Description of 'caffeine.dat' (free format) variables ------------------------------------------- Smoker 1 = YES 0 = NO Gender 1 = MALE 0 = FEMALE Subject subject number Time hours after injecstion Level caffeine concentration in saliva Description of 'caffplas.dat' (free format) variables ------------------------------------------- Subject subject number Time hours after injecstion Saliva caffeine concentration in saliva Plasma caffeine concentration in plasma - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Data by personal communication between jh and 1st author of... Effect of smoking on caffeine clearance Parsons, WD and Neims AH Clin Pharmacol Ther24(1) 40-45, 1978] Certain observations have led us to postulate a surprisingly close relationship in rats between aryl hydrocarbon hydroxylase activity (AHH) and the metabolism of caffeine[]: (i) pretreatment with 3-methylcholanthrene markedly enhances the animal's capacity to eliminate caffeine, whereas phenobarbital has only a small effect[1]; (2) pretreatment with 3- methylcholanthrene increases the catalytic activity of hepatic microsomal preparations toward caffeine[]; and (3) the differential effects of 7,8 benzoflavone and SKF-525A ,§-diethylaminoethyl 2,2-diphenylvalerate on basal and induced microsomal monooxygenase activities toward 3, 4-benzpyrene[] and caffeine[] are analogous. Cigarette smoke, a complex mixture[] containing a variety of polycyclic aromatic hydrocarbons, is known to induce AHH in certain human tissues.[] To further explore the relationship between AHH and the disposition of caffeine, we studied the effect of cigarette smoking on caffeine clearance in healthy young adults. The results bear directly on the question of whether caffeine might serve as a prob... study the role of AHH and its inducibility in relation to individual susceptibility to chemical carcinogenesis. Furthermore, since cigarette smoking and the consumption of caffeine are among the most common habits of our species, their interaction has significance quite apart from AHH. METHODS Subjects. Our subjects were 13 smokers and 13 control nonsmokers chosen from laboratory and hospital personnel. Each group consisted of 9 females and 4 males with an average age of [photocopy unclear] (range 20 to 45). No subjects in the nonsmoking group had ever used tobacco regularly. Smoking subjects consumed at least 20 cigarettes per day for a minimum of two years. With the exception of three women in each group who were taking oral contraceptives, none of the subjects took any medication regularly. The usual daily intake of caffeine, mostly as coffee, was found by questionnaire to approximate 320 mg in the smokers and 150 mg in the nonsmokers. Procedure. Subjects were instructed to abstain from caffeine containing foods and beverages for 24 hours prior to and during the study. On the day of study, they were permitted their usual breakfast excluding caffeine. In the five subjects in whom both plasma and salivary caffeine concentrations were measured, caffeine (5 mg/kg) was administered orally as a solution of caffeine citrate (1 mg/ml). Subjects were instructed to rinse their mouths thoroughly immediately after ingestion of the caffeine. Salivary samples (5 ml mixed saliva) were collected in polyethylene vials at 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 24 hr after ingestion and stored at 4¡ C until assay within two weeks. Blood samples (2 ml) were taken at the same time as saliva samples through an indwelling intravenous catheter which was flushed periodically with heparinized saline. The initial 0.5 ml of each blood collection was discarded. Plasma was separated and stored at 4¡ C for assay within two weeks. Only saliva was sampled in the other 21 subjects who were allowed to select 180 ml of coffee (n, 18), tea (n, 2) or cola (n, 1) as a source of the test dose of caffeine. An aliquot of the beverage was assayed for caffeine. Assay procedure; kinetic and statistical analyses. Caffeine was measured by the radioimmunoassay procedure developed and supplied by Cook and colleagues of Research Triangle Institute. The caffeine concentration:time curves were analyzed by assumption of a first-order one compartment model. The validity of this model was established when it was determined that mean caffeine clearance from plasma in the five subjects described subsequently in Table I was equivalent whether calculated by this model (158 ± 22 ml ¥ kgÐ1 ¥ hrÐ1) or the method of area under the curve(l59 ± 23 ml ¥ kgÐ1 ¥ hrÐ1). The elimination rate constant, kel, was computed by least-square log-linear regression