title: Human metabolism of α-pinene and metabolite kinetics after oral administration.
abstract: We studied the human in vivo metabolism and the elimination kinetics of α-pinene (αPN), a natural monoterpene which commonly occurs in the environment. Four volunteers were exposed to a single oral dose of 10 mg αPN. Each subject provided one pre-exposure and subsequently all post-exposure urine samples up to 24 h after administration. Additionally, blood samples were drawn hourly from two volunteers for 5 h. The analysis of the parent compound in blood was performed by a headspace GC-MS procedure, whereas the proposed αPN metabolites myrtenol (MYR) and cis- and trans-verbenol (cVER; tVER) were quantified in blood and urine using GC-PCI-MS/MS. Unknown metabolites were investigated using GC-PCI-MS full-scan analyses. The urinary concentration of the metabolites reached their maxima 1.6 h after exposure. Afterwards, they declined to the pre-exposure levels within the 24-h observation period with elimination half-lives of 1.5 h (MYR) and 1.6 h (cVER and tVER). The total eliminated amounts corresponded to 1.5 % (MYR), 5.6 % (cVER), and 4.1 % (tVER) of the orally applied dose. The GC-PCI-MS full-scan analyses identified three novel metabolites, of which one conforms to myrtenic acid (MYRA). A re-analysis of MYRA in urine showed maximum elimination 1.6 h after αPN ingestion, an elimination half-life of 1.4 h, and a share of the oral dose of 6.7 %. The study revealed that the human in vivo metabolism of αPN proceeds fast and elimination of metabolites takes places rapidly. The metabolism of αPN is dominated by extensive oxidation reactions at the methyl side-chains yielding in carboxylic acid structures as well as by allylic oxidation of the cyclohexenyl backbone, whereas predicted products of a double-bond oxidation were not detected.
authors.affiliation: Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schillerstrasse 25/29, 91054, Erlangen, Germany.
authors.forename: Lukas
authors.identifier: http://orcid.org/0000-0002-3206-6659
authors.initials: L
authors.lastname: Schmidt
authors.affiliation: 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.
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0002-8226-9227
authors.initials: T
authors.lastname: Göen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000081008:Bicyclic Monoterpenes; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006207:Half-Life; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008297:Male; D039821:Monoterpenes / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D000081008:Bicyclic Monoterpenes; D039821:Monoterpenes; C009951:verbenol; C005451:alpha-pinene; C534317:myrtenol
keywords: Human; Metabolites; Oral application; Renal elimination; α-Pinene