title: Ultra-performance liquid chromatography tandem mass spectrometry method for the determination of AZ66, a sigma receptor ligand, in rat plasma and its application to in vivo pharmacokinetics.
abstract: Methamphetamine abuse continues as a major problem in the USA owing to its powerful psychological addictive properties. AZ66, 3-[4-(4-cyclohexylpiperazine-1-yl)pentyl]-6-fluorobenzo[d]thiazole-2(3H)-one, an optimized sigma receptor ligand, is a promising therapeutic agent against methamphetamine. To study the in vivo pharmacokinetics of this novel sigma receptor ligand in rats, a sensitive ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) method was developed in rat plasma and validated. The developed method requires a small volume of plasma (100 μL) and a simple liquid-liquid extraction. The chromatographic separations were achieved in 3.3 min using an Acquity UPLC BEH Shield RP18 column. The mass spectrophotometric detection was carried out using a Waters Micromass Quattro MicroTM triple-quadrupole system. Multiple reaction monitoring was used for the quantitation with transitions m/z 406 → m/z 181 for AZ66 and m/z 448 → m/z 285 for aripiprazole. The method was validated over a concentration range of 1-3500 ng/mL and the lower limit of quantitation was determined to be 1 ng/mL. Validation of the assay demonstrated that the developed UPLC/MS/MS method was sensitive, accurate and selective for the determination of AZ66 in rat plasma. The present method has been successfully applied to an i.v. pharmacokinetic study in Sprague-Dawley rats.
authors.affiliation: The University of Mississippi, Department of Pharmaceutics, University of Mississippi, Mississippi, USA.
authors.forename: Seshulatha
authors.initials: S
authors.lastname: Jamalapuram
authors.forename: Pradeep Kumar
authors.initials: PK
authors.lastname: Vuppala
authors.forename: Ahmed H
authors.initials: AH
authors.lastname: Abdelazeem
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McCurdy
authors.forename: Bonnie A
authors.initials: BA
authors.lastname: Avery
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D008024:Ligands; D016014:Linear Models; D008297:Male; D010879:Piperazines / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism*; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: C584010:3-(4-(4-cyclohexylpiperazine-1-yl)pentyl)-6-fluorobenzo(d)thiazole-2(3H)-one; D052160:Benzothiazoles; D008024:Ligands; D010879:Piperazines; D017480:Receptors, sigma
keywords: AZ66; mass spectrometry; method validation; pharmacokinetics; rats
references.citation: Eur J Pharmacol. 1995 Feb 24;275(1):1-7
references.pmid: 7774655
references.citation: Eur J Pharmacol. 1994 Jun 15;268(1):9-18
references.pmid: 7925616
references.citation: Neuropsychopharmacology. 2002 Apr;26(4):444-55
references.pmid: 11927169
references.citation: Int J Neuropsychopharmacol. 2013 Jun;16(5):1033-44
references.pmid: 22932447
references.citation: Brain Res. 1980 Jul 7;193(1):153-63
references.pmid: 7378814
references.citation: Neuropharmacology. 2011 Oct-Nov;61(5-6):992-1000
references.pmid: 21762711
references.citation: J Neurosci. 2003 May 1;23(9):3924-9
references.pmid: 12736362
references.citation: Brain Res Rev. 2009 May;60(2):379-407
references.pmid: 19328213
references.citation: Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):8072-7
references.pmid: 8755605
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Apr 1;891-892:1-6
references.pmid: 22406103
references.citation: Curr Eye Res. 2009 Sep;34(9):785-90
references.pmid: 19839872
references.citation: Mol Pharmacol. 2012 Mar;81(3):299-308
references.pmid: 22101517
references.citation: J Pharmacol Exp Ther. 1976 Jun;197(3):517-32
references.pmid: 945347
references.citation: Cancer Res. 2007 Jul 15;67(14):6708-16
references.pmid: 17638881
references.citation: J Transl Med. 2009 Mar 26;7:24
references.pmid: 19323815
references.citation: Int Rev Neurobiol. 2009;88:65-100
references.pmid: 19897075
references.citation: Front Pharmacol. 2012 Jun 29;3:121
references.pmid: 22754527
references.citation: Eur J Pharmacol. 2006 Aug 7;542(1-3):61-8
references.pmid: 16797004
references.citation: Cancer Res. 2002 Jan 1;62(1):313-22
references.pmid: 11782394
references.citation: Curr Neuropharmacol. 2011 Mar;9(1):54-7
references.pmid: 21886562
references.citation: AAPS J. 2012 Mar;14(1):43-51
references.pmid: 22183188
references.citation: Drug Alcohol Depend. 2011 Jul 1;116(1-3):203-10
references.pmid: 21277708
references.citation: Eur Neuropsychopharmacol. 2008 Dec;18(12):871-81
references.pmid: 18755577
references.citation: Biol Psychiatry. 2011 Feb 1;69(3):208-17
references.pmid: 20950794
references.citation: J Pharmacol Exp Ther. 2010 May;333(2):491-500
references.pmid: 20100904
references.citation: Neuropharmacology. 2005 Oct;49(5):638-45
references.pmid: 15939443
references.citation: Br J Cancer. 2000 Mar;82(6):1223-32
references.pmid: 10735510
references.citation: Synapse. 2001 Jan;39(1):32-41
references.pmid: 11071707
references.citation: BMC Neurosci. 2012 Jun 14;13:65
references.pmid: 22697313
references.citation: Fundam Clin Pharmacol. 2002 Feb;16(1):1-8
references.pmid: 11903506
references.citation: Neurosci Lett. 2004 Sep 9;367(3):349-54
references.pmid: 15337264
references.citation: Neurotox Res. 2005 Nov;8(3-4):199-206
references.pmid: 16371314
references.citation: J Chem Neuroanat. 2009 Jan;37(1):18-32
references.pmid: 18773954