title: Oral and topical pharmacokinetic studies of a novel TRPV1 antagonist, PAC-14028 in rats and minipigs using liquid chromatography/tandem mass spectrometric method.
abstract: PAC-14028 ((E)-N-((R)-1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl)-3-(2-propyl-6-trifluoromethyl-pyridine-3-yl)-acrylamide) is a novel and potent transient receptor potential vanilloid type I (TRPV1) antagonist. We developed and validated a rapid, sensitive and selective liquid chromatography/tandem mass spectrometric method for determination of PAC-14028 in rat and minipig plasma. After protein precipitation PAC-14028 and internal standard (methylated analog, PAC-14026) were separated on a Symmetry C(18) column (4.6 mm × 75 mm, 3.5 μm) with an isocratic mobile phase, acetonitrile: water (8:2, v/v) containing 0.2% formic acid and monitored by electrospray positive ionization with multiple reaction monitoring mode (PAC-14028, 492→156; IS, 506→156, m/z). The calibration curve was linear over the range of 1.0-500 ng/ml (r(2)>0.999) and lower limit of quantitation (LLOQ) was 1 ng/ml. The precision and accuracy were within ± 15% and the stability was acceptable during bench-top, auto-sampler, 3 freeze-thaw cycles and 4-week storage in a freezer at -80°C. This method was successfully applied to the intravenous, oral and topical pharmacokinetic studies of PAC-14028 in rats and minipigs, which showed comparable pharmacokinetic parameters (T1/2, 2.1h and 3.8h; F%, 52.7% and 64.2% for rats and minipigs, respectively). Percutaneous absorption of PAC-14028 was negligible after topical application (F% 0.2-1.7%).
authors.affiliation: Amorepacific CO R&D Center, Yongin 446-729, Republic of Korea.
authors.forename: Yang-Hui
authors.initials: YH
authors.lastname: Park
authors.forename: Kyung-Mi
authors.initials: KM
authors.lastname: Joo
authors.forename: Byoung-Young
authors.initials: BY
authors.lastname: Woo
authors.forename: Eui Dong
authors.initials: ED
authors.lastname: Son
authors.forename: Sang Yo
authors.initials: SY
authors.lastname: Byun
authors.forename: Hong-Ju
authors.initials: HJ
authors.lastname: Shin
authors.forename: Ki-Wha
authors.initials: KW
authors.lastname: Lee
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Park
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Lim
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000592:standards; D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods / Q000592:standards; D008297:Male; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000592:standards; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013552:Swine; D013556:Swine, Miniature; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000097:blood / Q000592:standards; D053719:Tandem Mass Spectrometry / Q000379:methods* / Q000592:standards
chemical_list: D000178:Acrylamides; C559614:N-(1-(3,5-difluoro-4-methanesulfonylaminophenyl)ethyl)-3-(2-propyl-6-trifluoromethylpyridine-3-yl)acrylamide; D011725:Pyridines; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat