Theophylline + Tobacco - Drug Interactions

Tobacco smokers, and non-smokers heavily exposed to tobaccosmoke, may need more theophylline than non-smokers to achievethe same therapeutic benefits, because theophylline is clearedfrom body more quickly. This may also occur in those whochew tobacco or take snuff but not if they chew nicotine gum.

A study found that mean half-life of theophylline (given as a single oral dose of aminophylline) was 4.3 hrs in a group of tobacco smokers (20 to 40 cigarettes a day) compared with 7 hrs in a group of non-smokers, and that theophylline clearance was higher (mean 126%) and more variable in smokers (See reference number 1). Almost identical results were found in an earlier study,(See reference number 2) and a number of later studies in subjects given oral or intravenous theophylline or aminophylline confirm these findings (See reference number 3-7). The ability of smoking to increase theophylline clearance occurs irrespective of gender,(See reference number 3,6) and in presence of congestive heart failure or liver impairment (See reference number 7). The effects of ageing on induction of theophylline metabolism by tobacco smoking is less clear. One study has found that in both young subjects (less than 30-years-old) and elderly subjects (more than 67-yearsold) smoking decreased half-life and increased clearance of theophylline, when compared with non-smokers. The effect was greater in young subjects (See reference number 4). However, another study found no difference in pharmacokinetics of theophylline between asthmatic and healthy smokers and non-smokers aged over 65 years (See reference number 8). A similar high clearance of theophylline (given as intravenous aminophylline) has been seen in a patient who chewed tobacco (1.11 mL/kg per minute compared with more usual

0.59 mL/kg per minute) (See reference number 9). The half-life of theophylline (given as intravenous aminophylline) in passive smokers (non-smokers regularly exposed to tobacco smoke in air they breathe, for 4 hrs a day in this study) is reported to be shorter than in non-smokers (6.93 hrs compared with

In one study,3 of 4 patients who stopped smoking for 3 months (confirmed by serum thiocyanate levels) had a longer theophylline half-life, but only 2 had a slight decrease in theophylline clearance (See reference number 1). In another study,ex-smokers who had stopped heavy smoking 2 years previously had values for theophylline clearance and half-life that were intermediate between non-smokers and current heavy smokers (See reference number 3). In another study,7 hospitalised smokers who abstained from smoking for 7 days had a 35.8 % increase in theophylline half-life and a 37.6 % decrease in clearance (although clearance after abstinence was still higher than values usually found in non-smokers) (See reference number 12).

Tobacco smoke contains polycyclic hydrocarbons, which act as inducers of cytochrome P450 isoenzyme CYP1A2, and this results in a more rapid clearance of theophylline from body. Both N-demethylation and 8-hydroxylation of theophylline is induced (See reference number 13). Ageing appears to offset effects of smoking on theophylline metabolism (See reference number 8).

An established interaction of clinical importance. Heavy smokers (20 to 40 cigarettes daily) may need much greater theophylline dosage than nonsmokers,(See reference number 1) and increased doses are likely for those who chew tobacco or take snuff,(See reference number 9) but not for those who chew nicotine gum (See reference number 12,14). In patients who stop smoking, a reduction in theophylline dosage of up to 25 to 33 % may be needed after one week,(See reference number 12)but full normalisation of hepatic function appears to take many months or even years (See reference number 1,3). Investigators of possible interactions of theophylline with other drugs should take smoking habits into account when selecting their subjects (See reference number 6,10,11). Note that effects of cannabis, , may be additive with those of tobacco smoking.

Hunt SN,Jusko WJ, Yurchak AM. Effect of smoking on theophylline disposition. Clin Pharmacol Ther (1976) 19, 546–51.

Jenne J,Nagasawa H, McHugh R, MacDonald F, Wyse E. Decreased theophylline half-lifein cigarette smokers. Life Sci (1975) 17, 195–8.

Powell JR,Thiercelin J-F, Vozeh S, Sansom L, Riegelman S. The influence of cigarettesmoking and sex on theophylline disposition. Am Rev Respir Dis (1977) 116, 17–23.

Cusack B,Kelly JG, Lavan J, Noel J, O’Malley K. Theophylline kinetics in relation to age:the importance of smoking. Br J Clin Pharmacol (1980) 10, 109–14.

Jusko WJ,Schentag JJ, Clark JH, Gardner M, Yurchak AM. Enhanced biotransformation oftheophylline in marihuana and tobacco smokers. Clin Pharmacol Ther (1978) 24, 406–10.

Jennings TS,Nafziger AN, Davidson L, Bertino JS. Gender differences in hepatic inductionand inhibition of theophylline pharmacokinetics and metabolism. J Lab Clin Med (1993) 122, 208–16.

Harralson AF,Kehoe WA, Chen J-D. The effect of smoking on theophylline disposition inpatients with hepatic disease and congestive heart failure. J Clin Pharmacol (1996) 36, 862.

Samaan S,Fox R. The effect of smoking on theophylline kinetics in healthy and asthmaticelderly males. J Clin Pharmacol (1989) 29, 448–50.

Rockwood R,Henann N. Smokeless tobacco and theophylline clearance. Drug Intell Clin Pharm (1986) 20, 624–5.

Matsunga SK,Plezia PM, Karol MD, Katz MD, Camilli AE, Benowitz NL. Effects of passivesmoking on theophylline clearance. Clin Pharmacol Ther (1989) 46, 399–407.

Mayo PR. Effect of passive smoking on theophylline clearance in children. Ther Drug Monit (2001) 23,503–5.

Lee BL,Benowitz NL, Jacob P. Cigarette abstinence, nicotine gum, and theophylline disposition. Ann Intern Med (1987) 106, 553–5.

Grygiel J,Birkett DJ. Cigarette smoking and theophylline clearance and metabolism. Clin Pharmacol Ther (1981) 30, 491–6.

Benowitz NL,Lee BL, Jacob P. Nicotine gum and theophylline metabolism. Biomed Pharmacother (1989) 43, 1–3.