Theophylline

Brand Names: Elixophyllin, Quibron T/SR, Slo-Bid, Slo-Phyllin, Theolair, Theo-24, Theo-Dur, Uniphyl

Clinical Names: Theophylline, Aminophylline

Summary

generic name: Theophylline

trade names: Elixophyllin®, Quibron T/SR®, Slo-Bid®, Slo-Phyllin®, Theolair®, Theo-24®, Theo-Dur®, Uniphyl®

related drug: Aminophylline

trade names: Phyllocontin®, Truphylline®

type of drug: Bronchodilator

used to treat: reversible bronchoconstriction associated with bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, and related bronchospastic disorders.

overview of interactions:
• nutrient affected by drug: Vitamin B6 (Pyridoxine)

• food/herbal constituent affecting drug performance: Piperine, as in Pepper (Piper nigrum, Piper longum)

• herbal constituent affecting drug performance: Herbs containing Tannins in beverages such as Coffea arabica (Coffee) and Camellia sinensis (Tea)

• diet affecting drug performance: Food

• food/herb constituent affecting drug performance and toxicity: Caffeine, as in Theobroma cacao (Cacao, Chocolate tree), Cola nitida, Cola acuminata seed (Cola nut), Coffea arabica (Coffee), Paullinia cupana seeds (Guarana), Ilex paraguayensis leaves (Mate), and Camellia sinensis (Tea)

• herb/nutrient with potential pharmacokinetic activity as an absorption modifier: Capsicum spp. (Cayenne)
See also Herb Groups: Pharmacokinetic: GI Modifiers: Irritants

• herb affecting drug performance and toxicity: Nicotiana species (Tobacco)



Interactions

nutrient affected by drug: Vitamin B6 (Pyridoxine)

• mechanism: Theophylline is a potent inhibitor of pyridoxal kinase which is needed to convert vitamin B6 to pyridoxal-5'-phosphate (PLP). Thus theophylline induces a depression of circulating PLP levels while plasma pyridoxal levels remain unchanged. The resultant lack of PLP results in multiple decreased B6 dependent enzyme activities.
(Delport R, et al. Int J Vitam Nutr Res 1988;58(1):67-72; Ubbink JB, et al. J Lab Clin Med 1989 Jan;113(1):15-22; Ubbink JB, et al. Ann N Y Acad Sci 1990;585:285-294; Weir MR, et al. Ann Allergy 1990 Jul;65(1):59-62; Dan-Shya D. et al. Clinical Pharmacol Ther 1983;31:358; Weinberger M, Ginchansky E. J Pediatr 1977 Nov;91(5):820-824.)

• research: In a short-term study Ubbink et al found that theophylline reduced serum vitamin B6 levels in healthy adults and that subsequent supplementation with 10 mg per day normalized those vitamin B6 levels. Later Bartel et al found that vitamin B6 supplementation could reduce tremor and other nervous system side effects associated with a pyridoxal-5-phosphate deficiency due to theophylline. Shimizu et al in a study of twenty-six asthmatic children found a depression of serum PLP levels existed in asthmatic children treated with theophylline compared to those not receiving theophylline. Oral administration of 200 mg of theophylline (TheoDur) to 5 children with asthma significantly depressed serum PLP levels four hours after the drug intake, whereas theophylline did not affect serum pyridoxal levels. Finally, Martinez de Haas et al studied adults with chronic obstructive pulmonary disease and concluded that patients who used theophylline demonstrated a higher prevalence of subnormal vitamin B-6 status than did patients who did not.
(Shimizu T, et al. Pharmacology 1994 Dec;49(6):392-389; Martinez de Haas MG, et al. Ned Tijdschr Geneeskd 1997 Nov 8;141(45):2176-2179; Ubbink JB, et al. J Nutr 1990 Nov;120(11):1352-1359; Bartel PR, et al. Am J Clin Nutr 1994 Jul;60(1):93-99.)

• nutritional support: Theophylline clearly exerts an adverse impact on vitamin B6 status. Fortunately, these side effects are preventable, and may even be reversible, with vitamin B6 supplementation. The conservative daily dose of 10 mg vitamin B6 supported by the literature could provide the desired benefits at minimal risk. Even so, individuals concerned about the interaction between vitamin B6 and theophylline and its repercussions for their health should consult their prescribing physician and/or a nutritionally oriented health care professional.
(Bartel PR, et al. Am J Clin Nutr 1994 Jul;60(1):93-99; Ubbink JB, et al. J Lab Clin Med 1989 Jan;113(1):15-22; Ubbink JB, et al. J Nutr 1990 Nov;120(11):1352-1359.)

food/herbal constituent affecting drug performance: Piperine, as in Pepper (Piper nigrum, Piper longum)

• research: Black peppers contain a substance called piperine. In a human study Bano et al observed increased blood levels of theophylline in subjects given 20 mg of piperine daily for 7 days.
(Bano G, et al. Eur J Clin Pharmacol 1991;41:615-617.)

• herbal synergy: Though this interaction in a research setting may lack strong relevance to the typical dietary consumption of pepper, it could have therapeutic value. In clinical practice, the enhanced systemic availability of oral theophylline could conceivably be used to reduce doses and side effects, achieve better therapeutic control, and improve patient compliance. Further research will determine whether these potential benefits will bear out. In the meantime, individuals using theophylline should not change their dose of the medication without consulting their prescribing physician.

herbal constituent affecting drug performance: Herbs containing Tannins in beverages such as Coffee arabica (Coffee) and Camellia sinensis (Tea)
See also: GI Modifiers: Tannins.

• mechanism: Herbs high in tannins can impair the absorption of theophylline.

• herbal concerns: Individuals using theophylline should avoid using herbs high in tannins at the same time. High-tannin herbs include black tea, Camilla sinensis (green tea), Arctostaphylos uva-ursi (Uva ursi), Hamamelis virginiana (Witch hazel), Juglans nigra (Black walnut), Quercus spp. (Oak), and Rubus idaeus (red raspberry).
(Brinker F. J Naturopathic Med 1997;7(2):14-20.)

diet affecting drug performance: Food

• research: Food delays, but usually does not significantly reduce, absorption or activity of theophylline in the form of uncoated tablets and liquids. However, absorption and activity of extended release theophylline preparations can be significantly affected by certain dietary patterns and consumption of a number of foods. Diets high in protein and low in carbohydrate can reduce theophylline activity. Charbroiled beef and large amounts of broccoli, Brussels sprouts, cabbage and other cruciferous vegetables can also reduce theophylline activity. In contrast, diets rich in carbohydrates and fats and relatively low in protein can increase theophylline absorption and half-life, delay elimination, and aggravate side effects. One study, by Sangeet et al, questioned whether simultaneous protein consumption significantly altered theophylline absorption or elimination kinetics. Some physicians and pharmacists suggest that patients avoid mixing theophylline with hot food as it may dissolve the medication and increase the rate of absorption.
(Drabant S, et al. Acta Pharm Hung 1998; Threlkeld DS, ed. Feb 1991; Holt GA. 1998, 260; Sangeeta, et al. Indian J Physiol Pharmacol 1993 Oct;37(4):303-307.)

• nutritional concerns: The risk of dietary alteration of theophylline performance can be minimized by taking sustained-release forms of theophylline on an empty stomach. Extended release preparations should not be chewed or crushed; the contents of extended release capsules may be mixed with soft food and taken without chewing in patients who have difficulty swallowing solid dosage forms. Uncoated, non-sustained release tablets and liquid theophylline preparations are best taken on an empty stomach; they may be taken with food if digestive upset occurs. Individuals taking theophylline who are concerned with potential dietary effects on their medication should consult with their prescribing physician and/or pharmacist.

food/herb constituent affecting drug performance and toxicity: Caffeine, as in Theobroma cacao (Cacao, Chocolate tree), Cola nitida, Cola acuminata seed (Cola nut), Coffea arabica (Coffee), Paullinia cupana seeds (Guarana), Ilex paraguayensis leaves (Mate), and Camellia sinensis (Tea)

• mechanism: Theophylline is a methylxanthine that occurs naturally in tea and is chemically similar to caffeine and theobromine, found in cocoa beans. Individuals taking theophylline should avoid consuming large amounts of coffee, colas, cocoa, chocolate, guaraná, tea, and caffeine-containing supplements. These foods may increase the activity and side effects of the medication since they all contain a chemical with effects similar to theophylline.

• nutritional concerns: Individual using theophylline should eliminate or at least minimize their intake of foods and drinks that contain theophylline and caffeine. While this reaction may not be common individual variances in theophylline pharmacokinetics are well known and toxicity reactions can be severe and even life-threatening. Individuals taking theophylline who are concerned with potential interactions between such substances and their medication should consult with their prescribing physician and/or pharmacist.

herb/nutrient with potential pharmacokinetic activity as an absorption modifier: Capsicum spp. (Cayenne)
See also Herb Groups: Pharmacokinetic: GI Modifiers: Irritants

• mechanism: Due to its secretomotor and stimulant activity, Capsicum may affect the gastro-intestinal absorption of drugs.

• research: Capsicum has been found to increase the absorption and bioavaliability of theophylline.
(Bouraoui A, et al. Thérapie 1986; 41: 467-471, cited in Fugh-Berman A. Lancet 2000; 355: 134-138.)

• herbal concern: Individuals who have been prescribed theophylline should avoid internal consumption of Capsicum in significant amounts until they have discussed this potential interaction with the prescribing physician.

herb affecting drug performance and toxicity: Nicotiana species (Tobacco)

• mechanism: Smoking increases theophylline clearance, often dramatically shortens the drug's half-life, and significantly lowers plasma concentrations of theophylline. Consequently smokers require significantly higher doses of theophylline than do non-smokers to achieve the same therapeutic response.

• research: Several studies have looked at the effects that smoking exerts on the activity of theophylline. Every study has found that smokers had higher values of theophylline clearance than nonsmokers regardless of age and that the drug's half-life was prolonged in nonsmokers in proportion to decreased clearance. Even among elderly patients, tobacco smokers had significantly lower plasma concentrations of theophylline. Hunt et al found no significant reduction in increased theophylline clearance even after three months abstention from smoking and concluded that this was the result of induction of drug-metabolizing enzymes that do not readily normalize after cessation of smoking. Later, Grygiel and Birkett looked at the role of cytochrome P450 in the two N-demethylation pathways for theophylline metabolism and proposed that cigarette smoking induces both of the cytochrome P450-mediated pathways of theophylline metabolism.
(Talseth T, et al. Eur J Clin Pharmacol 1981;21(1):33-37; Crowley JJ, et al. J Pharmacol Exp Ther 1988 May;245(2):513-523; Hunt SN, et al. Clin Pharmacol Ther 1976 May;19(5 Pt 1):546-551; Grygiel JJ, Birkett DJ. Clin Pharmacol Ther 1981 Oct;30(4):491-496; Trembath PW, et al. Hum Toxicol 1986 Jul;5(4):265-268.)

• health concerns: The research clearly indicates that smoking has a significant detrimental on the performance of theophylline. Given the common side effects of and often severe toxicity reactions from theophylline the implications of the increased dosages required can present a major health risk for smokers who use theophylline. Quitting smoking would obviously provide great health benefits to those suffering from the respiratory conditions for which theophylline is prescribed. However, even upon cessation of smoking metabolism of theophylline may not normalize for an extended period of time. Individuals taking theophylline who are wish to quit smoking should consult with their prescribing physician for support in withdrawal and for subsequent monitoring and modification of their theophylline dosage.

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References

Bano G, Raina RK, Zutshi U, Bedi KL, Johri RK, Sharma SC. Effect of piperine on bioavailability and pharmocokinetics of propranolol and theophylline in healthy volunteers. Eur J Clin Pharmacol 1991;41(6):615-617.
Abstract: The effect of piperine on the bioavailability and pharmacokinetics of propranolol and theophylline has been examined in a crossover study. Six subjects in each group received a single oral dose of propranolol 40 mg or theophylline (150 mg) alone or in combination with piperine 20 mg daily for 7 days. An earlier tmax and a higher Cmax and AUC were observed in the subjects who received piperine and propranolol. It produced a higher Cmax, longer elimination half-life and a higher AUC with theophylline. In clinical practice, the enhanced systemic availability of oral propranolol and theophylline could be exploited to achieve better therapeutic control and improved patient compliance.

Bartel PR, Ubbink JB, Delport R, Lotz BP, Becker PJ. Vitamin B-6 supplementation and theophylline-related effects in humans. Am J Clin Nutr 1994 Jul;60(1):93-99.
Abstract: This study investigates whether vitamin B-6 supplementation reduces the stimulatory effects of theophylline (a pyridoxal kinase antagonist) on the nervous system. Twenty young, healthy adults entered this double-blind, randomized, crossover study but only 15 completed the experiment. The dependent measures were a battery of psychomotor tests, electrophysiological tests, and self-report questionnaires. Most tests, including spectral electroencephalography, aspects of the electromyograph, the Sternberg Test of information processing, and questionnaires of sleep quality and daytime sleepiness failed to distinguish between vitamin B-6 and placebo supplementation. However, theophylline-related tremor was markedly reduced (p < 0.01) with vitamin B-6 supplementation after a single dose of theophylline and a similar but nonsignificant trend was observed with repeated doses. There was a tendency for vitamin B-6 supplementation to reduce many side effects related to nervous system function. These findings suggest that vitamin B-6 supplementation with theophylline therapy may have some beneficial effects.

Brinker F. Interactions of pharmaceutical and botanical medicines. J Naturopathic Med 1997;7(2):14-20.

Crowley JJ, Cusack BJ, Jue SG, Koup JR, Park BK, Vestal RE. Aging and drug interactions. II. Effect of phenytoin and smoking on the oxidation of theophylline and cortisol in healthy men. J Pharmacol Exp Ther 1988 May;245(2):513-523.
Abstract: The effect of age on the induction of theophylline metabolism by phenytoin was examined in healthy young and old male cigarette smokers (greater than or equal to 20 cigarettes/day) and nonsmokers. Two single dose studies of theophylline pharmacokinetics were performed, one as a base-line control and another after a 2-week course of phenytoin. Phenytoin was administered as an i.v. loading dose followed by oral ingestion. The dose was adjusted to achieve total phenytoin plasma concentrations within a low therapeutic range (10-13 micrograms/ml). Free phenytoin concentrations in plasma were slightly higher in old (nonsmokers 0.84 +/- 0.13 micrograms/ml; smokers 0.89 +/- 0.12 micrograms/ml) than in young (nonsmokers 0.75 +/- 0.10 micrograms/ml; smokers 0.72 +/- 0.10 micrograms/ml) subjects, but the differences were not significant. Base-line plasma theophylline clearance was 30% lower in old compared with young nonsmokers (34.0 +/- 2.5 vs. 48.8 +/- 2.6 ml/hr/kg, P less than .001), whereas the small age difference between old and young smokers (86.0 +/- 8.4 vs. 72.4 +/- 8.0 ml/hr/kg) was not significant. Smokers had higher values of theophylline clearance than nonsmokers regardless of age. Half-life was prolonged in old nonsmokers in proportion to decreased clearance, despite a slight decrease in volume of distribution. Phenytoin induced theophylline metabolism to an equal degree in both age groups and in both smokers (young 42.6 +/- 6.5%; old 47.3 +/- 3.6%) and nonsmokers (young 56.3 +/- 8.8%; old 45.4 +/- 6.4%). The magnitude of its induction in smokers was additive to that of cigarette smoking. Old age was associated with a modest selective reduction in N-demethylated metabolic pathways to 3-methylxanthine and 1-methyluric acid, whereas smoking preferentially induced the formation of these products. Phenytoin increased the production of all theophylline primary metabolites to an equal degree in both old and young subjects. The urinary excretion of 6 beta-hydroxycortisol was not influenced significantly by age or smoking and increased 2- to 3-fold in all subject groups with phenytoin. These results confirm earlier observations of a reduction in basal oxidative capacity in elderly nonsmoking males. They also demonstrate that the ability to induce the metabolism of theophylline by smoking or phenytoin and the ability to induce the metabolism of cortisol by phenytoin are maintained in old age.

Dan-Shya D, et al. Non-linear theophylline elimination. Clinical Pharmacol Thera 1983;31:358.

Delport R, Ubbink JB, Vermaak WJ, Becker PJ. Theophylline increases pyridoxal kinase activity independently from vitamin B6 nutritional status. Res Commun Chem Pathol Pharmacol 1993 Mar;79(3):325-333.
Abstract: Asthmatics treated with theophylline, a potent inhibitor of pyridoxal kinase and therefore a vitamin B6 antagonist, demonstrated a significant correlation (r = 0.71; p < 0.001) between drug plasma levels and erythrocyte pyridoxal kinase activities. A cross-over, placebo controlled study was completed on 15 healthy volunteers to investigate the mechanism by which theophylline induces pyridoxal kinase activity. The subjects were supplemented with vitamin B6 or placebo for two weeks before theophylline therapy was started. Vitamin B6 supplementation resulted in a four-fold increase in circulating pyridoxal 5'-phosphate levels, while placebo had no effect. When theophylline therapy was commenced, erythrocyte pyridoxal kinase activities increased significantly (p < 0.001) irrespective of whether vitamin B6 or placebo was supplemented. It is concluded that a depressed vitamin B6 status is not responsible for higher erythrocyte pyridoxal kinase activities encountered during theophylline therapy, but that the drug is directly responsible for elevated enzyme levels.

Delport R, Ubbink JB, Serfontein WJ, Becker PJ, Walters L. Vitamin B6 nutritional status in asthma: the effect of theophylline therapy on plasma pyridoxal-5'-phosphate and pyridoxal levels. Int J Vitam Nutr Res 1988;58(1):67-72.
Abstract: Plasma pyridoxal-5'-phosphate concentrations were significantly lower (p less than 0.001) in a group of 28 asthmatic women when compared to 33 controls. Plasma pyridoxal levels in the two groups were not different. Theophylline was administered to a group of 17 volunteers and resulted in large reductions in plasma pyridoxal-5'-phosphate levels, while plasma pyridoxal levels and urinary 4-pyridoxic acid excretion were unaffected by theophylline therapy. An in vitro study showed that theophylline did not interfere with the high performance liquid chromatography assay for pyridoxal-5'-phosphate, indicating that theophylline could affect liver metabolism of vitamin B6.

