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

The environment in which the fetus develops is critical for its survival and long-term health. The regulation of normal human fetal growth involves many multidirectional interactions between the mother, placenta, and fetus. The mother supplies nutrients and oxygen to the fetus via the placenta. The fetus influences the provision of maternal nutrients via the placental production of hormones that regulate maternal metabolism. The placenta is the site of exchange between mother and fetus and regulates fetal growth via the production and metabolism of growth-regulating hormones such as IGFs and glucocorticoids. Adequate trophoblast invasion in early pregnancy and increased uteroplacental blood flow ensure sufficient growth of the uterus, placenta, and fetus. The placenta may respond to fetal endocrine signals to increase transport of maternal nutrients by growth of the placenta, by activation of transport systems, and by production of placental hormones to influence maternal physiology and even behavior. There are consequences of poor fetal growth both in the short term and long term, in the form of increased mortality and morbidity. Endocrine regulation of fetal growth involves interactions between the mother, placenta, and fetus, and these effects may program long-term physiology.

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Endocrine regulation of human fetal growth: the role of the mother, placenta, and fetus.

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

The major function of the placenta is to transfer nutrients and oxygen from the mother to the foetus and to assist in the removal of waste products from the foetus to the mother. In addition, it plays an important role in the synthesis of hormones, peptides and steroids that are vital for a successful pregnancy. The placenta provides a link between the circulations of two distinct individuals but also acts as a barrier to protect the foetus from xenobiotics in the maternal blood. However, the impression that the placenta forms an impenetrable obstacle against most drugs is now widely regarded as false. It has been shown that that nearly all drugs that are administered during pregnancy will enter, to some degree, the circulation of the foetus via passive diffusion. In addition, some drugs are pumped across the placenta by various active transporters located on both the fetal and maternal side of the trophoblast layer. It is only in recent years that the impact of active transporters such as P-glycoprotein on the disposition of drugs has been demonstrated. Facilitated diffusion appears to be a minor transfer mechanism for some drugs, and pinocytosis and phagocytosis are considered too slow to have any significant effect on fetal drug concentrations. The extent to which drugs cross the placenta is also modulated by the actions of placental phase I and II drug-metabolising enzymes, which are present at levels that fluctuate throughout gestation. Cytochrome P450 (CYP) enzymes in particular have been well characterised in the placenta at the level of mRNA, protein, and enzyme activity. CYP1A1, 2E1, 3A4, 3A5, 3A7 and 4B1 have been detected in the term placenta. While much less is known about phase II enzymes in the placenta, some enzymes, in particular uridine diphosphate glucuronosyltransferases, have been detected and shown to have specific activity towards marker substrates, suggesting a significant role of this enzyme in placental drug detoxification. The increasing experimental data on placental drug transfer has enabled clinicians to make better informed decisions about which drugs significantly cross the placenta and develop dosage regimens that minimise fetal exposure to potentially toxic concentrations. Indeed, the foetus has now become the object of intended drug treatment. Extensive research on the placental transfer of drugs such as digoxin and zidovudine has assisted with the safe treatment of the foetus with these drugs in utero. Improved knowledge regarding transplacental drug transfer and metabolism will result in further expansion of pharmacological treatment of fetal conditions.

Drug transfer and metabolism by the human placenta

New discoveries reveal how crucial interactions which determine our destiny occur before birth, when our genes interact with their environment as the embryo and fetus develop. These processes - in the matrix of the womb - are evolutionary echoes of mechanisms which allowed our hunter-gatherer ancestors to survive. These exciting insights into predictive adaptive responses suggest new ways of protecting the health of the fetus, infant and adult. If inappropriate they can trigger obesity, diabetes and heart disease, formerly thought to result solely from adult lifestyle. The new concepts in this book are crucial to understanding the daunting public health burden in societies undergoing rapid transition from poverty to affluence. They add an important new dimension to evolutionary theory. Synthesising developmental biology, evolutionary history, medical science, public health and social policy, this is a ground-breaking and fascinating account by two of the world's leading pioneers in this important emerging field.

https://bilder.buecher.de/zusatz/21/21302/21302478_vorw_1.pdf

The Fetal Matrix: Evolution, Development and Disease

Maternal cocaine use and cigarette smoking in pregnancy in relation to amino acid transport and fetal growth.

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.

Transfer of cocaine and benzoylecgonine across the perfused human placental cotyledon

The cardiac glycoside, digoxin, is clinically used to treat fetal tachyarrhythmias and congestive heart failure. The time course of digoxin transfer across the human placenta was studied by dually perfusing an isolated lobule of the human placenta in vitro. Viability of the placental preparation was validated by measuring the rates of glucose and oxygen consumption, lactate production and synthesis of the protein hormone, chorionic gonadotropin. Following administration of 5 ng/ml digoxin to the maternal circulation, digoxin appeared in the fetal circulation within 5 min. The disappearance of digoxin from the maternal circulation was biexponential and best fit a two-compartment pharmacokinetic model. Mean calculated volume of the central compartment (257 +/- 6.3 ml) was consistent with the actual volume of the in vitro maternal circulation (246 +/- 7.4 ml). The half-life of the distribution phase was 9.7 +/- 3.3 min, and half-life of the terminal elimination phase was 362 +/- 83 min. After 30 min of perfusion, the amount of digoxin leaving the maternal circulation and appearing in the fetal circulation was constant at a fetomaternal mass ratio of 0.36 +/- 0.04. This ratio was maintained through to the end of the 3-hr experiment. All of the digoxin leaving the maternal circulation could be accounted for either in the fetal circulation or bound to placental tissue. The time to achieve equal concentrations on both sides of the placenta was estimated to be 268 +/- 34 min. These data are consistent with in vivo data obtained in humans, and support the relevance of using the in vitro placental perfusion model to obtain information regarding placental drug transfer in humans.

L.O. Derewlany

Papers

Maternal cocaine use and cigarette smoking in pregnancy in relation to amino acid transport and fetal growth.

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.

Transfer of cocaine and benzoylecgonine across the perfused human placental cotyledon

The transport of digoxin across the perfused human placental lobule.