Pharmacokinetics and in vitro blood-brain barrier screening of the plant-derived alkaloid tryptanthrin
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Authors
Jähne, Evelyn A.
Eigenmann, Daniela E.
Sampath, Chethan
Butterweck, Veronika
Culot, Maxime
Cecchelli, Roméo
Gosselet, Fabien
Walter, Fruzsina R.
Deli, Maria A.
Smiesko, Martin
Author (Corporation)
Publication date
2016
Typ of student thesis
Course of study
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Type
01A - Journal article
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Parent work
Planta Medica
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Volume
82
Issue / Number
11-12
Pages / Duration
1021-1029
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Publisher / Publishing institution
Thieme
Place of publication / Event location
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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.
Keywords
tryptanthrin, UPLC-MS/MS, validation, pharmacokinetics (PK), blood-brain barrier (BBB)
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ISBN
ISSN
1439-0221
0032-0943
0032-0943
Language
English
Created during FHNW affiliation
Yes
Strategic action fields FHNW
Publication status
Published
Review
Peer review of the complete publication
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Citation
Jähne, E. A., Eigenmann, D. E., Sampath, C., Butterweck, V., Culot, M., Cecchelli, R., Gosselet, F., Walter, F. R., Deli, M. A., Smiesko, M., Hamburger, M., & Oufir, M. (2016). Pharmacokinetics and in vitro blood-brain barrier screening of the plant-derived alkaloid tryptanthrin. Planta Medica, 82(11-12), 1021–1029. https://doi.org/10.1055/s-0042-105295