Pharmacokinetic parameters of nicotine and its metabolites in Thai smokers with different CYP2A6 enzyme activity

抄録

Background

Cytochrome P450 2A6 (CYP2A6) enzyme is the major metabolizing enzyme of nicotine. Genetic variations of CYP2A6 causes changes in enzyme activity altering nicotine pharmacokinetics (PK) and may affect nicotine dependence in smokers. We assessed the differences in PK parameters of nicotine and its metabolites (cotinine (COT) and trans-3´-hydroxycotinine (3HC)) in CYP2A6 extensive metabolizers (EMs) and poor metabolizers (PMs) in Thai moderate smokers.

Methods

EMs (n=9¸ CYP2A6*1A/*1A¸ *1A/*1B and *1B/*1B) and PMs (n=9¸ CYP2A6*1A/*4¸ *1A/*9¸ *1B/*4¸ *1B/*9¸ *4/*4¸ *4/*9 and *9/*9) were enrolled. Nicotine gum (2 mg¸ 30 mins of chewing) were administered after 12 hrs of nicotine free period. Blood samples were collected at pre-dose and 0.25¸ 0.5¸ 1¸ 1.5¸ 2¸ 2.5¸ 3¸ 4.5 and 6 hrs post-dose. Nicotine¸ COT and 3HC levels in plasma were quantified using validated LC/MS/MS techniques. PK parameters including maximum concentration (Cmax)¸ time to Cmax (Tmax)¸ area under the plasma concentration-time curve from 0-6hrs and 0-infinity (AUC_0-6hrand AUC_0-inf)¸ half-life (T1/2) and elimination rate constant (Kel) and CYP2A6 activity (ratios of 3HC/COT) were compared between groups. PK parameters were calculated as non-compartmental analysis and AUC were calculated by the trapezoidal rule.

Results

Both groups showed similar demographic data¸ except EMs had higher body mass index compared with PMs (mean±SEM¸ 28.23±1.82 vs 23.38±0.82 kg/m²¸ p=0.05). EMs had lower plasma nicotine levels¸ corresponding with higher plasma COT and 3HC levels compared with PMs. Tmax¸ T1/2 and Kel of nicotine were significantly different between groups (Tmax 0.78±0.14 vs 1.33±0.12 hr¸ p=0.019¸ T1/2 2.50±0.32 vs 4.12±0.56 hr¸ p=0.024¸ and Kel 0.32±0.04 vs 0.19±0.07 hr^-1¸ p=0.024¸ EMs vs PMs¸ respectively). Cmax¸ AUC_0-6hr and AUC_0-inf of nicotine are similar. EMs had higher 3HC/COT ratios compared with PMs.

Conclusions

Thai moderate smokers who were CYP2A6 EMs had significant decreased Tmax¸ T1/2 and increased Kel of nicotine and had higher CYP2A6 activity measured by nicotine metabolites ratios. Genotyping of CYP2A6 and measuring of CYP2A6 activity using 3HC/COT ratios may help selecting the ultimate modalities for individualized smoking cessation program.