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EC number: 200-385-7 | CAS number: 58-55-9
Endpoint summary
Administrative data
Link to relevant study record(s)
Description of key information
Key value for chemical safety assessment
Additional information
Kinetics and metabolism of theophylline in animals have been reviewed by IARC (1991). Theophylline is rapidly and completely absorbed from the digestive tract and distributed to all organs of rats except adipose tissue. The substance readily crosses the placenta and no blood-brain barrier was observed in fetal rats. Plasma half-life is between 1.2 - 4 hours in rats and 6 - 11.5 hours in dogs and strongly dependent on protein binding and dose. Theophylline is metabolized in the liver, mainly by the microsomal system. The metabolites are excreted into the bile and eliminated with the urine.
Theophylline is metabolized similarly in animals and man and the same main metabolites are produced, though there are some quantitative differences between species.
The metabolism and pharmacokinetics of theophylline in humans have also been reviewed by IARC (1991). In humans (see Chapter 7.10.3), theophylline is readily absorbed after oral intake and distributed in the different body tissues and breast milk. Theophylline is metabolized in the liver and excreted by the kidney. Only 7 - 12 % is excreted unchanged in the urine. Major metabolites are 1,3 -dimethyluric acid (35 - 55 %), 1 -methyluric acid (13 -26 %) and 3 methylxanthine (9 - 18 %). The elimination half-time is 3 - 11 hours in adults.
The absorbed fraction of a dose of approx. 7.5 mg/kg bw averaged 99 % (Hendeles et al. 1977, Am. J. Hosp. Pharm., 34, 525 -527). Absorption rate and absorbed amount can be altered by food intake (Welling et al. 1975, Clin. Pharmacol. Ther., 17, 475-480). Peak serum levels were reached within 0.5 - 2 hours (Hendeles et al. 1977, Ogilvie 1978, Clin. Pharmacokinet., 3, 267-293).
About 50% of theophylline is bound reversibly to plasma proteins (Aranda et al.1976, New Engl. J. Med., 295, 413-416; Ogilvie R.I. 1978, Clin.Pharmacokinetics 3, 267-293). Theophylline is distributed in erythrocytes (Mitenko and Ogilvie 1973, Clin. Pharmacol. Ther. 14, 509-513; cited in: Ogilvie RI., Clin. Pharmacokinetics 3, 267-293, 1978), saliva (Culig et al. 1982, Br. J. Clin. Pharmac. 13, 243 -245) and breast milk (Yurchak, A.M. and Jusko, W .J., 1976, Pediatrics 57, 518 -525), and can cross the placenta (Arwood, L.L. et al. 1979, Pediatrics 63, 844 -846) and the blood-brain barrier (Kadlec, G.J. et al. 1978, Ann. Allergy 41, 337 -339). The apparent volumes of distribution averages 0.5 L/kg bw (Ogilvie 1978, Aranda et al, 1976).
The elimination half-time is 3 -11 hours in adults (Jenne et al. 1972, Clin. Pharmacol. Ther.,13, 349 -360; Hunt et al. 1976, Clin. pharmacol. Ther., 19, 546 -551; Chrzanowski et al.1977, Clin. pharmacol. Ther., 22, 188-195). Elimination half-time is shorter in smokers and is prolonged by the use of oral contraceptives (Jenne, J.W. et al., 1975, Life Sci. 17, 195 -198; Hunt, S.N. et al. 1976, Clin. Pharmacol. Ther. 19, 546 -551; Tornatore et al, 1982, Eur. J. clin. Pharmacol., 23, 129-134; Roberts et al, 1983, J. Lab. clin. Med., 101, 821-825).
Theophylline is metabolized by ring oxidation and N-demethylation mediated by microsomal enzymes (cytochrome P-450) in the liver and is excreted by the kidney. Major metabolites are 1,3-dimethyluric acid (35-55 %), 1-methyluric acid (13-26 %) and 3 -methylxanthine (9 -18 %). Only 7 -12 % is excreted unchanged in the urine (Lesko L.J. 1986, J. Allergy clin. Immunol., 78, 723 -727; Tang-Liu and Riegelman 1981, Res. Commun. chem. Pathol. Pharmacol., 34, 371-380, Birkett et al. 1985, Drug Metab. Disposition, 13, 725-728).
Dose-dependent pharmacokinetics are seen with plasma concentrations greater than 15 μg/ml (Weinberger and Ginchansky, 1977, J. Pediatr., 91, 820-824). Nonlinearity may be due to metabolic saturation of hepatic metabolism and changes in the renal clearance (Lesko 1986).
In neonates, methylation into caffeine is the predominant metabolic pathway (Bory et al. 1979, J. Pediatr., 94, 988-993). Methylation occurs also in adults (Tang-Liu and Riegelman 1981).
Elimination is modified by diet. High protein diet resulted in enhanced elimination (Feldman et al. 1980, Pediatrics, 66, 956-962; Anderson et al. 1979, Clin. pharmacol. Ther., 26, 493-501). Studies in twins showed large interindividual variations (Miller et al. 1985, J. Clin. Invest ., 75, 1415-1425).
The major pharmacological effects of theophylline are stimulation for cardiac muscle and CNS, relaxation of smooth muscle, especially bronchial muscle, vasodilator and act on the kidney as a diuretic (Cooling 1993, J. Emerg. Med., 11, 415 -425).
The proposed mechanisms of xanthine - induced physiologic and pharmacological effects have included inhibition of phosphodiesterases, thereby increasing intracellular cyclic AMP, direct effects on intracellular calcium concentration, indirect effects on intracellular calcium concentrations via cell membrane hyperpolarization, uncoupling of intracellular calcium increases with muscle contractile elements, and antagonism of adenosine receptors (Berardi 1996, Int. J. Immunopathol. Pharmacol. 9 , 29 -32; Sperelakis 1992, in: Acosta (ed.): Cardiovascular Toxicology, Raven Press, New York, pp 283 -338; Knutsen et al. 1994, Scand. J. Clin. Lab. Invest. 54, 119 -125); all cited in: NTP TR 473, 1998, PB99 -11334 2. For most pharmacological effects adenosine receptor antagonism is suggested as the most important factor.
Some of the adverse effects associated with theophylline appear to be mediated by inhibition of Phosphodiesterase III (e.g. hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g. alterations in cerebral blood flow) (OECD SIDS 2004).
The pharmacokinetics of theophylline varies widely among similar patients and cannot be predicted by sex, body weight, or other demographic characteristics. In general, pharmacokinetic characteristics of theophylline correlate poorly with the ingested dose, and are dependent on factors like age, bioavailability, certain concurrent illnesses, alterations in normal physiology, smoking habits and co-administration of other drugs (Helliwell and Berry 1979, Br. Med. J., II, 1114). Thereby, theophylline interacts with a wide variety of other drugs.
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