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II.6.5 Nicotine and Cotinine by Mariko Fukumoto

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II.6.5 Nicotine and Cotinine by Mariko Fukumoto 6.5 II.6.5 Nicotine and cotinine by Mariko Fukumoto Introduction Nicotine is a main water-soluble alkaloid being contained in the tobacco plant (Nicotiana taba- cum), which acts as an inducing compound for smoking-dependence. Twelve kinds of nicotine metabolites are known in rats [1]. Among them, cotinine is the major metabolite of nicotine; the half-life (T1/2) of cotinine is much longer (10–20 h) than that of nicotine (24–84 min). Th e qualitative analysis of cotinine in urine and saliva is being thus carried out as indicators for smoking during its abstinence therapy and for confi rming passive smoking. Th e cases of ingestion of cigarettes or their butts are household accidents taking place very frequently in Japan. Th e nicotine contents being contained in a single cigarette are 7–24 mg [2], which is suffi cient to kill an infant; but thanks to its vomiting-stimulating action or delayed absorption, the fatalities due to such accidental ingestion are rare. However, aft er suicidal in- gestion of nicotine sulfate solution (an insecticide) and of cigarette extract solution obtained by boiling, many people are being brought to critical care medical centers; in such cases, they may be fatal without appropriate and early treatments. For analysis of nicotine and cotinine in human blood and/or urine, methods by GC [3–5], GC/MS [6–8] and HPLC [9–13] were reported. In this chapter, the methods for GC/MS analy- sis of nicotine and cotinine in blood and for HPLC (UV detection) analysis of nicotine in to- bacco extract solutions are presented. GC/MS analysis of nicotine and cotinine in blood and urine Reagents and their preparation • Nicotine and cotinine (Sigma, St. Louis, MO, USA and other manufacturers) are dissolved in the Milli Q water (Millipore, Bedford, MA, USA) to prepare fi xed concentrations of their aqueous solutions. Th e calibration curves are constructed using human blank sera obtained from healthy nonsmokers; various concentrations of nicotine or cotinine are spiked into the blank sera • 5-Aminoquinoline (internal standard, IS, Aldrich, Milwaukee, WI, USA) is dissolved in the Milli Q water to prepare its 100 ng/mL solution • Th e solvent mixture of dichloromethane/isopropyl ether (85:15) is prepared just before use. © Springer-Verlag Berlin Heidelberg 2005 500 Nicotine and cotinine ⊡ Table 5.1 Molecular weights, fragment ions and retention times for nicotine, cotinine and 5-amino- quinoline Molecular weight Fragment ion (m/z) Retention time (min) nicotine 162.23 84, 133, 161 8.0 cotinine 176.22 98, 176 10.4 5-aminoquinoline 144.18 144 10.0 GC/MS conditions GC column: a DB-5MS capillary column (30 m × 0.25 mm i. d., fi lm thickness 0.25 µm, J & W Scientifi c, Folsom, CA, USA). Instrument: a FinniganMAT GCQ GC/MS system (Th ermoFinnigan, San Jose, CA, USA). Column temperature: 40 °C (2.5 min, split mode) → 30 °C/min → 145 °C → 15 °C/min → 220 °C; injection temperature: 250 °C; carrier gas: He; linear velocity: 40 cm/s; ionization: EI; electron energy: 70 eV; detection mode: selected ion monitoring (SIM); fragment ions to be used for SIM and each retention time are shown in > Table 5.1 (total time for the measure- ments, 11 min). Procedure i. A 300-µL aliquot of serum (or urine) is mixed with 20 µL of IS solution and 2 µL of 1 M NaOH solution. ii. Th e above mixture is poured into a ChemElut columna (Varian, Harbor City, CA, USA) and left at room temperature for 5 min; the target compounds are eluted with 3.0 mL of dichloromethane/isopropyl ether (85:15). iii. Th e eluate is evaporated to dryness under a stream of nitrogen; the residue is dissolved in 30 µL ethyl acetate and 1 µL of it is injected into GC/MS. Assessment and some comments on the method For pretreatments of clinical specimens for analysis of nicotine and cotinine, methods by liquid-liquid extraction [3–5], solid-phase extraction [9], headspace/solid-phase microextrac- tion (SPME) [6] and Extrelut (diatomite) extraction [7, 8, 10–13] were reported. For the liquid-liquid extraction, repeated extraction procedures (3 times on average) are required; recovery rates vary due to emulsion formation, thus resulting in poor reproduc- ibility. Th e solid-phase extraction is easier in operationality than liquid-liquid extraction. However, nicotine exists in a liquid form at room temperature; in view of the volatility of nicotine, the solid-phase extraction may not be suitable for nicotine analysis. For every extraction method, as much as 1–5 mL of a specimen is required. For clinical analysis of nicotine and cotinine dealing with many specimens, various technical problems should be overcome. GC/MS analysis of nicotine and cotinine in