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-ß-boswellic acid (KBA) and 3-acetyl-11-keto-ß-boswellic acid (AKBA). Therefore pharmacokinetic and pharmacodynamic studies focused mainly on these two boswellic acids (BAs). However, other BAs, like ß-boswellic acid (ßBA), 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, ßBA, 3-acetyl-ß-boswellic acid (AßBA), 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 AßBA, ßBA 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 8h after oral administration of 240mg/kg BSE to rats showing mean concentrations of 11.6ng/g for KBA, 37.5ng/g for AKBA, 485.1ng/g for αBA, 1066.6ng/g for ßBA, 43.0ng/g for AαBA and 163.7ng/g for AßBA.

Enhanced absorption of boswellic acids by a lecithin delivery form (Phytosome(®)) of Boswellia extract.

The anti-inflammatory potential of Boswellia serrata gum resin extracts has been demonstrated in vitro and in animal studies as well as in pilot clinical trials. However, pharmacokinetic studies have evidenced low systemic absorption of boswellic acids (BAs), especially of KBA and AKBA, in rodents and humans. This observation has provided a rationale to improve the formulation of Boswellia extract. We present here the results of a murine comparative bioavailability study of Casperome™, a soy lecithin formulation of standardized B. serrata gum resin extract (BE), and its corresponding non-formulated extract. The concentration of the six major BAs [11-keto-ß-boswellic acid (KBA), acetyl-11-keto-ß-boswellic acid (AKBA), ß-boswellic acid (ßBA), acetyl-ß-boswellic acid (AßBA), α-boswellic acid (αBA), and acetyl-α-boswellic acid (AαBA)] was evaluated in the plasma and in a series of tissues (brain, muscle, eye, liver and kidney), providing the first data on tissue distribution of BAs. Weight equivalent and equimolar oral administration of Casperome™ provided significantly higher plasma levels (up to 7-fold for KBA, and 3-fold for ßBA quantified as area under the plasma concentration time curve, AUC(last)) compared to the non-formulated extract. This was accompanied by remarkably higher tissue levels. Of particular relevance was the marked increase in brain concentration of KBA and AKBA (35-fold) as well as ßBA (3-fold) following Casperome™ administration. Notably, up to 17 times higher BA levels were observed in poorly vascularized organs such as the eye. The increased systemic availability of BAs and the improved tissue distribution, qualify Casperome™ for further clinical development to fully exploit the clinical potential of BE.

Myrtucommulone from Myrtus communis: metabolism, permeability, and systemic exposure in rats.

Nonsteroidal anti-inflammatory drug intake is associated with a high prevalence of gastrointestinal side effects, and severe cardiovascular adverse reactions challenged the initial enthusiasm in cyclooxygenase-2 inhibitors. Recently, it was shown that myrtucommulone, the active ingredient of the Mediterranean shrub Myrtus communis, dually and potently inhibits microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase, suggesting a substantial anti-inflammatory potential. However, one of the most important prerequisites for the anti-inflammatory effects in vivo is sufficient bioavailability of myrtucommulone. Therefore, the present study was aimed to determine the permeability and metabolic stability in vitro as well as the systemic exposure of myrtucommulone in rats. Permeation studies in the Caco-2 model revealed apparent permeability coefficient values of 35.9 ·â€Š10⁻6 cm/s at 37 °C in the apical to basolateral direction, indicating a high absorption of myrtucommulone. In a pilot rat study, average plasma levels of 258.67 ng/mL were reached 1 h after oral administration of 4 mg/kg myrtucommulone. We found that myrtucommulone undergoes extensive phase I metabolism in human and rat liver microsomes, yielding hydroxylated and bihydroxylated as well as demethylated metabolites. Physiologically-based pharmacokinetic modeling of myrtucommulone in the rat revealed rapid and extensive distribution of myrtucommulone in target tissues including plasma, skin, muscle, and brain. As the development of selective microsomal prostaglandin E2 synthase-1 inhibitors represents an interesting alternative strategy to traditional nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for the treatment of chronic inflammation, the present study encourages further detailed pharmacokinetic investigations on myrtucommulone.

Effect of phospholipid-based formulations of Boswellia serrata extract on the solubility, permeability, and absorption of the individual boswellic acid constituents present.

Boswellia serrata gum resin extracts are used widely for the treatment of inflammatory diseases. However, very low concentrations in the plasma and brain were observed for the boswellic acids (1-6, the active constituents of B. serrata). The present study investigated the effect of phospholipids alone and in combination with common co-surfactants (e.g., Tween 80, vitamin E-TPGS, pluronic f127) on the solubility of 1-6 in physiologically relevant media and on the permeability in the Caco-2 cell model. Because of the high lipophilicity of 1-6, the permeability experiments were adapted to physiological conditions using modified fasted state simulated intestinal fluid as apical (donor) medium and 4% bovine serum albumin in the basolateral (receiver) compartment. A formulation composed of extract/phospholipid/pluronic f127 (1:1:1 w/w/w) increased the solubility of 1-6 up to 54 times compared with the nonformulated extract and exhibited the highest mass net flux in the permeability tests. The oral administration of this formulation to rats (240 mg/kg) resulted in 26 and 14 times higher plasma levels for 11-keto-ß-boswellic acid (1) and acetyl-11-keto-ß-boswellic acid (2), respectively. In the brain, five times higher levels for 2 compared to the nonformulated extract were determined 8 h after oral administration.

Structural properties of so-called NSAID-phospholipid-complexes.

So-called NSAID-phospholipid-complexes have been recently reported in literature to reduce local gastrointestinal toxicity. The present work was dedicated to the structural characterization of so-called drug-phospholipid-complexes on the example of diclofenac sodium, ibuprofen and piroxicam complexes with dipalmitoylphosphatidylcholine (DPPC) at different stages of preparation. The applied techniques include (1)H/2D ROESY NMR for the structural characterization in organic solvents, FT-IR and X-ray diffraction for the structural characterization in the solid state and PCS, (31)P NMR, as well as MAS (1)H/2D NOESY NMR for the structural characterization in aqueous media following hydration. Whereas the formation of isolated 1:1 drug-phospholipid-complexes with a preferential location of diclofenac and ibuprofen at the polar head group, stabilized by cation-π interaction, seems reasonable in organic solvents, it was found that mainly liposomal and micellar structures are formed upon hydration of the drug-phospholipid-complexes. Hence the term "NSAID-phospholipid-complex" may be misleading in the context with physiologically relevant aqueous media. Piroxicam did not show significant interaction with DPPC.