matrin 3 gene and its two pseudogenes. The genuine mouse matrin 3 gene has an exon covering the N-terminal one third of matrin 3 with a sequence 99% identical to rat matrin 3 cDNA. The gene was localized to Chromosome 18C by in situ hybridization and mapped at 3.6 cM distal to D18Mit117 and 2.2 cM proximal to D18Mit14 on mouse Chromosome 18 by interspecific backcross analysis. One pseudogene has an exon-like sequence covering the N-terminal half of matrin 3 that is interrupted by an unknown sequence. Reverse transcription polymerase chain reaction (RT-PCR) of RNA from mouse liver and brain using unique sequences of the genuine gene and the pseudogene confirmed the expression of only the former. The other pseudogene has a sequence only 80% identical to rat cDNA and is partially deleted and reversed. These pseudogenes were localized to Chromosome 4E2 and 8D2, respectively.

A Large DNA-binding Nuclear Protein with RNA Recognition Motif and Serine/Arginine-rich Domain

cDNA species encoding a large DNA-binding protein (NP220) of 1978 amino acids was isolated from human cDNA libraries. Human NP220 binds to double-stranded DNA fragments by recognizing clusters of cytidines. Immunofluorescent microscopy with antiserum directed against NP220 revealed a punctate or "speckled" pattern and coiled body-like structures in the nucleoplasm of various human cell lines. These structures diffused in the cytoplasm during mitosis. Western blot analysis showed that NP220 is enriched in the lithium 3,5-diiodosalicylate-insoluble fraction of nuclei. The domain essential for DNA binding is localized in C-terminal half of NP220. Human NP220 shares three types of domains (MH1, MH2, and MH3) with the acidic nuclear protein, matrin 3 (Belgrader, P., Dey, R., and Berezney, R. (1991) J. Biol. Chem. 266, 9893-9899). MH1 is a 48-amino acid sequence near the N terminus of both human NP220 and rat matrin 3. MH2 is a 75-amino acid sequence homologous to the RNA recognition motifs of heterogeneous nuclear RNP I and L. It is repeated three times in NP220 and twice in matrin 3. MH3 is a 60-amino acid sequence at the C terminus of both NP220 and matrin 3. NP220 has an arginine/serine-rich domain commonly found in pre-mRNA splicing factors. Close to the domain essential for DNA binding, there are nine repeats of the sequence LVTVDEVIEEEDL. Thus, NP220 is a novel type of nucleoplasmic protein with multiple domains.

Identification and characterization of a prostaglandin transporter.

Carrier-mediated prostaglandin transport has been postulated to occur in many tissues. On the basis of sequence homology, the protein of unknown function encoded by the rat matrin F/G complementary DNA was predicted to be an organic anion transporter. Expression of the matrin F/G complementary DNA in HeLa cells or Xenopus oocytes conferred the property of specific transport of prostaglandins. The tissue distribution of matrin F/G messenger RNA and the sensitivity of matrin F/G-induced prostaglandin transport to inhibitors were similar to those of endogenous prostaglandin transport. The protein encoded by the matrin F/G complementary DNA is thus preferably called PGT because it is likely to function as a prostaglandin transporter.