The need for analytical chemistry support for clinical studies arose because of increased appreciation of the importance of pharmacokinetics in understanding drug action in the late 1970s. Neal Benowitz had initiated pharmacokinetic studies of nicotine and opioids and Reese Jones initiated studies of cocaine pharmacokinetics and pharmacodynamics, largely supported by a P50 award. At that time, our analytical laboratory consisted of a chemist, two technicians and two gas chromatographs. Since, many projects requiring analytical chemistry support were initiated and our laboratory staff has grown from three to 14: Two PhD Research Chemists, nine Staff Research Associates and three Laboratory Assistants. Major equipment includes two gas chromatographs, two desktop GC-MS systems, two HPLCs, three triple-stage quadrupole LC-MS/MS systems, and two triple-stage quadrupole GC-MS/MS systems. Support for the laboratories comes from the P30 Center, ROIs and contracts. In recent years, our group has made extensive, and we believe innovative, use of stable isotope methodology. Stable isotope-labeled drugs, unlike those labeled with radioisotopes, are no more hazardous than unlabeled drugs. A stable isotope, such as the hydrogen isotope deuterium, incorporated into a drug molecule allows the labeled drug to be used as a tracer. This is a powerful tool in studies of pharmacokinetics and metabolism, frequently used in bioavailability studies. While the natural drug is administered by its usual route, such as oral, transdermal, or by smoking, the labeled drug is simultaneously administered intravenously for pharmacokinetic characterization. We have used this technique to determine nicotine intake from smoking (Benowitz et al. 1991a) and from smokeless tobacco (Jacob et al. 1999), bioavailability of transdermal nicotine (Benowitz et al. 1991b) and bioavailability of cocaine administered by various routes. We have used stable isotope methodology to study the metabolic disposition of cocaine and ethanol, including determination of the fractional conversion of cocaine to cocaethylene (Jacob et al. 1997;Everhart et al. 1998). Stable isotope methodology was used to determine the bioavailablity of intranasal and smoked methamphetamine (Harris et al. 2003). Our use of stable isotopes is continuing and expanding. We will be utilizing labeled frans-3'-hydroxycotinine to further our understanding of nicotine pharmacogenetics and to better understand the mechanism of racial differences in nicotine metabolism.. Cotinine-d4 and the metabolite ratio will be used to study the association of the rate of metabolism and development of addiction in adolescent light smokers (Mark Rubinstein, MD, CA140216). We have used stable isotope methodology to address questions unique to the drug abuse area. One such question was to determine whether intravenous nicotine replacement would suppress nicotine intake from smoking (Benowitz and Jacob 1990). This led to the conclusion that nicotine replacement medications such as transdermal patches (at that time undergoing premarketing clinical trials) would suppress smoking even if subjects were unable to quit entirely. We have used deuterium-labeled cocaine administration to study the time course of distribution of cocaine and its metabolite benzoylecgonine into human hair. For ethical reasons, these studies had to be carried out in cocaine abusers, and the use of labeled drug guaranteed that subsequent street cocaine use would not invalidate the results (Henderson et al. 1996). We are also using labeled nicotine to study the time course of accumulation of nicotine into hair and nails, which appear to be good long term biomarkers of nicotine exposure. Such studies require laboratories with synthetic and analytical chemists, and modern analytical instruments. Extensive use of mass spectrometry is necessary when using stable isotopes. Suitably labeled drugs or metabolites may not be commercially available, and our capability in synthetic organic chemistry has been needed to prepare stable-isotope labeled drugs, metabolites, and internal standards for clinical studies and assays. In this application, we are requesting support for laboratory, and administrative staff, and for instrumentation to maintain and enhance our analytical chemistry capabilities.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Center Core Grants (P30)
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Special Emphasis Panel (ZDA1-EXL-T)
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University of California San Francisco
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Benowitz, Neal L; Nardone, Natalie; Hatsukami, Dorothy K et al. (2015) Biochemical estimation of noncompliance with smoking of very low nicotine content cigarettes. Cancer Epidemiol Biomarkers Prev 24:331-5
Benowitz, Neal L; Gan, Quan; Goniewicz, Maciej L et al. (2015) Different profiles of carcinogen exposure in Chinese compared with US cigarette smokers. Tob Control 24:e258-63
St Helen, Gideon; Benowitz, Neal L; Dains, Katherine M et al. (2014) Nicotine and carcinogen exposure after water pipe smoking in hookah bars. Cancer Epidemiol Biomarkers Prev 23:1055-66
Martins-Green, Manuela; Adhami, Neema; Frankos, Michael et al. (2014) Cigarette smoke toxins deposited on surfaces: implications for human health. PLoS One 9:e86391
Jones, Ian A; St Helen, Gideon; Meyers, Matthew J et al. (2014) Biomarkers of secondhand smoke exposure in automobiles. Tob Control 23:51-7
Goniewicz, Maciej Lukasz; Knysak, Jakub; Gawron, Michal et al. (2014) Levels of selected carcinogens and toxicants in vapour from electronic cigarettes. Tob Control 23:133-9
Zhu, Andy Z X; Zhou, Qian; Cox, Lisa Sanderson et al. (2014) Gene variants in CYP2C19 are associated with altered in vivo bupropion pharmacokinetics but not bupropion-assisted smoking cessation outcomes. Drug Metab Dispos 42:1971-7
Bahl, Vasundhra; Jacob 3rd, Peyton; Havel, Christopher et al. (2014) Thirdhand cigarette smoke: factors affecting exposure and remediation. PLoS One 9:e108258
St Helen, Gideon; Jacob 3rd, Peyton; Peng, Margaret et al. (2014) Intake of toxic and carcinogenic volatile organic compounds from secondhand smoke in motor vehicles. Cancer Epidemiol Biomarkers Prev 23:2774-82
Hsieh, S Jean; Zhuo, Hanjing; Benowitz, Neal L et al. (2014) Prevalence and impact of active and passive cigarette smoking in acute respiratory distress syndrome. Crit Care Med 42:2058-68

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