Weber Claudia-Carolin, Reising Karen, Müller Walter E, Schubert-Zsilavecz Manfred, Abdel-Tawab Mona
Institute of Pharmacology, ZAFES, Biocenter, University of Frankfurt, Germany.
Planta Med. 2006 May;72(6):507-13. doi: 10.1055/s-2006-931536.
Boswellic acids, the main active ingredients of Boswellia serrata, are gaining more and more importance in the treatment of peritumoural oedema and chronic inflammatory diseases. They may be even considered as alternative drugs to corticosteroids in reducing cerebral peritumoural oedema. An important focus for drugs acting in the central nervous system is achieving a high extent of brain penetration. Today there is increasing evidence for the importance of transporters, especially P-glycoprotein (Pgp), for drug disposition and resulting clinical response. Pharmacokinetic studies revealed that the concentrations of the potent keto derivatives, the 11-keto-beta-boswellic acid (KBA) and the acetyl-11-keto-beta-boswellic acid (AKBA), in proportion to boswellic acids lacking a keto group, like the beta-boswellic acid, are much lower in plasma than in the orally administered extract. Moreover the brain/plasma ratio for KBA and AKBA determined in preliminary experiments on rats was only about 0.51 and 0.81, respectively, in spite of their lipophilicity. Until now little is known about the cerebral pharmacokinetics of boswellic acids and how it may be influenced. Since many drugs are known to interact with Pgp at the level of the intestine and the blood-brain barrier the modulatory potencies of the Boswellia serrata extract of H15(R) and the major boswellic acids on the transport activity of Pgp have been determined in two in vitro assays. A human lymphocytic leukaemia cell line (VLB cells) expressing Pgp was chosen as model for human Pgp, and porcine brain capillary endothelial cells (PBCEC cells) were taken as model for the blood-brain barrier using calcein acetoxymethyl ester (calcein-AM) as Pgp substrate. It was found that the Boswellia extract, as well as the keto-boswellic acids inhibit the transport activity of Pgp in the micromolecular range in both cell types. No modulation was observed using those boswellic acids which have no keto group in their structure. The inhibition of Pgp at the blood-brain barrier by Boswellia extract is probably not relevant for the brain availability of other Pgp substrates, because of the low plasma levels determined for KBA and AKBA. However the presented data could not exclude the possibility of drug interactions caused by modulation of Pgp by extracts of Boswellia serrata on the gastrointestinal level.
乳香酸是乳香的主要活性成分，在治疗肿瘤周围水肿和慢性炎症性疾病方面越来越重要。在减轻脑肿瘤周围水肿方面，它们甚至可被视为皮质类固醇的替代药物。作用于中枢神经系统的药物的一个重要关注点是实现高脑渗透率。如今，越来越多的证据表明转运体，尤其是P-糖蛋白（Pgp），对药物处置及最终的临床反应具有重要意义。药代动力学研究表明，与不含酮基的乳香酸（如β-乳香酸）相比，强效酮衍生物11-酮-β-乳香酸（KBA）和乙酰-11-酮-β-乳香酸（AKBA）在血浆中的浓度远低于口服提取物中的浓度。此外，在大鼠初步实验中测定的KBA和AKBA的脑/血浆比值分别仅约为0.51和0.81，尽管它们具有亲脂性。到目前为止，关于乳香酸的脑药代动力学及其可能受到的影响知之甚少。由于已知许多药物在肠道和血脑屏障水平与Pgp相互作用，因此已通过两种体外试验测定了H15（R）乳香提取物和主要乳香酸对Pgp转运活性的调节能力。选择表达Pgp的人淋巴细胞白血病细胞系（VLB细胞）作为人Pgp的模型，并使用钙黄绿素乙酰氧基甲酯（calcein-AM）作为Pgp底物，将猪脑毛细血管内皮细胞（PBCEC细胞）作为血脑屏障的模型。结果发现，乳香提取物以及酮基乳香酸在两种细胞类型中均在微分子范围内抑制Pgp的转运活性。使用结构中不含酮基的那些乳香酸未观察到调节作用。由于测定的KBA和AKBA的血浆水平较低，乳香提取物对血脑屏障处Pgp的抑制作用可能与其他Pgp底物的脑可用性无关。然而，所提供的数据不能排除乳香提取物在胃肠道水平对Pgp的调节引起药物相互作用的可能性。
