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2.
Article in English | MEDLINE | ID: mdl-12551740

ABSTRACT

Even though 85% of adults drink caffeinated beverages daily, very limited studies on plasma caffeine concentration in the US population have been published. Smoking induces cytochrome P450 1A2 (CYP1A2), which is the main enzyme involved in caffeine metabolism. The current naturalistic pilot study explores plasma caffeine concentrations in a US sample, and presents a mathematical model of the relationship between caffeine intake and plasma concentrations for smokers and nonsmokers. Caffeine intake and average plasma caffeine concentrations from morning (7:30-9:30 a.m.) and afternoon (2:00-4:00 p.m.) samples were studied in 69 volunteers (21 smokers and 48 nonsmokers). The mean caffeine intake obtained from caffeinated beverages was 3.02 mg/kg/day, which is similar to the intake in the US population. Almost all subjects in the present sample (99%; 95% confidence interval [CI]: 96-100) had detectable plasma caffeine concentrations. Smokers had significantly higher caffeine intake than nonsmokers. The ratio of concentration/dose of caffeine from caffeinated beverages was approximately four-fold higher in nonsmokers (1.33 kgxday/l) than in smokers (0.29 kgxday/l). According to the model, the median plasma caffeine concentration was two- to three-fold higher in nonsmokers for each level of caffeine intake. Our model improves our understanding of the interactions between caffeine and smoking. Additional studies are needed to replicate the model. This model may help epidemiologists to correct for the effects of smoking on caffeine intake and pharmacologists to screen for the activity of CYP1A2.


Subject(s)
Caffeine/blood , Caffeine/metabolism , Central Nervous System Stimulants/blood , Central Nervous System Stimulants/metabolism , Smoking , Adult , Cytochrome P-450 CYP1A2/pharmacology , Epidemiologic Studies , Female , Humans , Male , Middle Aged , United States/epidemiology
3.
Drug Metab Dispos ; 30(12): 1478-83, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12433822

ABSTRACT

Two of the abundant conjugates of human nicotine metabolism result from the N-glucuronidation of S-(-)-nicotine and S-(-)-cotinine, transformations we recently demonstrated in liver microsomes. We further studied these microsomal N-glucuronidation reactions with respect to human hepatic interindividual, human intertissue, and interspecies hepatic variation. The reactivities of microsomes from human liver (n = 12), various human tissues, and liver from eight species toward the N-glucuronidation of S-(-)-nicotine and S-(-)-cotinine, and also R-(+)-nicotine in human liver were examined. Assays with (14)C-labeled substrates involved radiometric high-performance liquid chromatography. For the human liver samples examined there were 13- to 17-fold variations in the catalytic activities observed toward S-(-)-nicotine, R-(+)-nicotine, and S-(-)-cotinine. Gender and smoking effects were studied, and after exclusion of an outlier a decrease in catalytic activity in females was observed. Significant correlations were observed between all three analytes, indicating that the same UDP-glucuronosyltransferase(s) enzyme is likely to be involved in these transformations. Catalytic activities were not observed for human gastrointestinal tract (colon, duodenum, ileum, jejunum, and stomach), kidney, or lung microsomes. For the seven animal species examined, activity was measurable only for monkey, guinea pig, and minipig, and only for S-(-)-nicotine N-glucuronidation and at rates 10- to 40-fold lower than humans. Activity was not measurable in the case of dog, mouse, rabbit, or rat, for the latter under five different treatment conditions for one of the strains. In conclusion, there are large hepatic interindividual variations in N-glucuronidation of S-(-)-nicotine and S-(-)-cotinine, in human extrahepatic metabolism seems limited, and none of the animal strains examined resembled human.


Subject(s)
Cotinine/metabolism , Genetic Variation , Microsomes, Liver/metabolism , Nicotine/metabolism , Uridine Diphosphate Glucuronic Acid/metabolism , Animals , Cotinine/chemistry , Dogs , Female , Genetic Variation/genetics , Guinea Pigs , Humans , Macaca fascicularis , Male , Mice , Nicotine/chemistry , Rabbits , Rats , Rats, Inbred F344 , Rats, Sprague-Dawley , Rats, Wistar , Smoking/metabolism , Species Specificity , Swine, Miniature
4.
Drug Metab Dispos ; 30(10): 1070-6, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12228182

ABSTRACT

N-Glucuronidation at an aromatic tertiary amine of 5-membered polyaza ring systems was investigated for a model series of eight 1-substituted imidazoles in liver microsomes from five species. The major objectives were to investigate substrate specificities of the series in human microsomes and interspecies variation for the prototype molecule, 1-phenylimidazole. The formed quaternary ammonium-linked metabolites were characterized by positive ion electrospray mass spectrometry. The incubation conditions for the N-glucuronidation of 1-substituted imidazoles were optimized; where for membrane disrupting agents, alamethicin was more effective than the detergents examined. The need to optimize alamethicin concentration was indicated by 4-fold interspecies variation in optimal concentration and by a change in effect from removal of glucuronidation latency to inhibition on increasing concentration. For the four species with quantifiable N-glucuronidation of 1-phenylimidazole, there were 8- and 18-fold variations in the determined apparent K(m) (range, 0.63 to 4.8 mM) and V(max) (range, 0.08 to 1.4 nmol/min/mg of protein) values, respectively. The apparent clearance values (V(max)/K(m)) were in the following order: human congruent with guinea pig congruent with rabbit > rat congruent with dog (no metabolite detected). Monophasic kinetics were observed for the N-glucuronidation of seven substrates by human liver microsomes, which suggests that one enzyme is involved in each metabolic catalysis. No N-glucuronidation was observed for the substrate containing the para-phenyl substituent with the largest electron withdrawing effect, 1-(4-nitrophenyl)imidazole. Linear correlation analyses between apparent microsomal kinetics and substrate physicochemical parameters revealed significant correlations between K(m) and lipophilicity (pi(para) or log P values) and between V(max)/K(m) and both electronic properties (sigma(para) value) and pKa.


