R-Limonene metabolism in humans and metabolite kinetics after oral administration

Abstract

We studied the R-limonene (LMN) metabolism and elimination kinetics in a human in vivo study. Four volunteers were orally exposed to a single LMN dose of 100-130 µg kg bw. In each case, one pre-exposure and subsequently all 24 h post-exposure urine samples were collected. From two subjects, blood samples were drawn up to 5 h after exposure. The parent compound was analysed in blood using headspace GC-MS. The metabolites cis- and trans-carveol (cCAR), perillyl alcohol (POH), perillic acid (PA), limonene-1,2-diol (LMN-1,2-OH), and limonene-8,9-diol (LMN-8,9-OH) were quantified in both blood and urine using GC-PCI-MS/MS. Moreover, GC-PCI-MS full-scan experiments were applied for identification of unknown metabolites in urine. In both matrices, metabolites reached maximum concentrations 1-2 h post-exposure followed by rapid elimination with half-lives of 0.7-2.5 h. In relation to the other metabolites, LMN-1,2-OH was eliminated slowest. Nonetheless, overall renal metabolite elimination was completed within the 24-h observation period. The metabolite amounts excreted via urine corresponded to 0.2 % (cCAR), 0.2 % (tCAR), <0.1 % (POH), 2.0 % (PA), 4.3 % (LMN-1,2-OH), and 32 % (LMN-8,9-OH) of the orally administered dose. GC-PCI-MS full-scan analyses revealed dihydroperillic acid (DHPA) as an additional LMN metabolite. DHPA was estimated to account for 5 % of the orally administered dose. The study revealed that human LMN metabolism proceeds fast and is characterised by oxidation mainly of the exo-cyclic double bond but also of the endo-cyclic double bond and of the methyl side chain. The study results may support the prediction of the metabolism of other terpenes or comparable chemical structures.

Human Gut Microbiota Metabolism of Dietary Sesquiterpene Lactones: Untargeted Metabolomics Study of Lactucopicrin and Lactucin Conversion In Vitro and In Vivo

“…This shows that besides of the dehydroxylation produced by the gut microbiota, that leads to several deoxylactucin derivatives (8‐deoxylactucin, 15‐deoxylactucin), and the reduction of the double bonds leading to dihydro derivatives (Figure 1) (dihydro‐lactucin and dihydro‐lactucopicrin), they can also suffer the hydroxylation of double bonds by human phase I metabolism (CYP oxidation), as has already been reported for terpenes such as limonene. [ 21 ] In the case of R‐limonene, the exocyclic (preferentially) and endo‐cyclic double bonds were hydroxylated. As lettuce and escarole sesquiterpene lactones have several double bonds, they can also lead to different hydroxylated isomers ( Figure 3 ).…”

Systematic synthetic study of four diastereomerically distinct limonene-1,2-diols and their corresponding cyclic carbonates

“…(4 R )-Limonene-1,2-diols (LMdiols) are some of the most important LM derivatives because they act as precursors of bioactive molecules [12–14]. Furthermore, LMdiol is detected as metabolite in vivo in biochemistry [15], and is known to react in the atmosphere to afford the secondary organic aerosol as air pollutants [16]. Among the four diastereomers of LMdiols (Fig.…”

The Relative Content and Distribution of Absorbed Volatile Organic Compounds in Rats Administered Asari Radix et Rhizoma Are Different between Powder- and Decoction-Treated Groups

“…The double bond of M8 (limonene) was oxidized to form the epoxy bond and converted to M15 ( cis -limonene oxide) [ 15 ]. M33 ( l -menthol) was oxidized by cytochrome P450s, and M24 (isopulegol) was produced.…”