Drabant S, Klebovich I, Gachalyi B, Renczes G, Farsang C. [Role of food interaction pharmacokinetic studies in drug development. Food interaction studies of theophylline and nifedipine retard and buspirone tablets]. Acta Pharm Hung 1998 Sep;68(5):294-306. [Article in Hungarian]
Abstract: Due to several mechanism, meals may modify the pharmacokinetics of drug products, thereby eliciting to clinically significant food interaction. Food interactions with the drug substance and with the drug formulation should be distinguished. Food interaction of different drug products containing the same active ingredient can be various depending on the pharmaceutical formulation technology. Particularly, in the case of modified release products, the food/formulation interaction can play an important role in the development of food interaction. Well known example, that bioavailability of theophylline can be influenced in different way (either increased, decreased or unchanged) by concomitant intake of food in the case of different sustained release products. The role and methods of food interaction studies in the different kinds of drug development (new chemical entity, modified release products, generics) are reviewed. Prediction of food effect response on the basis of the physicochemical and pharmacokinetic characteristics of the drug molecule or formulations is discussed. The results of three food interaction studies carried out the products of EGIS Pharmaceuticals Ltd. are also reviewed. The pharmacokinetic parameters of theophyllin 400 mg retard tablet were practically the same in both fasting condition and administration after consumption of a high fat containing standard breakfast. The ingestion of a high fat containing breakfast, increased the AUC of nifedipine from 259.0 +/- 101.2 ng h/ml to 326.7 +/- 122.5 ng h/ml and Cmax from 34.5 +/- 15.9 ng/ml to 74.3 +/- 23.9 ng/ml in case of nifedipine 20 mg retard tablet, in agreement with the data of literature. The statistical evaluation indicated significant differences between the pharmacokinetic parameters in the case of two administrations (before and after meal). The effect of a high fat containing breakfast for a generic version of buspiron 10 mg tablet and the bioequivalence after food consumption were studied in a single-dose, three-way (test and reference products administered after consumption of standard breakfast, as well as test product in fasting condition), cross-over, food effect bioequivalence study. According to the results, the test product--which, in a former study proved to be bioequivalent with the reference product in fasting state--is bioequivalent with the reference product under feeding conditions and the food intake influenced the pharmacokinetics of the test tablets.

Fligner CL, Opheim KE, Ainardi V. Caffeine and its metabolites in caffeine overdose cause falsely elevated serum theophylline measurements. Vet Hum Toxicol 1984;26 Suppl 2:28

Glenn GM, Krober MS, Kelly P, McCarty J, Weir M. Pyridoxine as therapy in theophylline-induced seizures. Vet Hum Toxicol 1995 Aug;37(4):342-345.
Abstract: Theophylline-induced seizures have significant morbidity and mortality and are difficult to treat. Theophylline therapy for asthma has been observed to depress plasma pyridoxal 5'-phosphate (PLP) levels which may decrease gamma-aminobutyric acid (GABA) synthesis and thereby contribute to seizures. We hypothesized that treatment with pyridoxine might prove beneficial in theophylline-induced seizures. One hundred thirty-nine mice were injected with 250 mg theophylline/kg ip and 89 mice were injected with 250-750 mg pyridoxine/kg ip as treatment. Decreased rates of seizure (42 vs 70%, p < 0.002) and death (29 vs 56%, p < 0.002) were observed. Six New Zealand White rabbits were given 115 mg theophylline/kg iv over 50 min followed by treatment with an iv bolus of 115 mg pyridoxine/kg, with subsequent continuous drip infusion of 230 mg/kg over 50 min. Serum theophylline levels and plasma PLP levels showed significant negative correlation prior to pyridoxine infusion with a mean peak theophylline level of 182 micrograms/ml and a mean low PLP level of 64 nM/L. Electroencephalogram (EEG) tracings were obtained before infusions, during theophylline infusion and during pyridoxine infusion. All 6 rabbits developed abnormal EEGs during theophylline infusion and all 6 rabbit EEG patterns returned to baseline during treatment with pyridoxine. These findings suggest that pyridoxine may partially reverse theophylline-induced central nervous system toxicity.

Grygiel JJ, Birkett DJ,. Cigarette smoking and theophylline clearance and metabolism. Clin Pharmacol Ther 1981 Oct;30(4):491-496.
Abstract: Differences in plasma theophylline clearance (ClT) and metabolism between smoking and nonsmoking normal subjects were examined by analysis of plasma and urinary theophylline concentrations and of urinary metabolite concentrations under steady-state oral dosing conditions. ClT in smokers (0.053 +/- 0.006 1 . hr-1 . kg-1) was greater than in nonsmokers (0.032 +/- 0.002 l . hr-1 . kg-1, p less than 0.005). Analyses of urinary metabolites revealed that clearance to l-methyluric acid (Cl1MU) and clearance to 3-methylxanthine (Cl3MX) were increased in smokers 1.99-fold and 2.10-fold over nonsmoking controls (P less than 0.005). Clearance to 1.3-dimethyluric acid (ClDMU) was also enhanced in smokers 1.68-fold compared to controls (P less than 0.01). The positive relationship between Cl1MU and Cl3MX in both smokers and nonsmokers (r = 0.98, P less than 0.001) supports the concept that two N-demethylation pathways for theophylline metabolism are under common regulatory control and involve a form of cytochrome P450 distinct from that mediating 8-hydroxylation of theophylline to DMU. These results suggest that cigarette smoking induces both of the cytochrome P450-mediated pathways of theophylline metabolism but that N-demethylation may be increased to a greater extent than 8-hydroxylation.

