In each of three separate experiments mean plasma nicotine t1/2 beta was slightly, but statistically significantly, shorter in habituated compared to naive cigarette smokers. Two of these experiments involved nicotine administration by... more
In each of three separate experiments mean plasma nicotine t1/2 beta was slightly, but statistically significantly, shorter in habituated compared to naive cigarette smokers. Two of these experiments involved nicotine administration by smoking a cigarette containing a standardized amount of nicotine, whereas in the third experiment nicotine was injected intravenously as a single tracer dose of 14C-nicotine. In contrast to cigarette smokers, naive and habituated snuff dippers had similar mean plasma nicotine t1/2 beta. Habituated pipe smokers tended to have very slightly, but not statistically significantly, shorter plasma nicotine t1/2 beta S than naive pipe smokers. These distinctions are related to special features that characterize each form of tobacco intake.
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... On the basis of time-and dose-related changes in rates of nicotine elimination, Russell and Feyera-bend (121 and Rosenberg et al. [34] suggested that nicotine exhibits an ad-ditional slower terminal elimination phase not readily... more
... On the basis of time-and dose-related changes in rates of nicotine elimination, Russell and Feyera-bend (121 and Rosenberg et al. [34] suggested that nicotine exhibits an ad-ditional slower terminal elimination phase not readily detectable from plasma data. ...
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Research Interests: Traditional Medicine, Biology, Medicinal Plants, Medicine, Mice, and 4 morePubmed, Animals, Male, and Cardiac glycosides
A new HPLC assay was adapted for radiometric detection of nicotine metabolites in rat bile. Two glucuronides were identified as the principal biliary metabolites of nicotine. In addition to nicotine glucuronide and 3-hydroxycotinine... more
A new HPLC assay was adapted for radiometric detection of nicotine metabolites in rat bile. Two glucuronides were identified as the principal biliary metabolites of nicotine. In addition to nicotine glucuronide and 3-hydroxycotinine glucuronide, cotinine was also detected in bile after administration to rats of a single subcutaneous dose of (-)-S-nicotine (0.2 or 1.0 mg/kg) that contained a tracer dose of rac-[pyrrolidine-2'-14C]nicotine (20 microCi). Biliary metabolites accounted for only 3% of the [14C]nicotine dose, but phenobarbital pretreatment (100 mg/kg ip for 3 days) increased the amount of [14C]nicotine-derived radioactivity recovered in bile to 8% and also accelerated rates of biliary excretion of all three nicotine metabolites. Dose-dependency of nicotine metabolism occurred: less nicotine glucuronide was excreted at the low dose than at the high dose.
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A sensitive, rapid high-pressure liquid chromatographic assay was developed to compare the disposition of an intravenous dose of 14C-nicotine in normal, carefully matched smokers and nonsmokers. The elimination half-lifes of nicotine and... more
A sensitive, rapid high-pressure liquid chromatographic assay was developed to compare the disposition of an intravenous dose of 14C-nicotine in normal, carefully matched smokers and nonsmokers. The elimination half-lifes of nicotine and cotinine were shorter in smokers than in nonsmokers. Also consistent with an inductive effect of smoking was the increased nicotine elimination rate constant in smokers, but smoking induced more complex kinetic changes: nicotine volume of distribution was diminished in smokers, whereas nicotine clearance and area under the concentration-time curve were unchanged. The presence of nicotine and its principal metabolites in a morning specimen of urine obtained from nonsmokers before 14C-nicotine administration suggests ubiquitous, passive exposure to and absorption of chemicals present in cigarette smoke.
Research Interests:
Research Interests:
Stumptailed macaques received a single i.v. dose of 14C-nicotine (5 microCi and 300 micrograms/kg) on several separate occasions to establish baselines. Then they were pretreated with phenobarbital (2.0 mg/kg/day im for 7 days) and 8... more
Stumptailed macaques received a single i.v. dose of 14C-nicotine (5 microCi and 300 micrograms/kg) on several separate occasions to establish baselines. Then they were pretreated with phenobarbital (2.0 mg/kg/day im for 7 days) and 8 weeks later pretreated with cimetidine (8.5 mg/kg/day im for 4 days). Nicotine in the same dose as before was readministered after each pretreatment. The baseline pattern of nicotine metabolism observed in plasma and urine, highly reproducible within and between macaques, closely resembled that previously reported in humans using GC and HPLC analysis. In urine, nicotine and eight metabolites were identified, including high concentrations of metabolites A and G. Recently discovered in humans, metabolites A and G are of special interest for their long duration in the body. Phenobarbital pretreatment accelerated rates of production of all nicotine metabolites except nornicotine and nicotine-1'-N-oxide, whereas cimetidine retarded rates of production of five metabolites. Sex differences in nicotine metabolism resembled those reported in humans. Collectively, these results suggest that the stumptailed macaque may be a useful model for certain aspects of nicotine metabolism in humans.