Subject(s)
Glucuronides/metabolism , Imidazoles/metabolism , Microsomes, Liver/metabolism , Quaternary Ammonium Compounds/metabolism , Animals , Dogs , Female , Glucuronides/chemistry , Guinea Pigs , Humans , Imidazoles/chemistry , Male , Protein Structure, Quaternary/physiology , Quaternary Ammonium Compounds/chemistry , Rabbits , Rats , Rats, Sprague-Dawley , Species Specificity
5.
J Clin Psychopharmacol ; 22(5): 496-501, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12352273

ABSTRACT

Determination of plasma cotinine concentration is the predominant assay employed to quantify smoking and exposure to environmental tobacco smoke in epidemiological studies. However, cotinine is biotransformed into secondary metabolites. This pilot study determined plasma concentrations of cotinine, cotinine glucuronide, 3-hydroxycotinine, and 3-hydroxycotinine glucuronide. Total cotinine concentration was determined by summation of all four metabolites. The goals of this study were (1) to explore the stability and validity of total cotinine concentration as a measure of tobacco smoking and as a measure of exposure to environmental tobacco smoke in nonsmokers, (2) to explore the stability of plasma concentrations of each of the four nicotine metabolites in smokers by performing a.m. and p.m. measures, and (3) to explore the stability of indices of glucuronidation as measures of possible markers for enzymatic activity. The subject sample included 76 white volunteers (32% smokers and 68% nonsmokers). Plasma total cotinine concentration appeared to be very stable, suggesting that total cotinine concentration may be a good measure for epidemiological studies employing a single plasma sample. Moreover, plasma total cotinine concentration also reflected exposure to environmental tobacco smoke more accurately than did plasma cotinine concentration, which would have not identified 27% of passive smokers. 3-Hydroxycotinine glucuronide and 3-hydroxycotinine plasma concentrations were almost as stable as cotinine concentrations. However, cotinine glucuronide and its indices of glucuronidation were unstable, suggesting that cotinine glucuronide undergoes deconjugation. New studies of total cotinine in plasma using more than two blood collections during the day are needed to definitively establish that it is a stable biomarker for epidemiological studies.


Subject(s)
Cotinine/blood , Indicators and Reagents/analysis , Smoking/blood , Adult , Biomarkers/blood , Drug Stability , Female , Glucuronides/blood , Humans , Male , Middle Aged , Pilot Projects , Reproducibility of Results , Time Factors
6.
Drug Metab Dispos ; 30(9): 991-6, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12167564

ABSTRACT

Two predominant human glucuronide metabolites of nicotine result from pyridine nitrogen atom conjugation. The present objectives included determination of the kinetics of formation of S(-)-cotinine N1-glucuronide in pooled human liver microsomes and investigation of the UDP-glucuronosyltransferases (UGTs) involved in N-glucuronidation of nicotine isomers and S(-)-cotinine by use of recombinant enzymes (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15). Quantification was by radiochemical high-performance liquid chromatography with use of radiolabeled substrates. S(-)-Cotinine N1-glucuronide formation in human liver microsomes was proven by comparing the chromatographic behaviors and electrospray ionization-mass spectral characteristics of the metabolite with a synthetic reference standard. This glucuronide was formed by one-enzyme kinetics with K(m) and V(max) values of 5.4 mM and 696 pmol/min/mg, respectively, and the apparent intrinsic clearance value (V(max/Km)) was 9-fold less than that previously determined for S(-)-nicotine N1-glucuronide (0.13 versus 1.2 microl/min/mg) using the same pooled microsomes. This comparison of values is consistent with the observation that on smoking cigarettes, although the average S(-)-cotinine plasma levels usually far exceed S(-)-nicotine levels, the urinary recovery of S(-)-cotinine N1-glucuronide only averages 3-fold greater than for S(-)-nicotine N1-glucuronide. None of the UGTs examined catalyzed the N-glucuronidation of S(-)-nicotine, R(+)-nicotine, and S(-)-cotinine, including UGT1A3 and UGT1A4, the only isoforms known to catalyze many substrates at a tertiary amine. Also, neither S(-)-nicotine or S(-)-cotinine affected enzyme inhibition of trifluoperazine, a UGT1A4 substrate. It would appear that the same, as yet unexamined, UGT catalyzes the N-glucuronidation of both cotinine and nicotine.


Subject(s)
Cotinine/analogs & derivatives , Cotinine/metabolism , Glucuronates/metabolism , Glucuronides/metabolism , Glucuronosyltransferase/metabolism , Nicotine/analogs & derivatives , Nicotine/metabolism , Catalysis , Humans , In Vitro Techniques , Kinetics , Microsomes, Liver/metabolism , Recombinant Proteins/metabolism , Stereoisomerism
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