Holt GA. Food and Drug Interactions. Chicago: Precept Press, 1998, 260.

Hunt SN, Jusko WJ, Yurchak AM. Effect of smoking on theophylline disposition. Clin Pharmacol Ther 1976 May;19(5 Pt 1):546-551.
Abstract: The pharmacokinetics of theophylline were examined in a group of nonsmokers and in heavy smokers (1 to 2 packs/day) before and 3 to 4 mo after cessation of cigarette smoking. The half-life of theophylline in smokers averaged 4.3 (SD = 1.4) hr, significantly shorter than the mean value in nonsmokers (7.0, SD =1.7 hr). The apparent volume of distribution of theophylline was somewhat larger in smokers (0.50 +/-0.12 L/kg) than in nonsmokers (0.38 +/-0.04 L/kg). The body clearance of theophylline was appreciably larger and relatively more variable in smokers (100 +/-44 ml/min/1.73 m2) than in nonsmokers (45 +/-13 ml/min/1.73 m2). Serum concentrations of thiocyanate, a biotransformation product of cyanide which is inhaled with smoke, were used to monitor the smoking status of the subjects. The body clearances of theophylline showed a good correlation (r = 0.785, p less than 0.001) with the serum thiocyanate concentrations. Of the 8 smokers, only 4 managed to refrain from smoking for at least 3 mo, and these subjects showed no significant change in theophylline elimination. The increase in theophylline clearance caused by smoking is probably the result of induction of drug-metabolizing enzymes that do not readily normalize after cessation of smoking.

Jonkman JHG, Upton RA. Pharmacokinetic drug interactions with theophylline. Clin Pharmacol 1984;9:309-334.

Jonkman JH. Food interactions with once-a-day theophylline preparations: a review. Chronobiol Int 1987;4(3):449-458.
Abstract: At present, theophylline is used predominantly as sustained-release dosage forms. Since the mid-seventies many such products have been introduced and have found huge application for use with a dosage interval of 12 hr ('twice-a-day' preparations). Since 1983 theophylline has also been available as preparations that can be given with an interval of 24 hr ('once-a-day' preparations). The release of theophylline from sustained-release dosage forms can be influenced (either increased or decreased) by concomitant intake of food. Obviously, ultra-slow-releasing products are most vulnerable to food effects. With some preparations the composition of the meal, especially its fat content, determines the degree of the food effect. The effect of meal timing and content on once-a-day theophylline preparations must be known since rather large doses are ingested all at a single time. If food can alter the release of theophylline in an unexpected manner from ultra-slow preparations, drug effectiveness may be impaired if release is inhibited or toxicity might result if sudden release of drug occurs. Herein, information about food interaction with once-a-day theophylline preparations is reviewed as this topic is important both for clinicians as well as those concerned with chronopharmacologic investigations of such medications.

Martinez de Haas MG, Poels PJ, de Weert CJ, Thomas CM, Rooyackers JM, Hoefnagels WH. Subnormal vitamin B6 levels in theophylline users. Ned Tijdschr Geneeskd 1997 Nov 8;141(45):2176-2179 [in Dutch].
Abstract: OBJECTIVE: To study the effect of theophylline use on the vitamin B-6 status. DESIGN: Descriptive. SETTING: Department of Geriatric Medicine of Nijmegen Academic Hospital and Department of Pulmonary Diseases, University of Nijmegen, the Netherlands. PATIENTS AND METHODS: Vitamin B-6 status was determined by measuring pyridoxal-5'-phosphate (PLP) in whole blood (using a high performance liquid chromatography method, reference values: 35-107 mumol/l) in 141 patients from the Geriatric department (84 non-chronic obstructive pulmonary disease (COPD), 40 COPD patients without theophylline and 17 COPD patients with theophylline) and in 25 non-geriatric COPD patients on theophylline. RESULTS: Of the 84 geriatric non-COPD patients (mean age: 82 years; SD: 6) 56% had a subnormal vitamin B-6 status, of the 40 geriatric COPD patients without theophylline (82 years; SD: 6) 70%, of the 17 geriatric COPD patients on theophylline (80 years; SD: 5) 94% and of the 25 non-geriatric COPD patients on theophylline (62 years; SD: 11) 96%. CONCLUSION: In patients who used theophylline a higher prevalence of subnormal vitamin B-6 status was found than in patients who did not.

Sangeeta, Raina RK, Bano G. Effect of macrocomponents of food on the pharmacokinetics of a long acting preparation of anhydrous theophylline. Indian J Physiol Pharmacol 1993 Oct;37(4):303-307.
Abstract: In a single dose crossover study, the effect of macrocomponents of food on the pharmacokinetics of a long acting preparation of anhydrous theophylline was investigated. Compared to fasting subjects, carbohydrate and fat rich diet caused an enhancement of absorption half life and a lower Cmax with a delayed tmax and elimination of the bronchodilator. Protein coadministration decreased AUCO-OC of the drug without significantly altering its absorption or elimination kinetics.

