title: The stability of amitriptyline N-oxide and clozapine N-oxide on treated and untreated dry blood spot cards.
abstract: Procedures for drug monitoring based on Dried Blood Spot (DBS) sampling are gaining acceptance for an increasing number of clinical and preclinical applications, where ease of use, small sample requirement, and improved sample stability have been shown to offer advantages over blood tube sampling. However, to-date, the vast majority of this work has described the analysis of well characterized drugs. Using amitriptyline, clozapine, and their potentially labile N-oxide metabolites as model compounds, we consider the merits of using DBS for discovery pharmacokinetic (PK) studies where the metabolic fate of test compounds are often unknown. Both N-oxide metabolites reverted to parent compound under standard drying (2hr) and extraction conditions. Card type significantly affected the outcome, with 14% and 22% degradation occurring for clozapine-N-oxide and amitriptyline-N-oxide on a brand of untreated DBS cards, compared to 59 and 88% on a brand of treated DBS cards. Enrichment of the parent compound ex vivo leads to overestimation of circulating blood concentration and inaccurate determination of the PK profile.
authors: Astrazeneca R&D, DMPK Screening and Profiling, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors: David
authors: D
authors: Temesi
authors: John
authors: J
authors: Swales
authors: Warren
authors: W
authors: Keene
authors: Samuel
authors: S
authors: Dick
mesh_terms: D000639:Amitriptyline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003024:Clozapine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D059788:Dried Blood Spot Testing / Q000379:methods*; D016903:Drug Monitoring / Q000379:methods; D004355:Drug Stability; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D000639:Amitriptyline; D003024:Clozapine; C079149:clozapine N-oxide; C006566:amitriptyline N-oxide