R-Limonene metabolism in humans and metabolite kinetics after oral administration.
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-1bw. 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.
Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine, Friedrich-Alexander Universität Erlangen-Nürnberg, Schillerstrasse 25/29, 91054, Erlangen, Germany.
Lukas
http://orcid.org/0000-0002-3206-6659
L
Schmidt
Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine, Friedrich-Alexander Universität Erlangen-Nürnberg, Schillerstrasse 25/29, 91054, Erlangen, Germany. Thomas.Goeen@fau.de.
Thomas
http://orcid.org/0000-0002-8226-9227
T
Göen
D000284:Administration, Oral; D000328:Adult; D000081005:Cyclohexane Monoterpenes; D053138:Cyclohexenes / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006207:Half-Life; D006801:Humans; D000077222:Limonene; D008297:Male; D039821:Monoterpenes / Q000097:blood / Q000652:urine; D013729:Terpenes / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*
D000081005:Cyclohexane Monoterpenes; D053138:Cyclohexenes; D039821:Monoterpenes; D013729:Terpenes; C032208:perillyl alcohol; C078706:perillic acid; C075856:carveol; D000077222:Limonene
Human; Metabolites; Oral application; R-Limonene; Renal elimination; Terpene