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Research Interests: Chemistry, Physical Chemistry, Complementary and Alternative Medicine, Chromatography, Plant Biology, and 15 moreEthnopharmacology, Medicine, Smooth muscle, Animals, Gel Permeation Chromatography, Plant extracts, Ammonium, Muscle contraction, Molecular weight, Aqueous Solution, Acetone, Drug Stability, Guinea pigs, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
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Research Interests:
A new radiometric assay for nicotine and 12 of its metabolites disclosed that plasma nicotine and cotinine t1/2 beta were independent of dose after single intraarterial nicotine doses of 0.1, 0.5, or 1.0 mg/kg. At high doses, nicotine AUC... more
A new radiometric assay for nicotine and 12 of its metabolites disclosed that plasma nicotine and cotinine t1/2 beta were independent of dose after single intraarterial nicotine doses of 0.1, 0.5, or 1.0 mg/kg. At high doses, nicotine AUC and clearance tended to exhibit a small degree of dose dependency. The longest lived metabolites, cotinine-N-oxide and a previously unidentified metabolite now revealed to be allohydroxydemethylcotinine, persisted for 96 hr after nicotine injection, whereas cotinine was detected for only 48 hr. Cotinine, formerly considered the longest lived nicotine metabolite, serves widely as the most sensitive indicator of prior exposure to small concentrations of nicotine. The present studies disclose new, longer lasting metabolites that may perform this function more sensitively, at least in the rat. At the 3 doses of nicotine administered, plasma nicotine half-life ranged from 0.9 to 1.1 hr; total body clearance of nicotine ranged from 2.9 to 3.9 liters.hr-1.kg-1; and apparent volume of distribution of nicotine from 4.7 to 5.7 liters.kg-1. Also at these 3 doses, mean half-lives of urinary excretion of cotinine, cotinine-N-oxide, and allohydroxydemethylcotinine ranged from 4.8 to 5.3 hr, from 7.9 to 8.2 hr, and from 9.9 to 11.0 hr, respectively.
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Interpretation of sex differences in nicotine metabolism and disposition in rats required studies both in vivo and in vitro to provide both metabolic and pharmacokinetic data. In each of four rat strains studied in vitro, males... more
Interpretation of sex differences in nicotine metabolism and disposition in rats required studies both in vivo and in vitro to provide both metabolic and pharmacokinetic data. In each of four rat strains studied in vitro, males metabolized nicotine faster than did females. In Sprague-Dawley rats, studies of nicotine kinetics after a single iv dose of [14C]nicotine revealed a larger nicotine volume of distribution in females than in males. A prolonged plasma nicotine half-life in females balanced the larger volume of distribution, so that no sex difference appeared in plasma clearance of nicotine. Nevertheless, sex differences in nicotine metabolism are indicated inasmuch as 1) females had lower plasma cotinine concentrations than did males; 2) urinary recoveries of nicotine were higher in female than in male rats; 3) total urinary output of nicotine metabolites was higher in male than female rats, consistent with the enhanced N- and C-oxidation of nicotine by male rats observed in vitro. In female rats the reduced rate of nicotine metabolism, as well as a larger volume of distribution of nicotine, explains in part the reported increased lethality of female compared with male rats.
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A sensitive, reproducible radiometric-high-performance liquid chromatographic assay has been developed to measure concentrations of nicotine and twelve of its metabolites in biological fluids. Following administration of nicotine... more
A sensitive, reproducible radiometric-high-performance liquid chromatographic assay has been developed to measure concentrations of nicotine and twelve of its metabolites in biological fluids. Following administration of nicotine ([2-14C]pyrrolidine) to rats, the assay was used in a pharmacokinetic investigation.
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Research Interests: Biology, Medicinal Plants, Medicine, Nicaragua, Mice, and 4 morePubmed, Animals, Male, and Antidiarrhoeal
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A triple-tiered working model is projected for the pharmacological evaluation of crude drugs prescribed in traditional medical practices. Of the proposed component tests and procedures, the majority have had their usefulness already... more
A triple-tiered working model is projected for the pharmacological evaluation of crude drugs prescribed in traditional medical practices. Of the proposed component tests and procedures, the majority have had their usefulness already validated in natural product pharmacological research. First-level investigations (herbalist consultations/professional attestations, hippocratic screening and literature surveys) provide first-hand pharmacological information about traditional materia medica. Second-level investigation comprising bioassay-modelled tests (brine shrimp toxicity test, opiate receptor-binding studies, fertilized sea urchin egg test, platelet adenyl cyclase/phosphodiesterase assays, hexobarbital-induced sleeping time test, antimicrobial assays, isolated guinea pig ileum test and pharmacodynamic screening) are designed to extend the mode(s) of drug action suggested by the first-level procedures. Based on data from Level 1 and Level 2 findings, third-level experiments are specific tests tailored to confirm the pharmacodynamic/kinetic properties and clinical efficacy of traditional drugs. Level 2 and Level 3 tests may be combined in monitoring fractionations and subsequent isolation of unique crude drug constituents with potential application in conventional therapeutics.
