An analysis of the inter-subject variation in the metabolism of pentazocine

Significant inter-subject variation in the cumulative urinary excretion of pentazocine, following its oral administration, was observed. Individual variations in the rate of metabolic oxidation of pentazocine are responsible for the variations in the urinary excretion of pentazocine (24 h cumulative). Smoking did not affect the metabolism of the drug. Pharmacokinetic analysis of the urinary excretion rate of pentazocine, using an open three compartment model, indicated that the fractional metabolic clearance is correlated with the cumulative urinary excretion (24 h) of the drug under conditions of acidic urinary pH. A g.l.c. method for the determination of pentazocine in urine is described.     

Urinary acrylamide metabolites as biomarkers for short-term dietary exposure to acrylamide.

It has previously been reported that heat-treated carbohydrate rich foods may contain high levels of acrylamide resulting in consumers being inadvertently exposed to acrylamide. Acrylamide is mainly excreted in the urine as mercapturic acid derivatives of acrylamide and glycidamide. In a clinical study comprising of 53 subjects, the urinary excretion of these metabolites was determined using solid-phase extraction and liquid chromatography with positive electrospray MS/MS detection. The median (range) total excretion of acrylamide in urine during 24 h was 16 (7-47) microg acrylamide for non-smokers and 74 (38-106) microg acrylamide for smokers, respectively. It was found that the median intake estimate in the study based on 24 h dietary recall was 21 (13-178) and 26 (12-67) for non-smokers and smokers, respectively. The median dietary exposure to acrylamide was estimated to be 0.47 (range 0.17-1.16) microg/kg body weight per day. In a multiple linear regression analysis, the urinary excretion of acrylamide metabolites correlated statistically significant with intake of aspartic acid, protein, starch and coffee. Consumption of citrus fruits correlated negatively with excretion of acrylamide metabolites.     

Cadmium-induced nephropathy in the development of high blood pressure

In recognition of a central role of the kidney in long-term blood pressure control, we undertook an in-depth analysis of the relationship between blood pressure and kidney damage caused by environmental exposure to the common pollutants cadmium and lead. The subjects were 200 healthy Thais, 16 and 60 years of age (100 female non-smokers, 53 male non-smokers, and 47 male smokers). None of these subjects had been exposed to Cd or Pb in the workplace and their urinary Cd concentrations ranged from 0.4 to 37 nM, whereas their urinary Pb concentrations ranged from 0.1 to 30 nM. The prevalence of high blood pressure was 2%, 8% and 19%, respectively in subjects with low, average and high Cd-burden (linear trend chi2=6.4, P=0.01). Multiple regression analysis revealed a significant positive association between Cd-burden and blood pressure in male non-smokers (adjusted beta=0.31, P=0.02) and an inverse association between blood pressure and urinary Pb excretion rate in male smokers (adjusted beta=-0.38, P=0.005). Associations between Cd-burden and nephropathies were evidenced by increases in urinary excretion of beta2-microglobulin (P=0.02) and N-acetyl-beta-d-glucosaminidase (P=0.005) in subjects with high Cd-burden, compared with the subjects with average Cd-burden. In addition, an association between Cd-related nephropathy and high blood pressure was evidenced by a 20% increase in the prevalence of high blood pressure in people with NAG-uria (linear trend chi2=4.3, P=0.04). Our present study provides first evidence for a possible link between renal tubular damage and dysfunction caused by environmental Cd exposure and increased risk of high blood pressure.     

Hydroxy-phenanthrenes in the urine of non-smokers and smokers

Urinary hydroxy-phenanthrene (HO-PHE) excretion in non-smokers exposed to environmental tobacco smoke (ETS) is not increased. There is no significant difference in HO-PHE excretion between smokers (S) and non-smokers (NS), though excretion seems to be slightly elevated in smokers. A diet rich in polycyclic aromatic hydrocarbons leads to a rise in urinary HO-PHE excretion as compared to a diet low in polycyclic aromatic hydrocarbons (PAH), coming close to significance. HO-PHE excretion is not correlated with the mutagenic activity in urine.     

