# Antidiabetic Potential of Monoterpenes: A Case of Small Molecules Punching above Their Weight
## 5 Bioavailability  
Several studies on the absorption, distribution, metabolism, and excretion of monoterenes have been published in recent years. [PERSON] et al. [99] have studied the oral bioavailability of paeoniflorin in a single-pass \"four-site\" rat intestinal perfusion model and cultured Caco-2 cells. As expected, the absorption of this compound in cultured cells was slower than its aglycone (paeoniflorigenin). They have found that poor permeation, P-gp-mediated efflux, and hydrolysis via a glucosidase contributed to the poor bioavailability of paeoniflorin. When the crude plant extract preparation of _Paeonia lactisiflora_ roots (Chishao) that contain paeoniflorin as a major component (85.5%) was administered in human subjects by intravenous and multiple infusions, an elimination half-lives of 1.2-1.3 h was noted for paeoniflorin. After exposure to major organs, glomerular-filtration-based renal excretion has been found to be the major elimination pathway for this compound [100]. The bioavailability of paeoniflorin has been generally considered low in rabbit (7.24%) and rat (3.24%) after oral administration [101].  
Oral administration of the monoterene aglycones such as thymol and carvacrol has also been shown to result in their slow absorption into the blood stream [102]. Both unchanged and their glucuronide and sulfate conjugates have also been detected. For example, [PERSON] et al. [103] have shown that carvacrol, as a substrate to uridine diphosphate-glucuronosyl transferase, can inhibit the enzyme. In another study of a clinical trial involving 12 healthy volunteers, no thymol could be detected in plasma or urine [104]. However, its metabolites thymol sulfate and thymol glucuronide were found in urine and the reported mean terminal elimination half-life was 10.2 h. Moreover, thymol sulfate was detectable up to 41 h after administration and urinary excretion normally followed over 24 h [104].  
In a potential anticancer therapy study, administration of lemonene in women with newly diagnosed operable breast cancer indicated preferential concentration of the compound in the breast tissue, reaching high tissue concentration (mean of 41.3 ug/g tissue) while its major active circulating metabolite was reported to be perillic acid [105]. The accumulation of limonene on adipose tissues has also been described in other studies [106]. Oral administration of swertiamarin in rats has been shown to be associated with rapid and wide distribution in tissues with the highest amount obtained in the liver and kidney, perhaps indicating the possible metabolism and/or elimination sites [107]. As demonstrated for geniposide, administration of these compounds in the form of crude plant extract may be better for their bioavailability than the purified compounds [108].  
There is no doubt that more data is needed to establish a clear bioavailability and/or pharmacokinetic profile of monoterenes. The fact that these compounds display antidiabetic effect when administered orally and at even modest doses suggest that they can be absorbed/bioavailable to exert their action in the various organ systems. There distribution profile in tissues reported so far has also been promising although further studies on optimization and formulation studies are critical. The extreme nonpolar nature of the monoterene aglycones imply that they can easily travel across cell membranes but their poor water solubility is a challenge, and given this fact, the observed antidiabetic effect should be considered remarkable. On the other hand, the glycosides of these compounds are also shown to display antidiabetic effects and may constitute another route for optimizing their antidiabetic effects.