In vitro metabolism, permeation, and brain availability of six major boswellic acids from Boswellia serrata gum resins

Boswellia serrata gum resin extracts (BSE) revealed potent anti-inflammatory actions in preclinical and clinical studies. In 2002 BSE was assigned an orphan drug status by the European Medicines Agency (EMA) for the treatment of peritumoral edema. In the past pharmacological effects of BSE were mainly attributed to 11-keto-β-boswellic acid (KBA) and 3-acetyl-11-keto-β-boswellic acid (AKBA). Therefore pharmacokinetic and pharmacodynamic studies focused mainly on these two boswellic acids (BAs). However, other BAs, like β-boswellic acid (βBA), might also contribute to the anti-inflammatory actions of BSE. Here, we determined the metabolic stability, permeability and brain availability of six major BAs, that is, KBA, AKBA, βBA, 3-acetyl-β-boswellic acid (AβBA), α-boswellic acid (αBA), and 3-acetyl-α-boswellic acid (AαBA). For permeability studies, the Caco-2 model was adapted to physiological conditions by the addition of bovine serum albumin (BSA) to the basolateral side and the use of modified fasted state simulated intestinal fluid (FaSSIF) on the apical side. Under these conditions the four BAs lacking the 11-keto moiety revealed moderate permeability. Furthermore the permeability of AKBA and KBA was improved compared to earlier studies. In contrast to Aα- and AβBA, βBA and αBA were intensively metabolized after incubation with human and rat liver microsomes. Finally, the availability of all six major BAs could be confirmed in rat brain 8 h after oral administration of 240 mg/kg BSE to rats showing mean concentrations of 11.6 ng/g for KBA, 37.5 ng/g for AKBA, 485.1 ng/g for αBA, 1066.6 ng/g for βBA, 43.0 ng/g for AαBA and 163.7 ng/g for AβBA.