## 3 Discussion  
Phytochemicals are vital cofactors with powerful effects on the body, helping it regain functionality. As shown in this review, even though phytochemicals may have different mechanisms of action and different levels of effectiveness in the body, there are overlapping aspects such as antioxidant, anti-inflammatory, and corrective metabolic effects that produce various positive physiological impacts favoring the healthy state. The physiologic modulation induced by these phytonutrients and their phytochemicals produces functional changes that support repair mechanisms necessary to achieve the homeostasis or balance known as health.  
The physicochemical properties calculated for the main phytochemicals in the phytontutrients studied in this review are based on the combination of [PERSON]'s, [PERSON]'s, and [PERSON]'s rules (L-Ro5, GF, VR), described as an approximation for the pharmacokinetics of a molecule in the body [30]. Thus, a molecule whose structure falls out of the range of these rules is predicted to have poor absorption or permeation through the gastrointestinal system and low systemic bioavailability.  
From the evaluation of 25 phytochemicals through the mentioned parameters (Table 1), 23 of them fulfill the requirements of L-Ro5 (HBD \(\leq\) 5, HBA \(\leq\) 10, MW \(\leq\) 500, logP \(\leq\) 5) and VR (RB \(\leq\) 10, PSA \(\leq\) 140), while 2 (annonacin/acetogenin and rutin from graviola) violated more than one parameter. Per GF, the compounds should meet the following: MW (160-480), logP (\(-\)0.4-5.6), A (40-130), and TNA (20-70). Accordingly, 13 phytochemicals (curcumin, demethylox Curcumin, bisdemethoxys Curcumin, and \(\alpha\)-turmerone from turmeric; allin, allicin, and z-ajoene from garlic; (E)-cinnamyl acetate and eugenol from cinnamon; benzylisoquinoline, coumaric acid, and caffeic acid from graviola; and apigenin and luteolin from oregano) comply with [PERSON]'s rules.  
Considering GI tract absorption (Figure 2a), 54% of all phytochemicals studied in this review (curcumin, demethylox Curcumin, bisdemethoxys Curcumin, \(\alpha\)-turmerone, allin, z-ajoene, (E)-cinnamyl acetate, eugenol, coumaric acid, caffeic acid, apigenin, and luteolin) met all rules and, thus, have a higher probability of being highly absorbed. Based on L-Ro5, GF, and VR, all described turmeric's phytochemicals belong to highly absorbed compounds (100%) compared to garlic, cinnamon, oregano (40%) (Figure 2b,c,d,f); and graviola (50%) (Figure 2e).  
Graviola's phytochemicals, annonacin/acetogenin, and rutin violate most of the \"drug-likeness\" rules. For example, annonacin/acetogenin complies with only 50% L-Ro5 and VR and violates 100% of the GF. For rutin, the compliance for L-Ro5 was 25%, GF was 25%, and VR was 50%. Thus, it is predicted that annonacin/acetogenin and rutin have the lowest probability of absorption in the GI.  
Other researchers have proposed that the lipophilicity, considering the ionizable groups at pH 7.4 (LogD), is much more important for physiological absorption or permeation [265]. Thus, compounds that fall below 1 and above 5 for LogD are less likely to be absorbed. Based on this, allin from garlic; protocatechic acid from cinnamon; and annonacin/acetogenin, cinnamic acid, coumaric acid, caffeic acid, and rutin from graviola fall out this LogD range.  
However, the predictions of these rules are also based on molecules passively transported into the cells. This means that L-Ro5, GF, and VR do not take into consideration actively transported substrates by biological transporters (e.g., cellular receptors or channels) [266]. On the contrary, we understand that many therapeutic compounds are actively transported in the organism, especially plant-based compounds. Due to this, other studies have shown that most of the violators of these rules are natural products [267].