Comparative studies of the mutagenicity of urine from smokers and non-smokers on a controlled non-mutagenic diet

Measuring the mutagenicity of urine is widely viewed as a means of evaluating human exposure to potentially genotoxic materials. Diet and cigarette smoking have both been reported to affect the mutagenicity of human urine, but the relationship between smoking status and the expression of diet-related urinary mutagenicity is unknown. It has been reported that some promutagens are more active in in vitro assays when tested in the presence of urine from smokers than when tested in the presence of urine from non-smokers. We aimed to determine whether the differences in urinary mutagenicity between smokers and non-smokers result from increased urinary mutagenicity from dietary heterocyclic amine mutagens in smokers compared with non-smokers. Groups of smokers and non-smokers (6-12) were given identical diets, previously shown to be low in heterocyclic amines and very low in mutagenicity. The diet consisted exclusively of raw food and of food cooked in boiling water. After a 2-day dietary stabilization period, 24-hour urine samples were collected for three consecutive days. The regimen was repeated in the following week. For comparison, both groups were also placed on a "western" diet, consisting of a variety of foods prepared by several cooking methods, designed to reflect what a typical United States family might consume. Urine was concentrated using XAD-2 resin and then assayed for mutagenic activity in the Ames test. The urine of smokers was significantly more mutagenic than that of non-smokers when on both the raw/boiled and the "western" diets. These results indicate that the increased urinary mutagenicity observed in smokers compared with non-smokers is not due to enhanced mutagenicity of diet-related heterocyclic amine mutagens in the urine of smokers.     

Impact of smoking on the concentration and activity of alpha-1-antitrypsin in serum in relation to the urinary excretion of hydroxyproline

The impact of active and passive smoking on the serum levels of alpha 1-AT, the trypsin inhibitory capacity (TIC), the trypsin inhibitory activity (TIA) and the urinary hydroxyproline to creatinine ratio (HOP-ratio) was studied. The subjects used in the study on active smoking were 167 healthy adult men and in the study on passive smoking 189 healthy primary school children. Serum levels of alpha 1-AT in active smokers were significantly higher than those in non-smokers. The TIC as well as the TIA in active smokers decreased with increasing number of cigarettes smoked. The urinary HOP-ratio increased significantly with increasing number of cigarettes smoked. On the other hand, in the case of passive smokers a significant difference was obtained only for the HOP-ratio. The correlations between all markers in active smokers were significant. Less significant correlations were found in the case of passive smokers. These results suggest that the urinary excretion of hydroxyproline can be considered as a marker for the imbalance between proteases and anti-proteases as a result of smoking.     

Urinary hydroxyproline excretion in smokers, non-smokers and passive smokers

The hydroxyproline/creatinine ratio in urine was investigated in 200 cigarette smokers, 199 pipe and/or cigar smokers and 24 non-smokers. For cigarette smokers a statistically significant positive correlation is found between this ratio and daily cigarette consumption, COHb, serum cotinine and nicotine excretion in urine. This smoking-related increase in the hydroxyproline/creatinine ratio is, for the most part or completely, due to the fact that creatinine urine concentrations inversely correlate with the smoke uptake variables. Neither pipe and/or cigar smoking nor passive smoke exposure of non-smokers seem to affect the hydroxyproline/creatinine ratio. A seasonal influence is found in these studies as well as in two experiments with limited numbers of subjects: the hydroxyproline/creatinine ratio is higher in winter than in summer for both smokers and non-smokers. Our data do not favour the idea that measuring hydroxyproline/creatinine ratios in urine is an accurate method of investigating early effects of smoking, passive smoking and air pollution in man.     

Absorption and excretion of 3H-raubasine in human subjects and dogs

The pharmacokinetic behavior of (3,5,6-3H)-raubasine (RAU) was investigated in human subjects after oral administration and in dogs after both intravenous and oral administration. By the oral route RAU peak plasma levels appeared in human subjects after 1 h and in dogs after 2 h. Three-day cumulative urinary excretion was 22% by i.v. route and 13% by oral route in dogs, being 29% in human subjects after oral administration. Three-day cumulative faecal excretion in dogs was 51% by i.v. route and 57% by oral route whilst it was 24% in humans. From a comparison between the urinary excretion values observed after i.v. and oral administration, a RAU intestinal absorption of 59% may be obtained.     

The absorption,blood concentrations and excretion of pentazocine after oral,intramuscular or rectal administration to man

Blood concentrations, urinary excretion rates and faecal excretion of unchanged drug were measured after oral, intramuscular or rectal administration of pentazocine; Significant inter-subject variation was observed. Blood concentration-time curves are related to urinary excretion rates. Relative physiological availabilities by each route were determined.     

