Oral and topical pharmacokinetic studies of a novel TRPV1 antagonist, PAC-14028 in rats and minipigs using liquid chromatography/tandem mass spectrometric method

• Published in: Journal of pharmaceutical and biomedical analysis Vol. 61; pp. 8 - 14
• Main Authors: Park, Yang-Hui, Joo, Kyung-Mi, Woo, Byoung-Young, Son, Eui Dong, Byun, Sang Yo, Shin, Hong-Ju, Lee, Ki-Wha, Park, Young-Ho, Lim, Kyung-Min
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 05-03-2012; Elsevier
• Subjects: absorption; acetonitrile; Acrylamides - administration & dosage; Acrylamides - pharmacokinetics; Acrylamides - standards; Administration, Oral; Administration, Topical; Analysis; Analytical, structural and metabolic biochemistry; Animals; antagonists; Biological and medical sciences; Chromatography, Liquid - methods; Chromatography, Liquid - standards; formic acid; freeze-thaw cycles; Fundamental and applied biological sciences. Psychology; General pharmacology; intravenous injection; ionization; LC/MS/MS; liquid chromatography; Male; Medical sciences; monitoring; PAC-14028; Pharmacokinetic; pharmacokinetics; Pharmacology. Drug treatments; Pyridines - administration & dosage; Pyridines - pharmacokinetics; Pyridines - standards; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Swine; Swine, Miniature; tandem mass spectrometry; Tandem Mass Spectrometry - methods; Tandem Mass Spectrometry - standards; Topical; topical application; Transient receptor potential vanilloid type I; TRPV Cation Channels - antagonists & inhibitors; TRPV Cation Channels - blood; TRPV Cation Channels - standards; Topical; LC/MS/MS; PAC-14028; Pharmacokinetic; Transient receptor potential vanilloid type I; Rat; Rodentia; Oral administration; HPLC chromatography; Transients; Local administration; Vertebrata; Mammalia; TRP ion channel; Animal; Mass spectrometry MS/MS; Artiodactyla; Antagonist; Minipig; Vanilloid receptor; Pharmacokinetics; Ungulata; Topical administration
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2011.11.011

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, 2.1
h and 3.8
h;
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%).