Evaluation of Marine Diindolinonepyrane in Vitro and in Vivo: Permeability Characterization in Caco-2 Cells Monolayer and Pharmacokinetic Properties in Beagle Dogs
oleh: Zibin Ma, Ruihua Guo, Jeevithan Elango, Bin Bao, Wenhui Wu
| Format: | Article |
|---|---|
| Diterbitkan: | MDPI AG 2019-11-01 |
Deskripsi
A marine fibrinolytic compound was studied for use in thrombolytic therapy. Firstly, the absorption and transportation characteristics of 2,5-B<i>H</i>PA (2,5-B<i>H</i>PA:2,5-Bis-[8-(4,8-dimethyl-nona-3,7-dienyl)-5,7-dihydroxy-8-methyl-3-keto-1,2,7,8-tertahydro-6<i>H</i>-pyran[a]isoindol-2-yl]-pentanoic acid, a novel pyran-isoindolone derivative with bioactivity isolated from a rare marine microorganism in our laboratory) in the human Caco-2 cells monolayer model were investigated. We collected 2,5-B<i>H</i>PA in the cells to calculate the total recovery, and its concentration was analyzed by LC/MS/MS (Liquid Chromatography/ Mass Spectrum/ Mass Spectrum). The results showed that 2,5-B<i>H</i>PA has low permeability and low total recoveries in the Caco-2 cells membrane. Pharmacokinetics and tissue distribution of 2,5-B<i>H</i>PA were investigated in beagle dogs using HPLC (High Performance Liquid Chromatography) after intravenous administration of three different doses (7.5, 5.0, 2.5 mg·kg<sup>−1</sup>). Pharmacokinetic data indicated that 2,5-B<i>H</i>PA fitted well to a two-compartment model. Elimination half-lives (T<sub>1/2</sub>) were 49 ± 2, 48 ± 2, and 49 ± 2 min, respectively; the peak concentrations (C<sub>max</sub>) were 56.48 ± 6.23, 48.63 ± 5.53, and 13.64 ± 2.76 μg·mL<sup>−1</sup>, respectively; clearance rates (CL) were 0.0062 ± 0.0004, 0.0071 ± 0.0008, and 0.0092 ±0.0006 L·min<sup>−1</sup>·kg<sup>−1</sup>, respectively; mean retention times (MRT) were 28.17 ± 1.16, 26.23 ± 0.35, and 28.66 ± 0.84 min, respectively. The low penetrability of 2,5-B<i>H</i>PA indicated that the intravenous route of administration is more appropriate than the oral route. Meanwhile, 2,5-B<i>H</i>PA showed a good pharmacokinetic profile in beagle dogs. The tissue distribution showed that 2,5-B<i>H</i>PA could quickly distribute into the heart, intestines, liver, stomach, spleen, lungs, testicles, urine, intestine, kidneys, brain, and feces. The concentration of 2,5-B<i>H</i>PA was higher in the liver and bile. Interestingly, 2,5-B<i>H</i>PA was detected in the brain. Taken together, the above results suggested that our work might be beneficial in the development of agents for thrombolytic treatment.