blood and urine 501 In the extraction using a diatomite column, the water (containing target compound(s)) of a specimen adsorbs to the diatomite surface to act as a stationary phase; during the passage of an organic solvent through the diatomite column, the contact between the organic and aqueous phases makes the target compounds liquid-liquid extracted into the organic phase. Th ere is no emulsion formation, and excellent cleanup can be realized with high recovery rates. As mentioned above, Extrelut columns were used in many reports; however the author used ChemElut columns made of similar diatomite, which are relatively cheap and easy in handling. In every extraction method, the fi nal extracts are diluted more than 10 times; therefore, the fi nal solution should be evaporated to dryness, followed by the dissolution of the residue in a small amount of an organic solvent to be injected into GC/MS. Th e author tried various or- ganic solvents to test recovery rates of nicotine; it was found that an appreciable amount of nicotine is lost during the condensation (evaporation) step. Especially, when water-soluble or- ganic solvents such as acetone, acetonitrile, methanol and ethanol are used, the loss of nicotine during evaporation is remarkable; the recovery rates also become variable. It is known that the boiling point of nicotine is lowered upon its mixing with acetone, by the action of azeotropic eff ects, causing more volatility of nicotine. As extraction solvents for the diatomite columns, dichloromethane, diethyl ether, and di- chloromethane plus isopropyl alcohol or isopropyl ether are being used. In the author’s experi- ence, dichloromethane/isopropyl ether (85:15) gave the best recovery rate. To prevent nicotine from its loss due to evaporation, hydrochloric acid methanolic solution is sometimes added. Th e author also tried the addition of various acids including hydrochloric acid, but any acid addition could not improve the recovery rates. Th e adsorption of nicotine and cotinine to glassware was tested, because there was a report, in which glassware aft er the inactivation treatment (silylation) had been used. However, no adsorption of the compounds was found. ⊡ Figure 5.1 SIM chromatogram for nicotine, cotinine and 5-aminoquinoline (IS) extracted from human serum. The peaks of nicotine and cotinine were constructed by combining peak areas at m/z 84, 133 and 161, and at m/z 98 and 176, respectively. The peak of IS is detected with the peak area at m/z 144 only. 502 Nicotine and cotinine > Figure 5.1 shows an SIM chromatogram for nicotine and cotinine extracted from a clinical specimen. Th e detection limit by this method was 5 ng/mL (S/N = 3) for both nicotine and conitine. HPLC analysis of nicotine and cotinine in blood and urine Reagents and their preparation • Th e standard solutions of nicotine and cotinine, and spiked serum specimens are prepared as described in the GC/MS section. • 5-Aminoquinoline (IS) is dissolved in acetonitrile to prepare 500 ng/mL solution. HPLC conditions HPLC column: Mightysil RP18 (250 × 4.6 mm i. d., particle size 5 µm, Kanto Chemicals, To- kyo, Japan). Instrument: a Hitachi (Tokyo, Japan) HPLC system (pump: Hitachi-7100; data processor: Hitachi D7500; detector: Hitachi L7400 UV detector). Mobile phase: methanol/water/0.1 M acetate buff er solution (pH 4.0)/acetonitrile (13:65:20:2) is adjusted to pH 6.3 with triethylamine. Flow rate: 1.0 mL/min; detector wavelength: 262 nm; analysis time: about 25 min; reten- tion times: nicotine 8.5 min, cotinine 17.8 min and IS 22.3 min. Procedure i. A 100-µL aliquot of serum is mixed well with 100 µL IS solution in a sample tube. ii. Aft er centrifugation at 10,000 rpm for 10 min, the supernatant fraction is mixed with a saturating amount of sodium carbonate to separate the acetonitrile phase from the aqueous phase. iii. Aft er centrifugation at 10,000 rpm for 10 min, the upper phase (acetonitrile layer) is trans- ferred to a glass vial containing 50 mg anhydrous sodium sulfate and mixed well for dehy- dration. iv. A 20-µL aliquot of the above supernatant solution and 20 µL mobile phase are drawn into a microsyringe to mixb them in the syringe. An aliquot of the mixture is injected into HPLC. Assessment and some comments on the method In many reports on HPLC analysis of nicotine with a UV detector (UV: 262 or 254 nm), liquid- liquid extraction or diatomite column extraction was used. Th ey used as large as 1–5 mL serum for each analysis and fi nally condensed the extract solution by evaporation; their methods resulted in the detection limit as low as 5 ng/mL. However, as mentioned above, the loss of HPLC analysis of nicotine in tobaccos 503 ⊡ Figure 5.2 HPLC chromatogram for nicotine, cotinine and IS in rat serum after oral dose of cigarette extract solution.
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