Accelerated Metabolism of Nicotine and Cotinine in Pregnant Smokers

Abstract

Cigarette smoking is the foremost modifiable risk factor for adverse pregnancy outcomes. Nicotine is a suspected fetal neuroteratogen. There is concern that nicotine may achieve toxic levels during pregnancy if nicotine replacement therapies are prescribed at doses used in the nonpregnant state. Ten healthy, volunteer, pregnant smokers received infusions of deuterium-labeled nicotine and cotinine during pregnancy and again postpartum. From blood and urine measurements, the following were determined: clearance (renal and nonrenal) of nicotine and cotinine, clearance of nicotine via the cotinine pathway (an indicator of CYP2A6 activity), and daily intake of nicotine from smoking. The clearance of nicotine and cotinine was significantly higher (60 and 140%, respectively), and the half-life of cotinine was much shorter (8.8 versus 16.6 h, P Ͻ 0.01) during pregnancy. Although plasma levels of cotinine were lower during pregnancy (119 versus 202 ng/ml, P Ͻ 0.05), daily intake of nicotine from smoking was similar during pregnancy and postpartum. For a given level of intake, the pharmacologic and toxicologic effects of nicotine during pregnancy are anticipated to be less than expected from nicotine metabolism data in nonpregnant women. Our data indicate that no downward dose adjustment needs to be made for nicotine replacement therapy during pregnancy. Conversely, higher than usual doses of nicotine may be necessary to optimize efficacy. Lower cotinine levels observed during pregnancy do not necessarily reflect less smoke exposure, and cut-off levels used to classify nonsmokers, passive smokers, and active smokers need to be established for pregnancy.

Alternative Sampling Strategies for Cytochrome P450 Phenotyping

“…Nicotine/cotinine ratios in the third trimester were significantly decreased compared to those in the first trimester. According to the authors, these findings illustrated that nicotine metabolism to cotinine, mainly catalyzed by CYP2A6, increases as pregnancy advances [56], which was in agreement with previous findings [57]. In a more recent study by the same group, similar results for nicotine/cotinine ratios in hair of 74 smoking women were obtained [58].…”

Rapid Nicotine Clearance is Associated with Greater Reward and Heart Rate Increases from Intravenous Nicotine

“…The oxidation kinetics for nicotine and cotinine are considered to be different (Hukkanen et al, 2005;Benowitz et al, 2009), and conversion of cotinine to 3HC is likely more sensitive than altered clearance of nicotine to changes in CYP 2A6 activity. Dempsey et al, 2002 found that cotinine levels were lower in pregnancy despite similar nicotine (smoking) exposure, and that although nicotine clearance increased by 60% (54% via the cotinine pathway), cotinine clearance increased by 140%. This change was attributed to increased activity of CYP 2A6, which had greater effects on the clearance of cotinine than of nicotine.…”

Getting over the shock: taking action on Indigenous maternal smoking

“…In a large nonrandomised clinical sample (3500 participants), transdermal NRT combined with an oral form doubled the quit rate compared with no medication or monotherapy (OR = 1.93) (Brose et al 2013). The accelerated nicotine metabolism in pregnancy gives a physiological basis for higher doses being required (Dempsey et al 2002). Even short periods of abstinence are beneficial for foetal growth.…”