Pharmacokinetics and In Vitro Blood-Brain Barrier Screening of the Plant-Derived Alkaloid Tryptanthrin.
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.
Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
Evelyn A
EA
Jähne
Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
Daniela E
DE
Eigenmann
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
Chethan
C
Sampath
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
Veronika
V
Butterweck
Univ. Artois, EA 2465, Laboratoire de la Barrière Hémato-Encéphalique (LBHE), Lens Cedex, France.
Maxime
M
Culot
Univ. Artois, EA 2465, Laboratoire de la Barrière Hémato-Encéphalique (LBHE), Lens Cedex, France.
Roméo
R
Cecchelli
Univ. Artois, EA 2465, Laboratoire de la Barrière Hémato-Encéphalique (LBHE), Lens Cedex, France.
Fabien
F
Gosselet
Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.
Fruzsina R
FR
Walter
Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.
Mária A
MA
Deli
Molecular Modeling, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
Martin
M
Smieško
Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
Matthias
M
Hamburger
Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
Mouhssin
M
Oufir
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D006801:Humans; D031219:Isatis / Q000737:chemistry; D008297:Male; D015394:Molecular Structure; D010936:Plant Extracts / Q000493:pharmacokinetics; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D010936:Plant Extracts; D011799:Quinazolines; C046243:tryptanthrine