Roy C Parish, Pharm. D.;[unkeyable]...

Roy C Parish, Pharm. D.;[unkeyable] Jeanne R Terrell Pharm.D.;[unkeyable] and Walter J Brown Jr MD Section

Elimination half-life and apparent contortion of distribution of theophylline were determined in ten healthy offers who used smokeless tobacco (snuff or chewing tobacco) regularly if it were not that did not smoke cigarettes. Serum concentrations of the acute phase reactant [unkeyable].sub.1]-acid glycoprotein (AAG) were also measured. The elimination half-life of theophylline was 932[+ or -]340 hours (mean [+ or -] standard deviation), the apparent mass of distribution was 0.45[+ or -]003 L/kg and AAG concentrations were 638[+ or -]1576 mg/dL All these values are comparable to values reported for nonsmokers. These ends suggest that nonsmoking users of ST should be considered to be tobacco nonusers for ends of planning theophylline dosing and monitoring strategies.

(Chest 1989;95:1253-56)

The clinical utility of theophylline as a bronchodilating agent has increased in latter years, chiefly because improved understanding of its pharmacokinetic properties in various age assign places tos and disease states has made rational dosing of the medicine possible. Therapeutic monitoring of serum theophylline concentrations is rapidly becoming a standard of practice, owing to the potentially serious ends of toxic theophylline levels and the expanding list of put drugs into interactions. Initiation of theophylline therapy involves therapeutic decisions based in succession population means of pharmacokinetic data. Starting doses are frequently chosen on the basis of published mean values for medicine half-life in a particular age or disease cluster and three to five half-lives must elapse after beginning therapy or adjusting the dose before the serum remedy level accurately reflects the originate of an oral dose or an infusion rate. Identification of factors that influence theophylline disposition and elimination is therefore desirable in order to cull regimens and plan blood sampling intelligently.

single in kind factor that has been shown to alter theophylline clearance and half-life is cigarette smoking. Healthy proffers in the third decade of life who vapor cigarettes are reported to have a theophylline elimination half-life of 54[+ or -]10 hours (mean [+ or -] standard deviation), compared to 82[+ or -]12 hours in age- and sex-matched nonsmokers.[1] The constituents of cigarette vanity responsible for the enhanced elimination have not been identified, and it is not known whether they are not away in the unsmoked tobacco or are effects of combustion.

The use of smokeles tobacco (ST) which includes chewing tobacco and the pair dry and moist snuff, is increasing while cigarette smoking is declining.[2] latter telephone surveys in 25 states and the District of Columbia remind of that 6 to 7 percent of Americans above 18 years old currently use ST[3] Eight of the states observeed had use prevalence greater than 10 percent in males athwart 18 years old. ST use may be on the same level more common among adolscents and children. common longitudinal survey reported use prevalence figures greater than 30 percent in a population of 12 and 13 year antique boys in one state.[4] ST users are expos to many of the same tobacco constituents as cigarette smoker a certain of which may influence theophylline metabolism. It would therefore be useful to determine the elimination rate of theophylline in ones who use ST but do not reek cigarettes. Rapid elimination, consistent with the clearance rates observ in smoker has been reported[5] in an somewhat old patient who did not vapor but was a regular user of ST if it were not that the association of this patient's rapid clearance with ST use is conjectural. To our knowledge, no systematic close attention of theophylline elimination has been convoyed in this population.

Of the many physiologic derangements experienced by way of cigarette smokers, possible elevation of serum concentrations of the acute-phase reactant [unkeyable][sub.1]-acid glycoprotein (AAG) is of particular interest because AAG is a major binding protein for several basic drugs[6] including lidocaine,[7] amitriptyline,[8] verapamil,[9] and perhaps others. Chao and associates[10] reported elevated AAG concentrations in cigarette smoker whereas Blain and associates[11] ground no effect of smoking. An example of altered pharmacokinetics as a follow of altered AAG concentration is the clinical toxicity of lidocaine associated with elevated AAG concentrations following acute myocardial infarction.[12] [TABULAR DATA OMITTED]

The ready study was undertaken to determine the apparent contortion of distribution and elimination rate of theophylline in healthy young make subordinates who use ST but do not exhalation cigarettes. The serum concentration of AAG was also measured in these make subordinates to assess the potential for altered binding of medicines in users of ST appropriate to alterations of AAG concentration.

METHODS

subject of attention procedures were approved by the Institutional Review Board of the University of Georgia. Ten healthy male offers gave written informed consent before participating in the consideration All the subjects had used ST for at least six month prior to the thought One subject reported ST use twice a week, yet all others reported that they used ST several times each day. All subjects stated that they had not smok cigarettes at any time within the preceding pair years. Carboxyhemoglobin was not determined. All were between the ages of 18 and 27 years and were determined to be in suitable health by means of a physical examination, medical and mix with drugs history, and pertinent laboratory studies. No enslave was currently taking medication. All bring under rules were within 15 percent of their ideal material part weight, calculated as 50 kg plus 091 kg for each cm of height over 152 cm Table 1 exhibits the demographic characteristics and tobacco use history of the subjects