Evaluation of Marine Diindolinonepyrane in Vitro and in Vivo: Permeability Characterization in Caco-2 Cells Monolayer and Pharmacokinetic Properties in Beagle Dogs

• Published in: Marine drugs Vol. 17; no. 12; p. 651
• Main Authors: Ma, Zibin, Guo, Ruihua, Elango, Jeevithan, Bao, Bin, Wu, Wenhui
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 20.11.2019; MDPI
• Subjects: Administration, Oral; Animals; apparent permeability coefficients (papp); Aquatic Organisms - chemistry; Bile; Biological activity; Brain; caco-2 cell; Caco-2 Cells; Cells; Chemical kinetics; Chromatography, High Pressure Liquid; Distribution; Dogs; Drug dosages; Drug Evaluation, Preclinical; Fibrin; Fibrinolytic Agents - administration & dosage; Fibrinolytic Agents - chemistry; Fibrinolytic Agents - pharmacokinetics; fibrinolytic compound; Heart; High performance liquid chromatography; HPLC; Humans; Injections, Intravenous; Intestine; Intestines; Intravenous administration; Isoindoles - administration & dosage; Isoindoles - chemistry; Isoindoles - pharmacokinetics; Liquid chromatography; Liver; Male; Marine microorganisms; Membrane permeability; Metabolism; Metabolites; Models, Animal; Monolayers; Morphology; Oral administration; Permeability; Pharmacokinetics; Pharmacology; Plasma; Pyrans - administration & dosage; Pyrans - chemistry; Pyrans - pharmacokinetics; Spleen; Stomach; Tandem Mass Spectrometry; Testes; Thrombolysis; Thrombosis - drug therapy; Tissue; Tissue Distribution; Transportation; China; dogs; pharmacokinetics; apparent permeability coefficients (Papp); Caco-2 cell; fibrinolytic compound
• ISSN: 1660-3397; 1660-3397
• DOI: 10.3390/md17120651

A marine fibrinolytic compound was studied for use in thrombolytic therapy. Firstly, the absorption and transportation characteristics of 2,5-B PA (2,5-B 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 -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 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 PA has low permeability and low total recoveries in the Caco-2 cells membrane. Pharmacokinetics and tissue distribution of 2,5-B 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 ). Pharmacokinetic data indicated that 2,5-B PA fitted well to a two-compartment model. Elimination half-lives (T ) were 49 ± 2, 48 ± 2, and 49 ± 2 min, respectively; the peak concentrations (C ) were 56.48 ± 6.23, 48.63 ± 5.53, and 13.64 ± 2.76 μg·mL , respectively; clearance rates (CL) were 0.0062 ± 0.0004, 0.0071 ± 0.0008, and 0.0092 ±0.0006 L·min ·kg , 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 PA indicated that the intravenous route of administration is more appropriate than the oral route. Meanwhile, 2,5-B PA showed a good pharmacokinetic profile in beagle dogs. The tissue distribution showed that 2,5-B 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 PA was higher in the liver and bile. Interestingly, 2,5-B 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.