How is nicotine gum metabolized?

Nicotine Gum Metabolism

Nicotine from gum is absorbed through the oral mucosa and metabolized primarily in the liver by the cytochrome P450 enzyme CYP2A6, which converts approximately 70-80% of nicotine to cotinine, the major metabolite that is then further metabolized and excreted in urine. 1, 2

Primary Metabolic Pathway

• Nicotine undergoes first-pass hepatic metabolism, with almost 90% of absorbed nicotine metabolized in the liver 1
• CYP2A6 is the dominant enzyme responsible for nicotine C-oxidation to cotinine, accounting for the majority of nicotine metabolism 2, 3
• Cotinine formation shows a 30-fold variation among individuals due to variable CYP2A6 expression 2

Absorption Characteristics Specific to Gum

• Absorption from nicotine gum occurs through the oral mucosa rather than the gastrointestinal tract, which is critical because oral bioavailability would be less than 20% due to extensive first-pass metabolism 4
• Absorption through the oral mucosa is highly pH-dependent, with alkaline environments increasing the rate of nicotine permeation through biological membranes 1, 4
• This pH-dependency explains why acidic beverages should be avoided 15 minutes before and during gum use, as they reduce nicotine absorption 4

Additional Metabolic Enzymes

Beyond CYP2A6, several other enzymes contribute to nicotine metabolism 1, 5:

• UDP-glucuronosyltransferases (UGT) participate in conjugation reactions
• Flavin-containing monooxygenase 3 (FMO3) provides an alternative oxidative pathway
• Cytosolic aldehyde oxidase converts nicotine iminium ion to cotinine
• Amine N-methyltransferase catalyzes minor metabolic pathways

Major Metabolites

• Cotinine is the primary metabolite, serving as the most widely used biomarker of nicotine intake 6, 5
• Trans-3'-hydroxycotinine is formed from cotinine and represents the compound excreted in the largest amount in urine 1
• Six major metabolites of nicotine have been identified in total 1

Sites of Metabolism

While the liver is the primary site 1:

• Nicotine may also be metabolized in the kidneys, lungs, brain, and respiratory epithelium membranes 1
• Non-renal blood clearance averages 1.2 L/min, indicating nicotine elimination is dependent on hepatic blood flow 4

Factors Affecting Metabolism Rate

Nicotine metabolism varies substantially based on 5:

• Genetic polymorphisms in CYP2A6 (explaining the 30-fold variation in metabolism rates) 2
• Sex differences (women metabolize nicotine faster, especially when using estrogen-containing preparations)
• Diet and meals
• Age
• Pregnancy
• Kidney disease
• Concomitant medications that affect hepatic blood flow
• Racial/ethnic differences (likely influenced by both genetic and environmental factors)

Excretion

• Nicotine is excreted unchanged in urine in a pH-dependent fashion: with urinary pH less than 5, an average 23% is excreted unchanged; when pH is maintained above 7.0, unchanged nicotine excretion drops to 2% 4
• The majority of nicotine is excreted as metabolites, primarily trans-3'-hydroxycotinine 1

Clinical Relevance

• Total plasma clearance ranges from 0.92 to 2.43 L/min 4
• Plasma protein binding is negligible (4.9-20%), allowing extensive tissue distribution with a volume of distribution of 1.0-3.0 L/kg 4
• CYP2D6 plays no significant role in nicotine metabolism, as demonstrated by lack of inhibition with quinidine and failure of CYP2D6 expression systems to metabolize nicotine 2