['292', 'design', 'where', 'the', 'low', 'dose', 'of', 'nicotine', 'limited', 'the', 'number', 'of', 'urine', 'samples', 'that', 'had', 'measurable', 'quantities', 'of', 'nicotine.', '10.3.2.5.4.', 'Nicotine', 'Metabolism', 'The', 'metabolic', 'clearance', 'of', 'nicotine', 'is', 'obtained', 'by', 'subtracting', 'renal', 'clearance', 'from', 'total', 'clearance', '(See', 'Table', '10.3.5.3.4-1).', 'There', 'were', 'again', 'no', 'differences', 'between', 'the', 'metabolic', 'clearance', 'of', 'nicotine', 'absorbed', 'from', 'smoking', 'the', 'NEW', 'cigarette', 'compared', 'to', 'that', 'absorbed', 'from', 'smoking', 'the', 'reference', 'cigarette.', 'The', 'apparent', 'volume', 'of', 'distribution', 'of', 'nicotine', 'for', 'the', 'subjects', 'is', 'shown', 'in', 'Table', '10.3.5.3.4-2.', 'There', 'were', 'no', 'differences', 'in', 'the', 'apparent', 'volumes', 'of', 'distribution', 'for', 'nicotine', 'obtained', 'from', 'smoking.', 'However,', 'the', 'volume', 'of', 'distribution', 'of', 'nicotine', 'obtained', 'from', 'smoking', 'is', 'significantly', 'larger', 'than', 'that', 'obtained', 'from', 'intravenous', 'infusion', '(Table', '10.3.5.3.4-2).', 'One', 'of', 'the', 'major', 'metabolites', 'of', 'nicotine', 'in', 'man', 'is', 'cotinine.', 'Plasma', 'cotinine', 'concentrations', 'were', 'determined', 'in', 'all', 'samples', 'from', 'the', 'smoking', 'tests', 'and', 'are', 'shown', 'in', 'Figure', '10.3.5.3-4-1.', 'The', 'most', 'obvious', 'finding', 'was', 'that', 'the', 'amount', 'of', 'cotinine', 'present', 'in', 'plasma', 'was', 'proportional', 'to', 'the', 'amount', 'of', 'nicotine', 'absorbed', 'from', 'the', 'cigarettes.', 'The', 'amount', 'of', 'nicotine', 'absorbed', 'followed', 'the', 'order;', 'reference', '>', 'NEW', '(post-39-day-exposure)', '>', 'NEW', '(pre-39-day-exposure).', 'To', 'quantify', 'this', 'finding,', 'the', 'total', 'plasma', 'cotinine', 'AUC', 'was', 'divided', 'by', 'the', 'total', 'amount', 'of', 'nicotine', 'absorbed', 'from', 'smoking', '7', 'cigarettes', '(Table', '10.3.5.3.2-3)', 'and', 'the', 'result', 'is', 'shown', 'in', 'Table', '10.3.5.3.4-3.', 'There', 'was', 'no', 'difference', 'in', 'the', 'relative', 'amounts', 'of', 'cotinine', 'formed', 'from', 'nicotine', 'from', 'smoking', 'either', 'cigarette.', 'In', 'addition,', 'there', 'was', 'no', 'change', 'in', 'the', 'proportion', 'of', 'nicotine', 'metabolized', 'to', 'cotinine', 'following', 'smoking', 'the', 'NEW', 'product', 'exclusively', 'for', '39', 'days.', 'Although', 'the', 'number', 'of', 'data', 'points', 'available', 'for', 'calculating', 'cotinine', 'elimination', 'was', 'limited', '(Figure', '10.3.5.3.4-1),', 'the', 'elimination', 'rates', 'were', 'calculated', 'and', 'are', 'reported', 'in', 'Table', '10.3.5.3.4-4.', 'There', 'was', 'no', 'difference', 'in', 'the', 'rate', 'at', 'which', 'cotinine', 'was', 'eliminated', 'following', 'smoking', 'of', 'the', 'reference', 'or', 'NEW', 'cigarettes.', 'However,', 'there', 'was', 'a', 'decrease', 'in', 'the', 'rate', 'at', 'which', 'cotinine', 'was', 'eliminated', 'following', 'smoking', 'of', 'the', 'NEW', 'cigarette', 'exclusively', 'for', '39', 'days.', 'This', 'decrease', 'in', 'the', 'rate', 'of', 'elimination', 'resulted', 'in', 'an', 'increase', 'in', 'the', 'half-life', 'for', 'cotinine', 'from', '22', 'hr', '(pre-39-days’', 'exposure)', 'to', '26', 'hr', '(post-39-days’', 'exposure).', '(See', 'Table', '10.3.5.3.4-4).', '10.3.2.5.2.', 'Conclusions', 'These', 'data', 'indicate', 'that', 'the', 'absorption', 'of', 'nicotine', 'from', 'the', 'two', 'cigarettes', 'is', 'similar.', 'Although', 'the', 'average', 'maximum', 'plasma', 'nicotine', 'concentration', 'was', 'lower', 'for', 'the', 'NEW', 'Z6ET', 'BZSTS']