Planta Med 2016; 82(11/12): 1021-1029
DOI: 10.1055/s-0042-105295
Pharmacokinetic Investigations
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

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

Evelyn A. Jähne
1  Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
,
Daniela E. Eigenmann
1  Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
,
Chethan Sampath
2  Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA
,
Veronika Butterweck
2  Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA
3  Institute for Pharma Technology, Muttenz, Switzerland
,
Maxime Culot
4  Univ. Artois, EA 2465, Laboratoire de la Barrière Hémato-Encéphalique (LBHE), Lens Cedex, France
,
Roméo Cecchelli
4  Univ. Artois, EA 2465, Laboratoire de la Barrière Hémato-Encéphalique (LBHE), Lens Cedex, France
,
Fabien Gosselet
4  Univ. Artois, EA 2465, Laboratoire de la Barrière Hémato-Encéphalique (LBHE), Lens Cedex, France
,
Fruzsina R. Walter
5  Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary
,
Mária A. Deli
5  Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary
,
Martin Smieško
6  Molecular Modeling, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
,
Matthias Hamburger
1  Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
,
Mouhssin Oufir
1  Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
› Author Affiliations
Further Information

Publication History

received 19 January 2016
revised 03 March 2016

accepted 04 March 2016

Publication Date:
19 April 2016 (eFirst)

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.

* Dedicated to Prof. Dr. Dr. h. c. mult. Kurt Hostettmann in recognition of his outstanding contribution to natural product research.


Supporting Information