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A new HPLC assay was adapted for radiometric detection of nicotine metabolites in rat bile. Two glucuronides were identified as the principal biliary metabolites of nicotine. In addition to nicotine glucuronide and 3-hydroxycotinine... more
A new HPLC assay was adapted for radiometric detection of nicotine metabolites in rat bile. Two glucuronides were identified as the principal biliary metabolites of nicotine. In addition to nicotine glucuronide and 3-hydroxycotinine glucuronide, cotinine was also detected in bile after administration to rats of a single subcutaneous dose of (-)-S-nicotine (0.2 or 1.0 mg/kg) that contained a tracer dose of rac-[pyrrolidine-2'-14C]nicotine (20 microCi). Biliary metabolites accounted for only 3% of the [14C]nicotine dose, but phenobarbital pretreatment (100 mg/kg ip for 3 days) increased the amount of [14C]nicotine-derived radioactivity recovered in bile to 8% and also accelerated rates of biliary excretion of all three nicotine metabolites. Dose-dependency of nicotine metabolism occurred: less nicotine glucuronide was excreted at the low dose than at the high dose.
Research Interests:
Interpretation of sex differences in nicotine metabolism and disposition in rats required studies both in vivo and in vitro to provide both metabolic and pharmacokinetic data. In each of four rat strains studied in vitro, males... more
Interpretation of sex differences in nicotine metabolism and disposition in rats required studies both in vivo and in vitro to provide both metabolic and pharmacokinetic data. In each of four rat strains studied in vitro, males metabolized nicotine faster than did females. In Sprague-Dawley rats, studies of nicotine kinetics after a single iv dose of [14C]nicotine revealed a larger nicotine volume of distribution in females than in males. A prolonged plasma nicotine half-life in females balanced the larger volume of distribution, so that no sex difference appeared in plasma clearance of nicotine. Nevertheless, sex differences in nicotine metabolism are indicated inasmuch as 1) females had lower plasma cotinine concentrations than did males; 2) urinary recoveries of nicotine were higher in female than in male rats; 3) total urinary output of nicotine metabolites was higher in male than female rats, consistent with the enhanced N- and C-oxidation of nicotine by male rats observed in v...
Research Interests:
A new radiometric assay for nicotine and 12 of its metabolites disclosed that plasma nicotine and cotinine t1/2 beta were independent of dose after single intraarterial nicotine doses of 0.1, 0.5, or 1.0 mg/kg. At high doses, nicotine AUC... more
A new radiometric assay for nicotine and 12 of its metabolites disclosed that plasma nicotine and cotinine t1/2 beta were independent of dose after single intraarterial nicotine doses of 0.1, 0.5, or 1.0 mg/kg. At high doses, nicotine AUC and clearance tended to exhibit a small degree of dose dependency. The longest lived metabolites, cotinine-N-oxide and a previously unidentified metabolite now revealed to be allohydroxydemethylcotinine, persisted for 96 hr after nicotine injection, whereas cotinine was detected for only 48 hr. Cotinine, formerly considered the longest lived nicotine metabolite, serves widely as the most sensitive indicator of prior exposure to small concentrations of nicotine. The present studies disclose new, longer lasting metabolites that may perform this function more sensitively, at least in the rat. At the 3 doses of nicotine administered, plasma nicotine half-life ranged from 0.9 to 1.1 hr; total body clearance of nicotine ranged from 2.9 to 3.9 liters.hr-1...
Research Interests:
Stumptailed macaques received a single i.v. dose of 14C-nicotine (5 microCi and 300 micrograms/kg) on several separate occasions to establish baselines. Then they were pretreated with phenobarbital (2.0 mg/kg/day im for 7 days) and 8... more
Stumptailed macaques received a single i.v. dose of 14C-nicotine (5 microCi and 300 micrograms/kg) on several separate occasions to establish baselines. Then they were pretreated with phenobarbital (2.0 mg/kg/day im for 7 days) and 8 weeks later pretreated with cimetidine (8.5 mg/kg/day im for 4 days). Nicotine in the same dose as before was readministered after each pretreatment. The baseline pattern of nicotine metabolism observed in plasma and urine, highly reproducible within and between macaques, closely resembled that previously reported in humans using GC and HPLC analysis. In urine, nicotine and eight metabolites were identified, including high concentrations of metabolites A and G. Recently discovered in humans, metabolites A and G are of special interest for their long duration in the body. Phenobarbital pretreatment accelerated rates of production of all nicotine metabolites except nornicotine and nicotine-1'-N-oxide, whereas cimetidine retarded rates of production of...
