Ess vital, with time, thus explaining the decreasing curcumin concentrations (Figure 5). Intracellular metabolism is one more issue that may contribute to decreasing curcumin concentrations with time. As observed in human and rat intestinal and hepatic microsomes, curcumin is primarily conjugated to curcumin glucuronide and curcumin sulfate, but in addition lowered to dihydro-, tetrahydro-, hexahydro-, or octahydrocurcumin [49]. In human plasma, no absolutely free curcumin is detectable following oral administration, even at really high doses of up to 12 g curcumin [10]. Interestingly, in time-dependent efflux and preliminary uptake experiments, curcumin concentrations with (cost-free conjugated) and with out (free curcumin) treatment with -glucuronidase have been equal in Dehydroemetine medchemexpress supernatants and cell lysates after 1 h incubation with native or micellar curcumin or, as shown in Figure 5, right after 1 h preincubation with native and micellar curcumin and, further, six, 8, and 24 h incubation using a curcumin-free medium. Consequently, and in contradiction to data on curcumin plasma concentrations from human trials [8,103,50], no or negligible amounts of glucuronidated or sulfated curcumin have been detectable in cell culture medium, despite the fact that the expression from the relevant enzymes (UDP-glucuronosyltransferase and sulfotransferase) in LS180 cells was reported previously [51,52]. In other publications reporting on curcumin uptake and transport via intestinal cells, no enzyme remedy was described and exclusively totally free curcumin was quantified [46,53]. Dempe et al., (2013) did not detect any curcumin glucuronide or sulfate in Caco-2 cell pellets immediately after three h incubation with native curcumin. Curcumin glucuronide was observed in little amounts within the supernatants. Following 1 h, no curcumin sulfate, small amounts of curcumin glucuronides, and, primarily, no cost curcumin have been quantified within the basolateral and apical chambers [54]. Although UDP-glucuronosyltransferase and sulfotransferase isoforms, involved in curcumin metabolism, are expressed in Caco-2 cells [55], their activities in this cell line are low compared to other model systems [56]. Therefore, the presently readily available cell culture systems do not appear to adequately reflect the metabolism of curcumin in humans. 5. Conclusions In conclusion, native and formulated curcumin inhibited P-glycoprotein activity in cultured intestinal cells, devoid of considerable influences of the galenic formulation. In addition, cellular uptake by, and efflux from, intestinal cells were not drastically impacted by its formulation, even though substantial variations in the bioavailability of unique curcumin formulations, front and foremost micellar curcumin, have already been reported. Consequently, the presented data suggest that intestinal uptake and efflux might not be vital regulatory points, limiting the bioavailability on the direct and indirect antioxidant curcumin. Nonetheless, the inhibition of P-glycoprotein activity by curcumin warrants further investigation, as it may perhaps pose the danger of undesired interactions with prescription drugs.Author Contributions: Conceptualization, S.F. and J.F. (www.nutrition.red); methodology, S.F. and J.F.; investigation, S.F. and R.M.; information curation, S.F. and R.M.; writing–original draft preparation, S.F.; writing–review and editing, R.M. and J.F.; visualization, S.F. and J.F.; supervision, J.F. All authors have study and SN-38 custom synthesis agreed for the published version of your manuscript. Funding: This study received no external funding. Institut.