Shimizu T, Maeda S, Mochizuki H, Tokuyama K, Morikawa A. Relation between therophylline and circulating vitamin levels in children with asthma. Pharmacology 1994 Dec;49(6):392-389.
Abstract: This study was undertaken to investigate the effect of theophylline on circulating vitamin B6 levels in children with asthma. Twenty-six asthmatic children, including 20 patients who were treated with slow-release theophylline and 6 patients not receiving any type of theophylline preparation, were enrolled in this study. Steady state serum theophylline and vitamin B6 [pyridoxal 5'-phosphate (PLP) and pyridoxal (PL)] levels were evaluated in these patients. A depression of serum PLP levels existed in asthmatic children treated with theophylline compared to those not receiving theophylline (5.3 +/- 0.5 vs. 9.0 +/- 1.4 ng/ml, mean +/- SEM; p < 0.05). A significant negative correlation between the serum levels of PLP and theophylline was demonstrated in the subjects of this study (rs = -0.609, p < 0.001). Oral administration of 200 mg of theophylline (TheoDur) to 5 children with asthma significantly depressed serum PLP levels 4 h after the drug intake (p < 0.05), whereas theophylline did not affect serum PL levels. From these results, we conclude that theophylline induces a depression of circulating PLP levels in asthmatic children.

Talseth T, Boye NP, Kongerud J, Bredesen JE. Aging, cigarette smoking and oral theophylline requirement. Eur J Clin Pharmacol 1981;21(1):33-37.
Abstract: In a prospective study in 73 patients with obstructive pulmonary disease, aged 63.5 +/- 13.5 years (SD), it was found that theophylline dose, cigarette smoking and age were all significant determinants of the steady-state trough plasma theophylline level during oral administration of the drug. As the predictive efficiency of the three factors combined amounted only to 25%, firm dosage recommendations cannot be made. Even among elderly patients, tobacco smokers had significantly lower plasma concentrations of theophylline. It is suggested that in order to obtain trough plasma concentrations of 50 mumol/l (approximately equal to 9 micrograms/ml), a non-smoking 50 year-old patient would require 9.8 mg/kg/day of oral theophylline, the dose increasing to 14.2 mg/kg/day in smokers of the same age. These doses should probably be reduced by 15-20% in 75 year-old patients.

Threlkeld DS, ed. Respiratory Drugs, Bronchodilators, Xanthine Derivatives. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Feb 1991.

Trembath PW, Thorsborne-Palmer DD, Jarrott B, Hammond JJ, Prinsley DM. Theophylline pharmacokinetics in patients from a geriatric hospital: influence of cigarette smoking. Hum Toxicol 1986 Jul;5(4):265-268.
Abstract: The influence of cigarette smoking on plasma theophylline elimination half-life was examined in a group of elderly in-patients, to determine whether the modifying effect of cigarette smoking is also present in this age-group. The plasma theophylline half-life was determined in five non-smokers and seven smokers aged 66-88 years after administration of 320 mg of theophylline syrup. A wide range of plasma theophylline half-lives was observed in each group. However, there was a significant difference (P less than 0.05) between the mean plasma theophylline half-life in smokers (5.41 h, SEM 0.69 h) and non-smokers (10.40 h, SEM 1.90 h). It was concluded that, although plasma theophylline half-life tends to be longer in this age-group, the modifying influence of cigarette smoking on plasma theophylline half-life can be demonstrated in the elderly, as well as in young adults.

Ubbink JB, Delport R, Becker PJ, Bissbort S. Evidence of a theophylline-induced vitamin B6 deficiency caused by noncompetitive inhibition of pyridoxal kinase. J Lab Clin Med 1989 Jan;113(1):15-22.
Abstract: A placebo-controlled, double-blind study indicated that theophylline administration to apparently healthy, young men induced significantly depressed plasma pyridoxal-5'-phosphate levels. Plasma pyridoxal levels were not affected by theophylline therapy. The effect of theophylline on circulating pyridoxal-5'-phosphate levels is explained by the observation that theophylline acts as a noncompetitive inhibitor for erythrocyte pyridoxal kinase (EC 2.7.1.35) with an apparent inhibition constant (Ki) of 1.28 x 10(-5) mol/L. Theophylline did not affect erythrocyte pyridoxamine (pyridoxine)-5'-phosphate oxidase (EC 1.4.3.5) activity. During theophylline therapy, erythrocyte pyridoxal kinase levels increased nearly twofold from an initial mean level of 24.2 +/- 4.0 (+/- SD) nmol to 46.9 +/- 7.3 nmol pyridoxal-5'-phosphate per gram of hemoglobin per hour. This partially counteracted the effect of theophylline on vitamin B6 metabolism. Nevertheless, erythrocyte pyridoxal-5'-phosphate levels in subjects given theophylline decreased significantly (p = 0.03) from pretreatment levels. The oral tryptophan load test resulted in significantly (p = 0.007) increased urinary xanthurenic acid excretion after 4 weeks of theophylline therapy. Both plasma pyridoxal-5'-phosphate levels and the tryptophan load test results normalized after 1 week of pyridoxine supplementation, indicating that 10 mg pyridoxine per day was effective to counteract the antagonistic effect of short-term theophylline therapy on vitamin B6 metabolism.

