Pharmacokinetics and In Vitro Blood-Brain Barrier Screening of the Plant-Derived Alkaloid Tryptanthrin

Abstract

The indolo[2,1-b]quinazoline alkaloid tryptanthrin was previously identified as a potent anti-inflammatory compound with a unique pharmacological profile. It is a potent inhibitor of cyclooxygenase-2, 5-lipooxygenase-catalyzed leukotriene synthesis, and nitric oxide production catalyzed by the inducible nitric oxide synthase. To characterize the pharmacokinetic properties of tryptanthrin, we performed a pilot in vivo study in male Sprague-Dawley rats (2 mg/kg bw i. v.). Moreover, the ability of tryptanthrin to cross the blood-brain barrier was evaluated in three in vitro human and animal blood-brain barrier models. Bioanalytical UPLC-MS/MS methods used were validated according to current international guidelines. A half-life of 40.63 ± 6.66 min and a clearance of 1.00 ± 0.36 L/h/kg were found in the in vivo pharmacokinetic study. In vitro data obtained with the two primary animal blood-brain barrier models showed a good correlation with an immortalized human monoculture blood-brain barrier model (hBMEC cell line), and were indicative of a high blood-brain barrier permeation potential of tryptanthrin. These findings were corroborated by the in silico prediction of blood-brain barrier penetration. P-glycoprotein interaction of tryptanthrin was assessed by calculation of the efflux ratio in bidirectional permeability assays. An efflux ratio below 2 indicated that tryptanthrin is not subjected to active efflux.

Biologically active quinoline and quinazoline alkaloids part II

“…The compound potently inhibited COX‐2 and 5‐LOX‐catalyzed leukotriene synthesis in vitro and in vivo, as well as iNOS‐catalyzed NO production and prostaglandin E 2 production by activated macrophages . In view of these proven pharmacological effects, in 2016, the pharmacokinetic properties of tryptanthrin and its ability to cross blood–brain barrier (BBB) were evaluated in vivo and in vitro . A high BBB permeation potential was found in vivo that correlated well with an immortalized human monoculture BBB model (hBMEC cell line) and corroborated with the in silico prediction of BBB penetration.…”

“…A high BBB permeation potential was found in vivo that correlated well with an immortalized human monoculture BBB model (hBMEC cell line) and corroborated with the in silico prediction of BBB penetration. In addition, tryptanthrin was not subject to active efflux …”

Assessment of HBEC-5i endothelial cell line cultivated in astrocyte conditioned medium as a human blood-brain barrier model for ABC drug transport studies

“…This parameter completely determines the interaction between the drugs and ABC transporter function (Food and drug administration, 2012;Hubatsch et al, 2007;Kikuchi et al, 2013). To date, only few studies on human BBB cell lines have evaluated this parameter (Eigenmann et al, 2016a;Jähne et al, 2016;Ma et al, 2014). In our model, ER parameter was higher in HBEC-5i with the HA conditioned medium than HBEC-5i alone.…”

Study on pharmacokinetics and tissue distribution of single dose oral tryptanthrin in Kunming mice by validated reversed-phase high-performance liquid chromatography with ultraviolet detection

“…This indicated that the clinical application of tryptanthrin should focus on its pharmacodynamics and safety study in liver, kidney, and lung tissues at least. The content of tryptanthrin in the mouse brain was the lowest (less than 0.2 μg/g), suggesting that it may be difficult for tryptanthrin to cross the in vivo blood–brain barrier of KM mice, 24 so that the development of tryptanthrin drug therapy method based solely on the nature of tryptanthrin itself is impractical for curing brain diseases.

Fig.

…”