Nicotine is of importance as the addictive chemical in tobacco, pharmacotherapy for smoking cessation, a potential medication for several diseases, and a useful probe drug for phenotyping cytochrome P450 2A6 (CYP2A6). We review current knowledge about the metabolism and disposition kinetics of nicotine, some other naturally occurring tobacco alkaloids, and nicotine analogs that are under development as potential therapeutic agents. The focus is on studies in humans, but animal data are mentioned when relevant to the interpretation of human data. The pathways of nicotine metabolism are described in detail. Absorption, distribution, metabolism, and excretion of nicotine and related compounds are reviewed. Enzymes involved in nicotine metabolism including cytochrome P450 enzymes, aldehyde oxidase, flavin-containing monooxygenase 3, amine N-methyltransferase, and UDP-glucuronosyltransferases are represented, as well as factors affecting metabolism, such as genetic variations in metabolic enzymes, effects of diet, age, gender, pregnancy, liver and kidney diseases, and racial and ethnic differences. Also effects of smoking and various inhibitors and inducers, including oral contraceptives, on nicotine metabolism are discussed. Due to the significance of the CYP2A6 enzyme in nicotine clearance, special emphasis is given to the effects and population distributions of CYP2A6 alleles and the regulation of CYP2A6 enzyme.

Metabolism and Disposition Kinetics of Nicotine

A biomarker is desirable in quantitating systemic exposure both in smokers and nonsmokers to constituents of tobacco smoke. Self-report measures in smokers, such as cigarettes smoked per day, are highly imprecise owing to individual differences in how cigarettes are smoked, with ranges of nicotine intake per cigarette from 0.3 to 3.0 mg (1, 2). Self-report measures, such as hours per day exposed to environmental tobacco smoke (ETS) by nonsmokers, are also likely to be imprecise indicators of intake of tobacco smoke owing to variations in the number of cigarettes smoked, proximity of nonsmokers to smokers, room ventilation and other environmental characteristics, as well as individual differences in sensitivity to and/or concern about adverse effects of ETS. The optimal assessment of exposure to tobacco smoke would be by analysis of the concentrations of a component of smoke in the body fluids of an exposed individual— i.e., a biologic marker or biomarker. There are two broad questions that need to be considered in assessing the validity of a biomarker of tobacco smoke exposure. The first is how well does the concentration of a marker chemical in the air reflect exposure to toxic constituents of smoke that are of concern? The second is how well does a concentration of a particular chemical in a biologic fluid reflect an individual's intake of that chemical (or a related chemical) from tobacco smoke? The National Research Council (3) has proposed criteria for a valid marker of ETS in the air as follows: The marker 1) should be unique or nearly unique for ETS so that other sources are minor in comparison; 2) should be easily detectable; 3) should be emitted at similar rates for a variety of tobacco products; and 4)

Cotinine as a Biomarker of Environmental Tobacco Smoke Exposure

State of the art in hair analysis for detection of drug and alcohol abuse.

The International Federation of Gynecology and Obstetrics (FIGO) Initiative on gestational diabetes mellitus: A pragmatic guide for diagnosis, management, and care#

The maternal and fetal physiologic effects of nicotine

Background. —To date, no biological markers have been identified that can predict the extent of fetal exposure to the toxic constituents of cigarette smoke. A variety of xenobiotic agents have been shown to accumulate in growing hair. Patients and Methods. —We measured maternal and neonatal hair concentrations of nicotine and cotinine in 94 mother-infant pairs. Mothers who were active smokers, nonsmokers, and passive smokers and their infants were included. Results. —Mothers who were active smokers (n=36) had mean (SEM) hair concentrations of 19.2 (4.9) ng/mg for nicotine and 6.3 (4.0) ng/mg for cotinine, significantly higher than concentrations in nonsmokers (n=35) (1.2 [0.4] ng/mg for nicotine and 0.3 [0.06] ng/mg for cotinine, P P P P P =.0001). Conclusions. —This is the first biochemical evidence that infants of passive smokers are at risk of measurable exposure to cigarette smoke. Hair accumulation of cigarette smoke constituents reflects long-term systemic exposure to these toxins and therefore may be well correlated with perinatal risks. ( JAMA . 1994;271:621-623)

