## 3 Pharmacokinetics of Tanshinones  
### The Pharmacokine (PK) Characteristics of Single Administered Agents or as Mixtures  
The major tanshinones (TIIA, CT, TI, DH-TI) have been studied in a number of animal models including rats, rabbits and pigs. Table 2 summarizes representative studies and maximal/peak concentration (\(C_{\text{max}}\)) in plasma (central) compartment, providing useful reference ranges to evaluate cell culture based studies and guidance on dosing regimens for future efficacy studies. In spite of differences in the analytical methods, dosing solvents/vehicles, and lack of uniformity in reporting of PK parameters and data interpretation, some general conclusions could be reached. First, tanshinones are poorly bioavailable with conventional delivery formulations through oral administration (_p.o._). This was best illustrated by a systematic comparison of the area under the curve (AUC) of _p.o._ intraperitoneal (_i.p._), _vs._ intravenous (_i.v._) administration of CT by [PERSON] and colleagues [94] (See Table 2). The _p.o._ and i.p. bioavailability in rats was estimated as 2.1% and 10.6%, respectively, when CT was dosed at 100 milligrams per kilogram (mg/kg) body weight. Maximal/peak concentration (\(C_{\text{max}}\)) values in the nano-molar (nM) to lower micromolar (\(\upmu\)M) range after _p.o._ administration were reported in most studies on tanshinones, except that [PERSON] _et al._[95] reported for TIIA a \(C_{\text{max}}\) value that was several orders of magnitude higher than most reports (see Table 2). The low aqueous solubility and poor membrane permeability might be responsible for impeding the absorption of TIIA [96]. [PERSON] and coworkers have shown [94] in rats that a mechanism \begin{table}
\begin{tabular}{l l l l} \hline
**Alternative Source** & **Characteristics** & **Products** & **References** \\ \hline Callus culture (root, stem, leaf blade, and petiole) & Well established conventional strategy, potential to form a whole plant, and easy maintenance of tissue in culture & Cryptotanshinone, tanshinone I, and tanshinone IIA & [72; 73; 74; 75] \\ Cell suspension & Reliable, sustainable, free of adverse culture & Tanshinone I, tanshinone IIA, cryptotanshinone, and ferruginol & [76; 77; 78; 79] \\ Cell immobilization & High cell densities, continuous removal culture & Tanshinone IIA, cryptotanshinone, and ferruginol & [80, 81] \\  & biocatalysts, and protection for shear-sensitive cells by matrix & Tanshinone I, tanshinone IIA, & [82; 83; 84; 85; 86; 87; 88] \\ Rhizogenesis & Genetic and biosynthetic stability, plant hormone-independent growth, multi-enzyme biosynthetic potential, and relatively low cost & Tanshinone I, tanshinone IIA, tanshinone V, & [82; 83; 84; 85; 86; 87; 88] \\ Crown gall cultures & Fast growth rate, independent of exogenous phytohormones, high productivity of secondary metabolites & Tanshinone I, tanshinone I, tanshinone V, & [89; 90; 91; 92] \\  & that are low in normal cell cultures & & \\ Endophytic fungi & Economic, reproducible, ecology-friendly, and easy to scale up & & \\ \hline \end{tabular}
\end{table} 
Table 1: Alternative sources of _S. miliotrrhiza_ and tanshinone production. for the poor intestinal absorption of CT is the presence of an efflux pump (p-glycoprotein) on intestinal apical lumen cells to pump CT into the luminal side.