1. Chemical and Physical Data

1.2. Structural and molecular formulae and molecular weight

2. Production, Use, Occurrence and Analysis

3. Biological Data Relevant to the Evaluation of Carcinogenic Risk to Humans

3.2. Other relevant data

(a) Experimental systems

(i) Absorption, distribution, metabolism and excretion

The metabolism and pharmacokinetics of theophylline have been reviewed (Arnaud, 1984).

Theophylline was rapidly and completely absorbed from the digestive tract of dogs (McKiernan et al., 1981; Tse & Szeto, 1982). Large variations in its bioavailability were reported in pigs (Koritz et al., 1981) while complete bioavailability was found in cats and rats (Arnaud et al., 1982; McKiernan et al., 1983).

Transport of theophylline from blood to the intestinal lumen was demonstrated in rats (Arimori & Nakano, 1985). After intravenous administration, theophylline was distributed to all organs of rats except adipose tissue (Shum & Jusko, 1984). Whole-body autoradiographs showed no accumulation of radioactivity in any specific tissue 24 h after oral administration of [8–¹⁴C]theophylline to rats. By 1 h after oral administration, theophylline had crossed the placenta and was distributed among the organs of fetuses and of pregnant rats, except for the brain of adults. Low theophylline concentrations were found in fetal brain; no blood-brain barrier was observed (Arnaud et al., 1982). Similar results were found after intravenous administration to rats (Gabrielsson et al., 1984). In rabbits, transplacental transfer of theophylline from maternal to fetal circulation occurred within less than 1 h (Brashear et al., 1982).

Mean serum protein binding of theophylline was lower in dogs (10%) than in man (60%) and rabbits (74%) (Brashear et al., 1980; May & Jarboe, 1981; Munsiff et al., 1988a), and less was bound in pregnant rats [6%] than in non-pregnant rats [20%] (Ramzan & DeDonato, 1988). Similarly, a significant increase in the half-time of theophylline was found in pregnant as compared to non-pregnant rabbits (Brashear et al., 1982) and rats (Brandstetter et al., 1986). The half-time in newborn rabbits was approximately 15 times longer than that in adult animals (Brashear et al., 1982).

Theophylline is distributed rapidly within the body, and plasma half-times were 5.7–11.5 h in dogs (Barnhart & Combes, 1974; McKiernan et al., 1981), 11 h in pigs (Koritz et al., 1981), 7.8 h in cats (McKiernan et al., 1983), 3.8–5.5 h in rabbits (Ng & Locock, 1979; May & Jarboe, 1981) and 1.2–4 h in rats. At higher doses (52–115 mg/kg bw), rats had longer half-times probably because of a combination of increased diuresis and saturation of the metabolism (Teunissen et al., 1985).

Linear pharmacokinetics apply in rats only with intra-arterial doses not exceeding 10 mg/kg bw (Teunissen et al., 1985); similar results were obtained in guinea-pigs (Madsen & Ribel, 1981a,b). In rabbits, there was no evidence of concentration-dependent clearance of theophylline at 15, 22.5 and 30 mg/kg bw (El-Yazigi & Sawchuk, 1981). The clearance and disposition were unchanged in rats with dietary induced obesity (Shum & Jusko 1984).

Theophylline is metabolized only in the liver, mainly by the microsomal system (Lohmann & Miech, 1976; McManus et al., 1988). In rats, oral doses of 40 mg/kg bw per day for three days did not induce liver microsomal enzyme activity, as measured by aromatic ring hydroxylation of acetanilide (Mitoma et al., 1968), while doses of 75–150 mg did.

The pathways of theophylline metabolism reported in rats are presented in Figure 1. Unchanged theophylline (35% of urinary radioactivity) and 1,3-dimethyluric acid (34%) are the main compounds excreted in urine, followed by 1-methyluric acid (18%), 3-methylxanthine (3%) and unidentified polar metabolites (4.8%). Theophylline metabolism was impaired in rats at day 18 of gestation, as shown by increased excretion of theophylline (73%); this was explained by a decreased formation of 1,3-dimethyluric acid (−68%) and 1-methyluric acid (−30%) (Arnaud et al., 1982). Essentially similar results were obtained with pregnant baboons (Logan et al., 1983). Each animal species is characterized by differences in the profile of the metabolites recovered in urine; in addition, quantitative differences in theophylline metabolic pathways were seen even in different strains of mice (Betlach & Tozer, 1980).