Hair Concentrations of Nicotine and Cotinine in Women and Their Newborn Infants

OBJECTIVE —Insulin lispro (Humalog), a human insulin analog, has a more rapid onset, earlier peak, and shorter duration of glucose lowering activity than regular human insulin. However, it is not known whether insulin lispro crosses the human placenta and reaches the fetus. Therefore, the objective of the present study was to examine whether insulin lispro crosses the placenta using the technique of perfusing a human placental lobule in vitro. RESEARCH DESIGN AND METHODS —Term human placentae from uncomplicated pregnancies were obtained immediately after delivery. Insulin lispro, at concentrations ranging from 100 to 1000 μU/ml, was introduced into the maternal reservoir. The maternal side of the placenta was perfused with constant concentration of lispro insulin; the fetal circulation was closed. Samples were drawn from both the maternal and fetal circulations at regular intervals. The appearance of insulin lispro in the fetal circulation was analyzed by a specific radioimmunoassay. RESULTS —No placental transfer of lispro could be detected during perfusion with 100 and 200 μU/ml. In contrast, there was a small concentration-dependent transfer to the fetus at concentrations of 580 μU/ml and higher, detectable after at least an hour of constant concentration of insulin lispro during perfusion. The rate of placental transfer was 0.019 μU · min −1 · g tissue −1 at maternal levels of 580 μU/ml and 0.045 μU · min −1 · g −1 tissue at maternal levels of 1000 μU/ml. Measuring lispro levels in 11 pregnant women revealed that a dose of 50 units may achieve serum concentrations >200 μU/ml with apparent linear correlation between dose and levels. CONCLUSIONS —Insulin lispro is not likely to cross the placenta at a single standard dose. This study suggests that insulin lispro is unlikely to reach or harm the unborn baby.

https://care.diabetesjournals.org/content/diacare/26/5/1390.full.pdf

Transfer of insulin lispro across the human placenta: in vitro perfusion studies.

Transplacental transfer and biotransformation studies of nicotine in the human placental cotyledon perfused in vitro.

The measurement of fatty acid ethyl esters (FAEE) in neonatal meconium is a novel test to confirm prenatal ethanol exposure. The origin of FAEE in the maternal-placental-fetal unit is not known. The objectives of this study were to investigate whether FAEE are transferred and metabolized by the human placenta. Isolated placental cotyledons were perfused with a mixture of four FAEE (palmitic, stearic, oleic, and linoleic acid ethyl esters) commonly detected in the meconium of neonates exposed to ethanol in utero, and the transfer of FAEE to the fetal unit was investigated in the absence and presence of albumin. The metabolic degradation of FAEE by human placental microsomes was subsequently determined. FAEE disappeared from the maternal circulation but remained undetectable in the fetal unit following perfusions. The addition of albumin had no effect on FAEE transfer. The unrecoverable fraction of individual FAEE in the perfusion system accounted for >50% of the initial amount used, suggesting significant metabolic degradation. Subcellular studies documented the enzymatic degradation of FAEE by placental microsomes (mean K m, 35–95 μM; V , max 0.6–1.8 nmol/min/mg for individual FAEE). FAEE at levels found in alcoholics that are originated from the mother are not transferred to the fetus because they are taken up and degraded extensively by the human placenta. Hence, FAEE detected in neonatal matrices are likely produced by the fetus from ethanol that has been transferred to and metabolized by the fetus, rendering FAEE a powerful direct biomarker reflective of true fetal exposure to ethanol in utero.

https://jpet.aspetjournals.org/content/jpet/early/2004/03/05/jpet.104.066597.full.pdf

Brenda Knie

Papers

Hair Concentrations of Nicotine and Cotinine in Women and Their Newborn Infants

Transfer of insulin lispro across the human placenta: in vitro perfusion studies.

Transplacental transfer and biotransformation studies of nicotine in the human placental cotyledon perfused in vitro.

Placental Handling of Fatty Acid Ethyl Esters: Perfusion and Subcellular Studies

Transfer of cocaine and benzoylecgonine across the perfused human placental cotyledon