title: Bioanalytics and pharmacokinetics of the nociceptin/orphanin FQ peptide receptor agonist RO0646198 in Wistar rats and Cynomolgus monkeys.
abstract: This manuscript describes the determination of the nociceptin/orphanin FQ peptide (NOP) receptor agonist RO0646198 in rat and Cynomolgus monkey plasma using liquid chromatography coupled to tandem mass spectrometry. The structural analogue RO0658791 served as internal standard. After protein precipitation with ethanol, clean up and enrichment was carried out by on-line solid-phase extraction on a 10mm C18 trapping column. Gradient separation was performed on a 50 mm C18 analytical column, followed by electrospray ionization and detection in positive ion selected reaction monitoring (SRM) mode. The total run time was 2.5 min. The lower limit of quantification (LLOQ) was 10 pg/mL. Precisions were below 19% and accuracies were between 86% and 118%. The recoveries were above 90%, and no significant matrix effect was observed. The method was successfully applied to low dose pharmacokinetic studies. The bioavailability after oral dosing was below 5% for rats and below 1% in Cynomolgus monkeys, limiting the application of RO0646198 in the clinic to parenteral routes.
authors.affiliation: F. Hoffmann-La Roche Ltd., Pharma Research, Non-clinical Safety, CH-4070 Basel, Switzerland. katja.heinig@roche.com
authors.forename: Katja
authors.initials: K
authors.lastname: Heinig
authors.forename: Nicole
authors.initials: N
authors.lastname: Kratochwil
authors.forename: Franz
authors.initials: F
authors.lastname: Bucheli
authors.forename: Anita
authors.initials: A
authors.lastname: Thomae
mesh_terms: D000818:Animals; D004333:Drug Administration Routes; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008252:Macaca fascicularis / Q000097:blood*; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000819:agonists*; D012015:Reference Standards; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D013141:Spiro Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013997:Time Factors; D000094942:Nociceptin Receptor
chemical_list: D007093:Imidazoles; D011957:Receptors, Opioid; C408068:Ro 64-6198; D013141:Spiro Compounds; D000094942:Nociceptin Receptor