title: Pharmacokinetic study of nicotine and its metabolite cotinine to clarify possible association between smoking and voiding dysfunction in rats using UPLC/ESI-MS.
abstract: The present study was undertaken to clarify the possible association between nicotine intake/cigarette smoking and detrusor instability. For pharmacokinetic characterization of nicotine and cotinine (a major and pharmacologically less active metabolite of nicotine), a rapid ultra-performance liquid chromatography/electrospray ionization-mass spectrometry (UPLC/ESI-MS) method was developed that requires only a small amount of sample and simple pretreatment. The UPLC/ESI-MS method was validated with a focus on specificity, sensitivity (limit of detection, 2.5 ng/mL; limit of quantification, 5 ng/mL), linearity (r > 0.998), accuracy (97.2-102.8%), precision (relative standard deviation <8%) and robustness in accordance with ICH guidelines (Q2B Validation of Analytical Procedures: Methodology). The developed method was successfully applied to determine nicotine and cotinine levels in rat biological samples such as plasma, urine and several tissues. After subcutaneous administration of nicotine ditartrate (2 mg/kg of body weight) in rats, the absorbed nicotine was rapidly and extensively metabolized into cotinine. However, nicotine was found to be predominant in cortex and bladder, where nicotinic acetylcholine receptors were expressed for neuronal control of voiding function. Repeated administration of nicotine led to a ca. 3-fold higher accumulation of nicotine than that of cotinine in rat urine. The results of the pharmacokinetic study using the UPLC/ESI-MS method further support the possible involvement of nicotine in increased risk of urinary dysfunction in smokers.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, Japan. onoue@u-shizuoka-ken.ac.jp
authors.forename: Satomi
authors.initials: S
authors.lastname: Onoue
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Seto
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid; D003367:Cotinine / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D009538:Nicotine / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D012907:Smoking / Q000009:adverse effects* / Q000503:physiopathology; D021241:Spectrometry, Mass, Electrospray Ionization; D014555:Urination Disorders / Q000209:etiology* / Q000503:physiopathology
chemical_list: D009538:Nicotine; D003367:Cotinine