The influence of CYP2A6 polymorphisms and cadmium on nicotine metabolism in Thai population

We investigated the influence of genetic, cadmium exposure and smoking status, on cytochrome P450-mediated nicotine metabolism (CYP2A6) in 182 Thai subjects after receiving 2 mg of nicotine gum chewing for 30 min. The urinary excretion of cotinine was normally distributed over a 2 h period (logarithmically transformed). Individuals with urinary cotinine levels in the ranges of 0.01–0.21, and 0.52–94.99 μg/2 h were categorized as poor metabolizes (PMs: 6.5%), and extensive metabolizers (EMs: 93.5%), respectively. The majority of EMs (45%) carried homozygous wild-type genotypes (CYP2A6*1A/*1A, CYP2A6*1A/*1B and CYP2A6*1B/*1B), whereas only 1% of PMs carried these genotypes. Markedly higher frequencies of EMs were also observed in all heterozygous defective genotypes including the null genotype (*4C/*4C; 1 subject).A weak but significant positive correlation was observed between total amounts of urinary cadmium excretion and total cotinine excretion over 2 h. Our study shows generally good agreement between CYP2A6 genotypes and phenotypes. Smokers accumulated about 3–4-fold higher mean total amounts of 2-h urinary cadmium excretion (127.5 ± 218.2 ng/2 h) than that of non-smokers (40.5 ± 78.4 ng/2 h). Among the smokers (n = 16), homologous wild-type genotype *1/*1 was significantly the predominant genotype (6/16) compared with other defective allele including *4C/*4C. In addition, 2 h urinary excretion of cotinine in smokers of all genotypes was significantly higher than non-smokers. The proportion of smokers who smoked more than 5 cigarettes/day was significantly higher in EMs in all CYP2A6 genotypes (n = 14) than in PMs (n = 0).     

Antipyrine metabolism in relation to polymorphic oxidations of sparteine and debrisoquine.

Thirty-five healthy subjects who had been classified as extensive or poor metabolizers of both sparteine and debrisoquine were given a single oral dose of antipyrine. Saliva concentration of antipyrine and urinary excretion of its three major oxidation metabolites were measured. All the parameters of antipyrine metabolism which were estimated had similar distributions in both the 28 EM and 7 PM genetic phenotypes defined by the metabolism of sparteine and debrisoquine. The clearance of antipyrine by the formation of 4-hydroxy-antipyrine and 3-hydroxy-antipyrine respectively were closely correlated (r = 0.83, P less than 0.001) and both were significantly higher in smokers than in non-smokers. Demethylation of antipyrine also seemed to be influenced by smoking, but not to a statistically significant extent. These findings confirm the influence of the environmental factor of smoking in antipyrine oxidative biotransformations.     

The effect of smoking on nicotine metabolism in vivo in man

Nicotine and a basic metabolite, cotinine, were determined in the urine by gas-liquid chromatography after intravenous administration of (—)-nicotine hydrogen (+)-tartrate to groups of male and female smokers and non-smokers in whom the urine was maintained at an acid pH. The urinary recoveries of nicotine and cotinine from male smokers fell in two groups. One showed a lower recovery of both alkaloids than was seen with male non-smokers. The other showed a similar recovery of nicotine but more cotinine than the male non-smokers. Female smokers excreted less nicotine but more cotinine than female non-smokers. More nicotine but less cotinine was excreted by female non-smokers than by male non-smokers. The results show sex dependent metabolism of nicotine occurs in non-smoking humans and that smoking causes alterations in nicotine metabolism.     

Lack of effect of smoking on the metabolism and pharmacokinetics of quinidine in patients

The urinary metabolite profile of quinidine and the oral clearance of this drug were studied under steady state conditions in five smoking and nine non-smoking patients. No significant differences were observed in the urinary recovery of unchanged quinidine, 3S-3-hydroxyquinidine, 2'-oxoquinidinone or quinidine-N-oxide between smokers and non-smokers. In addition, the plasma clearance of quinidine was not affected by the smoking status of subjects. These results suggest that cigarette smoke does not induce any of the main pathways for quinidine metabolism in a typical patient population and that the consideration of smoking status is of little utility in aiding in the selection of initial dosage regimens for this drug.     