Research Interests:
A sensitive, rapid high-pressure liquid chromatographic assay was developed to compare the disposition of an intravenous dose of 14C-nicotine in normal, carefully matched smokers and nonsmokers. The elimination half-lifes of nicotine and... more
A sensitive, rapid high-pressure liquid chromatographic assay was developed to compare the disposition of an intravenous dose of 14C-nicotine in normal, carefully matched smokers and nonsmokers. The elimination half-lifes of nicotine and cotinine were shorter in smokers than in nonsmokers. Also consistent with an inductive effect of smoking was the increased nicotine elimination rate constant in smokers, but smoking induced more complex kinetic changes: nicotine volume of distribution was diminished in smokers, whereas nicotine clearance and area under the concentration-time curve were unchanged. The presence of nicotine and its principal metabolites in a morning specimen of urine obtained from nonsmokers before 14C-nicotine administration suggests ubiquitous, passive exposure to and absorption of chemicals present in cigarette smoke.
Research Interests:
A sensitive, reproducible radiometric-high-performance liquid chromatographic assay has been developed to measure concentrations of nicotine and twelve of its metabolites in biological fluids. Following administration of nicotine... more
A sensitive, reproducible radiometric-high-performance liquid chromatographic assay has been developed to measure concentrations of nicotine and twelve of its metabolites in biological fluids. Following administration of nicotine ([2-14C]pyrrolidine) to rats, the assay was used in a pharmacokinetic investigation.
Research Interests:
Research Interests:
A rapid thermospray liquid chromatography-mass spectrometry (TSP LC-MS) method is described for the simultaneous determination of nicotine and 17 of its metabolites. Chemical ionization of nicotine and its metabolites separated by... more
A rapid thermospray liquid chromatography-mass spectrometry (TSP LC-MS) method is described for the simultaneous determination of nicotine and 17 of its metabolites. Chemical ionization of nicotine and its metabolites separated by reversed-phase HPLC is achieved by postcolumn addition of ammonium acetate buffer with the filament of the ion source turned off. Quantification is accomplished by selectively monitoring the unique protonated molecular ion of each metabolite. Trideuterated cotinine serves as an internal standard. Linear responses for cotinine, demethylcotinine, and trans-3'-hydroxycotinine were observed over a concentration range of 20-8000 ng/mL, and 80-8000 ng/ml for nicotine and nicotine-1'-N-oxide. Of the 17 metabolites examined, only nicotine, cotinine, demethylcotinine, and trans-3'-hydroxycotinine were detected in smokers' urine.
Research Interests:
... On the basis of time-and dose-related changes in rates of nicotine elimination, Russell and Feyera-bend (121 and Rosenberg et al. [34] suggested that nicotine exhibits an ad-ditional slower terminal elimination phase not readily... more
... On the basis of time-and dose-related changes in rates of nicotine elimination, Russell and Feyera-bend (121 and Rosenberg et al. [34] suggested that nicotine exhibits an ad-ditional slower terminal elimination phase not readily detectable from plasma data. ...
Research Interests:
Research Interests:
Research Interests:
Research Interests: Chemistry, Physical Chemistry, Complementary and Alternative Medicine, Plant Biology, Ethnopharmacology, and 11 moreMedicine, Smooth muscle, Animals, Plant extracts, Muscle contraction, Molecular weight, Acetone, Drug Stability, Guinea pigs, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
Research Interests:
In each of three separate experiments mean plasma nicotine t1/2 beta was slightly, but statistically significantly, shorter in habituated compared to naive cigarette smokers. Two of these experiments involved nicotine administration by... more
In each of three separate experiments mean plasma nicotine t1/2 beta was slightly, but statistically significantly, shorter in habituated compared to naive cigarette smokers. Two of these experiments involved nicotine administration by smoking a cigarette containing a standardized amount of nicotine, whereas in the third experiment nicotine was injected intravenously as a single tracer dose of 14C-nicotine. In contrast to cigarette smokers, naive and habituated snuff dippers had similar mean plasma nicotine t1/2 beta. Habituated pipe smokers tended to have very slightly, but not statistically significantly, shorter plasma nicotine t1/2 beta S than naive pipe smokers. These distinctions are related to special features that characterize each form of tobacco intake.