# Recent Advances and Insights into Bromelain Processing, Pharmacokinetics and Therapeutic Uses
## 5 Pharmacodynamics and Pharmacokinetics Profiles of Bromelain  
The mechanisms of action of bromelain have not yet been fully established. However, the anti-inflammatory activity of this supplement on three different pathways has been highlighted in several in vivo and in vitro studies. The first is the kallikrein-kinin pathway; bromelain regulates the plasma fibrinogen levels and blood levels of bradykinin and improves serum fibrinolytic activity by activating factor XI, which subsequently activates plasma prekallikrein [54; 74]. Secondly, bromelain acts on the arachidonic acid pathway (Figure 2); it modulates proinflammatory prostaglandandins (via the inhibition of prostaglandin E2 and thromboxane A2) and enhances the anti-inflammatory mediators, increasing platelet cyclic adenosine monophosphate (cAMP), and, thus, the levels of prostaglandin (PG) I2 and PGE1. Finally, bromelain modulates cell-migration immunity: acting on the migration of neutrophils to inflammation sites [75]. In detail, it removes several cell-surface molecules (including CD128a/CXCR1, CD128b/CXCR2, CD14, CD16 and CD21) that are vital to leukocyte trafficking, cellular adhesion, the induction of pro-inflammatory mediators and immunomodulatory effect on T cells. It also reduces P-selectin-mediated neutrophil recruitment (Figure 1) [76]. These actions permit bromelain to be potentially effective in several conditions associated with inflammation, with or without oedema, and alterations in blood coagulation. In fact, RCTs that have been carried out highlight the activity of bromelain in diseases such as rheumatoid arthritis, osteoarthritis, perioperative sport injuries, cancer, cardiovascular diseases, chronic rhinosinusitis and skin wounds and burns, which are all conditions with an inflammatory component [3].  
The pharmacokinetics profile of bromelain is still unclear because of difficulties determining this component in serum and the poor knowledge of its bioaccessibility and bioavailability. It would appear that bromelain is absorbed into the small intestine, rapidly forming a complex with anti-proteases (\(\alpha\)2-macroglobulin and \(\alpha\)1-trypsin) [7]. On the other hand, the possibility that bromelain penetrates the lamina propria intact has been underlined, with \(\alpha\)2-macroglobulin-bromelain complexes being formed, leaving bromelain proteolytic activity untouched [15]. Bromelain is considered to be a safe nutraceutical. As reported by [PERSON] et al., it is impossible to determine the LD50 (mg/kg body weight) of this supplement at doses above 10 g/kg per os in mice, rats and rabbits. However, the LD50 for intraperitoneal administration is 37 mg/kg and 85 mg/kg for mice and rabbits respectively, while for intravenous administration it is 30 mg/kg and 20 mg/kg [77]. No relevant side effects have been observed at doses of up to 2000 mg/kg per os, even with prolonged periods of administration [7]. However, although bromelain is well tolerated and considered a safe nutraceutical, clinical trials have reported a few side effects, including transitory diarrhea, nausea and vomiting, allergic reactions and a risk of bleeding, especially in people treated with anticoagulant drugs, such as warfarin and clopidogrel [78].