Ubbink JB, Delport R, Bissbort S, Vermaak WJ, Becker PJ. Relationship between vitamin B-6 status and elevated pyridoxal kinase levels induced by theophylline therapy in humans. J Nutr 1990 Nov;120(11):1352-1359.
Abstract: Theophylline administration to seven healthy male volunteers resulted in a rapid and significant decline in both plasma and erythrocyte pyridoxal-5'-phosphate levels. Total erythrocyte pyridoxal kinase levels increased during 15 wk of theophylline treatment from a mean initial activity of 19.23 +/- 5.03 (mean +/- SD) to 62.64 +/- 11.59 nmol pyridoxal-5'-phosphate formed/(g hemoglobin.h). Although plasma pyridoxal levels remained normal, the threefold increase in total erythrocyte pyridoxal kinase activity levels did not normalize plasma and erythrocyte pyridoxal-5'-phosphate levels. Pyridoxal-5'-phosphate hydrolysis was not affected by theophylline therapy. Increased pyridoxal oxidation was confirmed by elevated urinary 4-pyridoxic acid excretion after 15 wk of theophylline treatment. Mean erythrocyte alanine aminotransferase activity declined by 70%, and aspartate aminotransferase activity declined by 50%, indicating that decreased availability of pyridoxal-5'-phosphate can have widespread metabolic consequences. We conclude that the effect of theophylline on vitamin B-6 metabolism is not transitory and cannot be overcome by elevated intracellular levels of pyridoxal kinase. However, pyridoxine supplementation (10 mg/d for 1 wk) normalized indices of vitamin B-6 status and reversed the downward trend in both alanine aminotransferase and aspartate aminotransferase activity levels.

Ubbink JB, Vermaak WJ, Delport R, Serfontein WJ, Bartel P. The relationship between vitamin B6 metabolism, asthma, and theophylline therapy. Ann N Y Acad Sci 1990;585:285-294. (Review)

Weinberger M, Ginchansky E. Dose-dependent kinetics of theophylline disposition in asthmatic children. J Pediatr 1977 Nov;91(5):820-824.
Abstract: Prior assumptions of first-order elimination for theophylline were tested by administering theophylline by intravenous infusion at two dosage levels to 20 children with chronic asthma. The resulting steady-state serum concentrations increased to a greater degree than would have been predicted if increases in serum concentration were proportional to changes in dose, and the subsequent calculation of clearance revealed values of 1.37 +/- 0.09 ml/kg/minute (mean +/- SE of the mean) at the lower infusion rate and of 1.21 +/- 0.06 ml/kg/minute at the higher infusion rate (p less than 0.02). Even greater differences in clearance were present among ten of these children whose higher infusion rates were at least two times greater than the lower rate. An additional child was observed who experienced a seizure following a medication error that resulted in a 50% increase in daily dosage and a greater than threefold increase of serum concentration. The nonlinear nature of the relationship between dose and serum concentration suggests that theophylline dosage adjustment should be performed cautiously using small increments.

Weir MR, Keniston RC, Enriquez JI, McNamee GA. Depression of vitamin B6 levels due to theophylline. Ann Allergy 1990 Jul;65(1):59-62.
Abstract: Theophylline overdosage can cause life-threatening symptoms, that include seizures and cardiac arrhythmias, and can be fatal. Neither the onset of toxicity nor the severity of symptoms is well predicted by serum theophylline concentrations. Since depressed vitamin B6 plasma levels can occur in patients receiving theophylline, we explored a B6-theophylline interaction in a rabbit model. Administration of theophylline preparations intraperitoneally (aminophylline) or orally (sustained release anhydrous theophylline) resulted in a 47% depression of plasma pyridoxal 5'-phosphate (PLP) levels. The 87% increase in PLP with pyridoxine administration was only 18% when aminophylline was also given. The mechanism of the theophylline-B6 interaction is obscure. Ethylenediamine in some theophylline preparations binds directly to PLP, potentially increasing the less direct theophylline effect. Pyridoxine supplementation resulted in higher average PLP levels but did not prevent death in animals with profoundly low PLP levels. If these data apply to humans, B6 deficiency may contribute to chronic theophylline toxicity; however, pyridoxine administration in the dosage used may not prevent toxicity. Larger doses may prove beneficial after further investigation.