The influence of CYP2A6 polymorphisms and cadmium on nicotine metabolism in Thai population

We investigated the influence of genetic, cadmium exposure and smoking status, on cytochrome P450-mediated nicotine metabolism (CYP2A6) in 182 Thai subjects after receiving 2 mg of nicotine gum chewing for 30 min. The urinary excretion of cotinine was normally distributed over a 2 h period (logarithmically transformed). Individuals with urinary cotinine levels in the ranges of 0.01–0.21, and 0.52–94.99 μg/2 h were categorized as poor metabolizes (PMs: 6.5%), and extensive metabolizers (EMs: 93.5%), respectively. The majority of EMs (45%) carried homozygous wild-type genotypes (CYP2A6*1A/*1A, CYP2A6*1A/*1B and CYP2A6*1B/*1B), whereas only 1% of PMs carried these genotypes. Markedly higher frequencies of EMs were also observed in all heterozygous defective genotypes including the null genotype (*4C/*4C; 1 subject).A weak but significant positive correlation was observed between total amounts of urinary cadmium excretion and total cotinine excretion over 2 h. Our study shows generally good agreement between CYP2A6 genotypes and phenotypes. Smokers accumulated about 3–4-fold higher mean total amounts of 2-h urinary cadmium excretion (127.5 ± 218.2 ng/2 h) than that of non-smokers (40.5 ± 78.4 ng/2 h). Among the smokers (n = 16), homologous wild-type genotype *1/*1 was significantly the predominant genotype (6/16) compared with other defective allele including *4C/*4C. In addition, 2 h urinary excretion of cotinine in smokers of all genotypes was significantly higher than non-smokers. The proportion of smokers who smoked more than 5 cigarettes/day was significantly higher in EMs in all CYP2A6 genotypes (n = 14) than in PMs (n = 0).     

Influence of renal insufficiency on the pharmacokinetics of cicletanine and its effects on the urinary excretion of electrolytes and prostanoids.

1. The kinetics of a single oral dose (300 mg) of cicletanine a new antihypertensive drug with diuretic properties, and its effects on the urinary excretion of electrolytes and of the major stable metabolites of prostacyclin and thromboxane A2 were studied in patients with normal renal function (n = 6), mild (n = 9) and severe (n = 10) renal insufficiency. 2. In normotensive subjects with normal renal function, cicletanine was rapidly and regularly absorbed, its apparent elimination half-life established around 7 h, and both its renal clearance (0.4 ml min-1) and its cumulative renal excretion (0.85% of the administered dose), were low. Mild renal insufficiency did not significantly alter these parameters, while severe renal impairment reduced the renal clearance and the cumulative urinary excretion of cicletanine and increased its apparent elimination half-life (31 h). However the area under the plasma curve was not changed due to reduced plasma concentrations in these patients. 3. Cicletanine induced a rapid and marked (four fold as a mean) increase in the urinary excretion of water, sodium and potassium which lasted for 6 to 10 h, in subjects with normal renal function. Renal insufficiency did not alter the slope of the calculated plasma concentration-effects curves but reduced the maximum effect observed for water, sodium and potassium. 4. A single oral dose of cicletanine did not change the urinary excretion of 6-keto-prostaglandin F1 alpha and thromboxane B2 in the three groups of patients studied, the basal values of which being found to be closely related to the creatinine clearance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of Smoking and Smoking Deprivation on the Articulatory Loop of Working Memory

This study examined the effects of smoking and smoking deprivation on the articulatory loop of working memory. Forty subjects (20 smokers and 20 non-smokers) performed tasks involving serial recall of letters on two occasions 1 week apart. In each test one part was conducted with articulatory suppression and the other without it. The smokers completed one test following 12 h of smoking deprivation, and the other after smoking a cigarette. The order of suppression/non-suppression conditions and the order of smoking and smoking deprivation were balanced across subjects. The results showed that deprived smokers performed significantly worse than both smoking smokers and non-smokers in the task without suppression. Although all the subjects performed significantly worse whilst under articulatory suppression, smoking status was not found to influence performance here. These results imply that smoking has the effect of returning the smoker to a comparable level of performance to that seen in non-smokers, and suggest that smoking abstinence has a negative effect when performance involves the articulatory loop. © 1997 John Wiley & Sons, Ltd.     