analysis of the descending portion of caffeine concentration as a function of time. The apparent volume of distribution (aVd) was calculated from the dose of caffeine administered divided by the extrapolated caffeine concentration at time 0 after subtraction of the actual 0-time value (a 24-hr abstinence from caffeine was usually sufficient to make this value negligible). The body clearance (Cl) was computed as the product of kel and aVd. Since caffeine is absorbed rapidly and completely, one-compartmental kinetic computations after oral and intravenous dosing are similar[] So also, the small differences in rate of absorption of caffeine from different beverages[] should not affect our results. The unpaired Student's t test was used in statistical comparisons. Comparison of the salivary and plasma modes of sampling. Simultaneous salivary and plasma caffeine decay curves were studied in five subjects. Except for a transiently high salivary:plasma concentration ratio in a few subjects during the first 1 to 1.5 hr, the salivary and plasma caffeine concentrations both decrease proportionally in a fashion consistent with first-order elimination. Typical results are presented in Fig. 1. The initially high salivary concentrations probably reflect residual caffeine in the mouth, and were ignored in computations. The salivary and plasma caffeine concentrations in each subject were subjected to linear least- squares regression analysis. The lowest correlation coefficient was 0.90, the mean correlation coefficient 0.96, and the y intercept 0.02. The salivary: plasma caffeine concentration ratio for the five subjects was 0.90 ± 0.17. Similar results have been reported by Cook and co-workers[] Values for kel, aVd, and Cl were computed separately from the salivary and plasma data of each subject (Table I). Agreement is generally good, and there is no significant difference between the mean value of any of the three parameters whether calculated from salivary or plasma data. Cigarette smoking and caffeine elimination. Individual values for kel, aVd, and Cl are presented in Table II for nonsmokers and in Table III for smokers. The mean caffeine tl/2 in smokers was 3.5 hr, while that in the non smokers was 6.0 hr Plasma and Saliva Caffeine Concentration (µg/ml) after ingestion of Caffeine (5mg/kg) as Caffeine Citrate (5mg/ml) 0.5h lh l.5h 2h 4h 6h 8h lOh 12h 13h ss 4.0 5.4 2.0 5.2 3.0 1.10 0.45 0.02 2 8.5 6.3 4.5 3.6 2.5 0.74 0.24 0.04 0.05 0.04 7.88 6.95 5.52 4.49 3.27 1.43 1.00 12 8.95 5.95 5.05 4.62 2.05 1.55 0.94 5.48 5.82 5.29 5.29 3.81 3.61 2.85 4 5.56 4.89 4.25 4.44 3.76 2.49 2.30 1.5 1.40 3.78 3.57 4.65 3.21 3.0 1.5 l.O8 0.37 3 8.38 4.88 4.80 3.89 2.62 1.40 0.56 0.45 0.16 5.9 3.94 3.15 3.20 2.45 2.25 1.40 0.90 25 5.82 5.07 4.08 4.14 2.75 2.9S l.94 1.6 1.2 0.90 Caveat: Data in tables initially extracted from authors' notebook by jh in 1984; data and text here electronically scanned in 1996 from typewritten 1984 version of jh's case study description. Caffeine Concentration (µg/ml) in saliva of 13 SMOKERS after injestion of caffeine (Table III) ss 0h .5h lh 1.5h 2h 4h 6h 8h lOh 24h males 1 8.5 6.5 4.5 3.5 2.5 0.74 0.24 0.04 2 8.38 4.88 4.80 3.89 2.62 1.40 0.56 0.45 3 5.56 4.89 4.25 4.44 3.26 2.49 2.30 l.50 4 females 5 1.0 2.1 2.4 2.75 2.0 1.15 0.6 0 9 0.08 6 0.11 2.04 2.31 1.93 1.66 1.03 1.09 0.74 0.64 0.115 7 1.00 0.90 0.75 0.62 0.49 0.12 0.009 0.0156 8 0.08 0.76 0.66 0.33 0.48 0.3 0.02 9 0.46 0.19 0.09 0.04 O.Ol5 10 0.67 3.5 2.4 2.6 2.4 1.66 1.30 0.79 0.55 0.05 11 0.61 0.6 0.44 0.28 0.30 0.016 12 8.95 5.95 5.05 4.62 2.05 1.55 0.94 0.248 13 0.01 4.4 3.0 2.60 1.89 1.03 0.53 0.21 Caffeine Concentration (µg/ml) in saliva of 13 NONSMOKERS after injestion of caffeine (Table II) ss 0h .5h lh 1.5h 2h 4h 6h 8h lOh 12h 24h males 14 0.12 3.05 2.95 2.62 2.25 2.39 1.78 0.81 0.07 15 0.16 0.69 0.51 0.47 0.31 0.24 0.13 0.12 0.05 0.002 16 0.36 l.92 2.08 1.86 2.30 1.63 1.28 1.1 0.54 0.29 17 0.06 3.41 3.06 2.86 2.70 2.1l 1.52 1.06 0.98 0.05 18 5.2 4.95 4.78 4.44 4.16 3.25 3.15 2.85 19 0. 1.6 1.6 1.12 1.1 0.59 20 0.20 5.97 5.27 4.69 5.09 4.59 3.90 2.88 21 0.05 4.5 3.4 2.7 2.9 2.3 2.2 1.0 1.0 0.30 22 0.14 3.79 4.31 5.62 4.38 3.84 3.32 2.33 1.93 0.14 females 23 24 25 5.9 3.94 3.15 3.20 2.45 2.25 1.40 0.90 26 EXERCISE a Sketch the caffeine concentration:time curves for two subjects from Table II and two from Table III. Do not take the 4 with the most data. b Fit a kel constant for each of the four (see sentence in bold on previous page), and determine the statistical precision (SE) of the 4 estimates. Rank the estimates by their precision and explain why they rank in this order.