title: Human metabolism of Δ3-carene and renal elimination of Δ3-caren-10-carboxylic acid (chaminic acid) after oral administration.
abstract: We studied the human in vivo metabolism of Δ(3)-carene (CRN), a natural monoterpene which commonly occurs in the human environment. Four healthy human volunteers were orally exposed to a single dose of 10 mg CRN. Each volunteer gave one urine sample before administration and subsequently collected each urine sample within 24 h after administration. The concentration of the proposed CRN metabolites Δ(3)-caren-10-ol (CRN-10-OH), Δ(3)-caren-10-carboxylic acid (chaminic acid, CRN-10-COOH), and Δ(3)-caren-3,4-diol (CRN-3,4-OH) were determined using a very specific and sensitive GC-MS/MS procedure. Other CRN metabolites were investigated using GC-PCI-MS Q1 scan analyses. CRN-10-COOH was detected in each urine sample with maximum concentration (113.0-1,172.9 µg L(-1)) 2-3 h after administration, whereas CRN-10-OH and CRN-3,4-OH were not detected in any of the samples. The renal excretion kinetics of CRN-10-COOH showed an elimination half-life of about 3 h. The cumulative excretion of CRN-10-COOH within 24 h after exposure correlated with about 2 % of the applied dose. The GC-PCI-MS Q1 scan analysis indicated several additional human CRN metabolites; thereof, six spectra enabled the prediction of the corresponding chemical structure. The results of the study indicate that CRN-10-COOH is a relevant product of the human in vivo metabolism of CRN. The oxidation of its allylic methyl group proceeds until the acidic structure without interruption. Thus, the generation of the alcoholic intermediate appeared to be the rate-determining step of this metabolic route. Nevertheless, the proportion of CRN-10-COOH in the CRN metabolism is low, and other oxidative metabolites are likely. This hypothesis was confirmed by the discovery of additional human CRN metabolites, whose predicted chemical structures fit in with further oxidative products of CRN metabolism.
authors.affiliation: Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine, University of Erlangen-Nuremberg, Schillerstrasse 25/29, 91054, Erlangen, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Schmidt
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Belov
authors.forename: Thomas
authors.initials: T
authors.lastname: Göen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000081008:Bicyclic Monoterpenes; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D002138:Calibration; D002264:Carboxylic Acids / Q000737:chemistry / Q000652:urine*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D000432:Methanol / Q000031:analogs & derivatives / Q000737:chemistry / Q000652:urine; D015394:Molecular Structure; D039821:Monoterpenes / Q000737:chemistry / Q000652:urine*; D015203:Reproducibility of Results
chemical_list: D000081008:Bicyclic Monoterpenes; D001643:Bridged Bicyclo Compounds; D002264:Carboxylic Acids; D039821:Monoterpenes; C000603108:chaminic acid; C507856:delta(3)-carene-10-ol; C030218:3-carene; D000432:Methanol