The absorption, distribution and excretion of pentazocine in man after oral and intravenous administration

Gas-liquid chromatography is a sensitive technique for the analysis of pentazocine in biological samples. Dose for dose, the concentration in blood and the urinary excretion rate of pentazocine are much lower after oral administration than after intravenous administration. The recovery of the unchanged drug in faeces is low whether it is given by mouth or intravenously.     

An association between smoking habits and blood pressure in normotensive Japanese men: a 5-year follow-up study

BACKGROUND: There are few studies on the effects of smoking on blood pressure (BP) that consider confounding factors such as age, obesity, lifestyle and blood chemistry. As such, we conducted a 5-year follow-up study to clarify the effects of smoking habits on blood pressure in normotensive Japanese men. METHODS: The subjects were 2107 normotensive male steelworkers aged 40-54 years. They were classified using three indices: smoking habits in 1990, changes in smoking habits, and changes in amount of smoking. The associations between these indices and changes in blood pressure were evaluated using analysis of covariance (ANCOVA). As analyses, BMI, salt intake, physical activity, drinking habit, and results of blood chemistry in 1990 and their changes, age and blood pressure in 1990 were used as covariates. RESULTS: The cumulative incidence of hypertension in smokers was lower than in non- and ex-smokers. The adjusted mean of change in blood pressure of smokers was significantly lower than in non- and ex-smokers. No significant difference between non-smokers and ex-smokers, or among groups of smokers who varied their amount of smoking was observed. CONCLUSION: Chronic smoking reduces changes in blood pressure and 5-year cumulative incidence of hypertension. However, no significant dose-dependent effect of smoking on changes in blood pressure was observed.     

Urinary NNAL in hookah smokers and non-smokers after attending a hookah social event in a hookah lounge or a private home

Tobacco smoking and exposure to tobacco secondhand smoke (SHS) can cause lung cancer. We determined uptake of NNK (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone), a tobacco specific potent pulmonary carcinogen, in hookah smokers and non-smokers exposed to hookah tobacco SHS. We analyzed data from a community-based convenience sample of 201 of adult (aged ≥18 years) exclusive hookah smokers (n = 99) and non-smokers (n = 102) residing in San Diego County, California. Participants spent an average of three consecutive hours indoors, in hookah lounges or private homes, where hookah tobacco was smoked exclusively. Total NNAL [the sum of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides], the major metabolites of NNK, were quantified in spot urine samples provided the morning of and the morning after attending a hookah event. Among hookah smokers urinary NNAL increased significantly (p<0.001) following a hookah social event; the geometric mean doubled, from 1.97 to 4.16 pg/mg. Among non-smokers the increase was not significant (p = 0.059). Post hookah event urinary NNAL levels were highest in daily hookah smokers, and significantly higher than in non-daily smokers or non-smokers (GM: 14.96 pg/mg vs. 3.13 pg/mg and 0.67 pg/mg, respectively). For both hookah smokers and non-smokers, pre-to-post event change in urinary NNAL was not significantly different between hookah lounges and homes. We suggest posting health warning signs inside hookah lounges, and encouraging voluntary bans of smoking hookah tobacco in private homes.     

Effects of tobacco smoking on the human pupil

OBJECTIVE: Determine the effects of tobacco cigarette or sham placebo-smoking on pupil diameter. SUBJECTS: Ten non-smokers and 10 tobacco smokers (all healthy, drug free adults) were studied while resting in a comfortable lounger. METHODS: Tobacco smokers abstained from smoking and all subjects abstained from caffeine-containing products for at least 8 h prior to testing. The smokers each smoked one tobacco cigarette, and the non-smokers each inhaled air through an unlit sham cigarette. Right pupil diameter, heart rate, systolic and diastolic blood pressure were measured before and after sham- or tobacco-smoking in each subject. Pupil size was measured from a colored photograph taken with a Polaroid camera equipped with a high-speed flash with the subject in a standardized, dimly lit quiet room. RESULTS: There was no significant difference in baseline pupil diameter between non-smokers and smokers prior to sham- or tobacco-smoking. After sham- or tobacco-smoking, both non-smokers and smokers showed slight but statistically significant pupillary constriction. CONCLUSIONS: Shortly after smoking one tobacco cigarette, pupillary constriction was greater than after sham-smoking.