# Curcumin Innovative Delivery Forms: Paving the Yellow Brick Road' of Antitumoral Phytotherapy
## 3 Pharmacokinetics and Bioavailability of Curcumin from Different Administration Routes
### Oral Administration  
Curcumin has extremely poor bioavailability from oral intake, which poses serious limitations to its widespread use as a therapeutic agent. In fact, serum levels following the ingestion of curcumin are so low that a dose-response profile is difficult to establish. When curcumin is taken in low amounts (30 or 180 mg daily), its levels in plasma or urine are null or within the experimental error [150; 151], as evidenced by the first two entries in the Table 2. Ingestion of daily doses of 3.6 g caused half of the patients to show serum levels of 11 nM [152], but for higher levels there is not a straightforward dose-response behavior (see also Table 2). Daily doses of 4 or 6 g corresponded to average serum peaks of 510 and 640 nM [153], while daily doses of 10 or 12 g resulted in average serum peaks of 138 nM and 157 nM, respectively [154]. Taken together, the results demonstrate that curcumin has a quite low absorption rate at the intestine, estimated at less than 1%, meaning that most of it is passed through the feces.  
The amount of curcumin that does get absorbed is further decreased due to the hepatic first pass metabolism, involving extensive O-conjugation to form curcumin glucuronides (Figure 2) and curcumin sulphate, and bioreduction to tetra-hydro Curcumin, hexahydro-curcumin, octahydroc curcumin, and hexahydrocuncuminol [155; 156]. Seric levels of curcumin peak at around 1-2 h after the ingestion, followed by a gradual decline within 12 h [153]. Curcumin and its conjugates are excreted in the urine [156].  
Some authors claim that serum levels of free curcumin show a deceivingly low bioavailability because a significant fraction of the compound occurs in plasma as glucuronide and sulfate conjugates [72; 158]. In the abovementioned clinical study with patients taking 3.6 g of curcumin, serum levels of the conjugates averaged 0.016 uM for curcumin glucuronide and 0.009 for curcumin sulphate [152]. The real therapeutic properties of these metabolites are, however, different from those of curcumin. Curcumin mono- or di-glucuronides have lower anti-inflammatory and anti-proliferative activities [159], and curcumin sulfate inhibits the activity of prostaglandin E2 very poorly when compared with curcumin [160].  
\begin{table}
\begin{tabular}{c c c c} \hline \hline
**Daily Dose** & \(\mathbf{C_{\max}}\) **Mean \(\pm\) S.D. (nM)** & \(\mathbf{T_{max}}\) **(h)** & **Ref.** \\ \hline
0.18 g & n.d. a [FOOTNOTE:a]Footnote a: n.d. means not detected. b The large standard deviation value may be due to the fact that data was collected from only two subjects. * No average available because data is from only one subject; no curcumin was detected in the plasma of the remaining subjects. \\
3.6 g & 11.1 \(\pm\) 0.6 & 1 & [152] \\
4.0 g & 510 \(\pm\) 110 & 1.67 & [153] \\
6.0 g & 640 \(\pm\) 60 & 2 & [153] \\
8.0 g & 1770 \(\pm\) 1870 b  & 1.75 & 1 & [153] \\
10.0 g & 138 c  & 4 & [154] \\
12.0 g & 157 c  & 2 & [154] \\
0.03 g/kg & 4.9 \(\pm\) 7.6 & 6 & [151] \\
2.0 g/kg & 16.3 \(\pm\) 13.5 & 1 & [157] \\ \hline \hline \end{tabular}
\end{table}
Table 2: Reported maximal serum levels (\(C_{\max}\)) and time (\(T_{\max}\)) in human subjects after ingestion of different dosages of curcumin.  
Figure 2: The metabolite curcumin \(\beta\)-D-glucuronide.