Quantitation of urinary metabolites of a tobacco-specific lung carcinogen after smoking cessation

We quantified urinary levels of two metabolites of the tobacco-specific lun g carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in people who had stopped smoking: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NN AL) and its O-glucuronide, 4-[(methylnitrosamino)-1-(3-pyridyl)but-1-yl]-be ta-O-D-glucosiduronic acid (NNAL-Gluc). Twenty-seven people completed the s tudy. Thirteen used the nicotine patch starting at the quit date, whereas t he others used no patch. Two 24-h urine samples were collected on 2 consecu tive days before smoking cessation; blood was also obtained, Beginning at t heir quit date, subjects provided 24-h urine samples on days 7, 21, 42, 70, 98, and 126, and some subjects also provided samples at later times. The u rine was analyzed for NNAL, NNAL-Gluc, nicotine plus nicotine-N-glucuronide , and cotinine plus cotinine-N-gglucuronide, Some blood samples were also a nalyzed for NNAL. The decline of urinary NNAL and NNAL-Gluc after smoking c essation was much slower than expected. This was clearly demonstrated by co mparison with cotinine and nicotine levels in urine. One week after smoking cessation, 34.5% of baseline NNAL plus NNAL-Gluc was detected in urine, wh ereas the corresponding values for cotinine and nicotine were 1.1 and 0.5%, respectively. Even 6 weeks after cessation, 7.6% of the original levels of NNAL plus NNAL-Gluc remained. In some subjects, NNAL plus NNAL-Gluc were d etected 281 days after cessation. The distribution half-life for NNAL and N NAL-Gluc was 3-4 days, whereas the elimination half-life was 40-45 days. To tal body clearance of NNAL was estimated to be 61.4 +/- 35.4 ml/min, and vo lume of distribution in the beta-phase was estimated to be 3800 +/- 2100 li ters, indicating substantial distribution into the tissues. Parallel studie s in rats treated chronically or acutely with NNK in the drinking water sup port the conclusion that NNAL, has a large volume of distribution. There wa s no effect of the nicotine patch on levels of NNAL plus NNAL-Gluc, indicat ing that NNK is not formed endogenously from nicotine. The results of this study demonstrate that NNAL and NNAL-Gluc are slowly cleared from the body after smoking cessation, indicating the presence of a high-affinity compart ment where NNK, NNAL, and/or NNAL-Gluc are retained or sequestered and slow ly released.