Fig. 1.

Metabolism of theophylline

Experiments in hepatectomized dogs have shown that the liver plays a central role in theophylline elimination (Brashear et al., 1980). Theophylline and its metabolites are excreted into the bile; in rats, 0.2% (Arimori & Nakano, 1985) and in dogs, 2–4% (Barnhart & Combes, 1974) of the dose was recovered.

(ii) Toxic effects

The acute intraperitoneal LD₅₀ of theophylline in rats was reported to be 206 mg/kg bw, and accompanying clinical signs were delayed convulsions and tetanic spasm. Acute studies in mice showed an oral LD₅₀ of 332 mg/kg bw and an intraperitoneal LD₅₀ of 217 mg/kg bw; clinical signs included convulsions, profuse salivation and emesis (Tarka, 1982).

A single oral dose of 400 mg/kg bw theophylline was acutely toxic to rats and mice. Administration of the same daily dose as two separate doses of 200 mg/kg bw was acutely toxic to rats but not to mice (Lindamood et al., 1988). In dogs, the minimal oral toxic concentration of theophylline appears to be higher (37–60 µg/ml plasma) than in man (> 20 µg/ml) (Munsiff et al., 1988b). Theophylline has been reported to be more toxic than caffeine or theobromine to the heart, bronchi and kidneys (Tarka, 1982).

Two weeks’ feeding 800 ppm (mg/kg) theophylline in the diet to rats induced no significant toxicity except for dose-related uterus hypoplasia (Lindamood et al., 1988).

(iii) Effects on reproduction and prenatal toxicity

Reproductive toxicity: Feeding theophylline to immature (five to six weeks old) Osborne-Mendel rats at 0.5% in the diet [approximately 300 mg/kg bw per day] for 75 weeks produced severe testicular atrophy in 50% of animals, oligo-spermatogenesis and aspermatogenesis. These results were confirmed in Holtzman rats fed 0.5% theophylline for 19 weeks: 86% showed testicular atrophy (Friedman et al., 1979).

In 13-week toxicity studies, weanling B6C3F₁ mice and Fischer 344 rats were administered theophylline by gavage or in the diet. Gavage with 300 mg/kg bw per day led to a slight but significant decrease in testicular weight in mice, but 150 mg/kg bw or less had no effect. In rats, a significant decrease in testicular weight was observed after gavage with 150 mg/kg bw per day but not with 75 mg/kg bw or less. No effect on sperm motility, sperm density or the number of abnormal sperm was observed in male rats or mice, and no effect was seen on the mean length of the oestrous cycle in females. Daily administration of 184–793 mg/kg bw theophylline in the diet to mice had no effect on sperm, whereas abnormal sperm were seen in rats given 258 mg/kg in the diet but not at lower doses (Morrissey et al., 1988).

In a reproductive study, Swiss CD-1 mice were administered 0.075, 0.15 or 0.30% theophylline in the diet (average daily doses, 125, 265 or 530 mg/kg bw) for one week before mating and during 13 weeks of cohabitation. Litters were removed one day after birth, except for the last litter which was raised to 21 days of age. Among all treated groups, there was a dose-related decrease in the number of live pups per litter; in the high-dose groups, there was a significant decrease in the number of litters per breeding pair and a significant decrease in live pup weight. In the high- and mid-dose groups, a significant decrease in the percentage of pups born alive was observed. Only mild toxicity was observed in adults at these doses. In a cross-over mating trial at the end of a 19-week exposure to 0.3% theophylline, animals of each sex were found to be affected, although females were more severely affected than males. The decrease in reproductive capacity was considered by the authors to be related partially to embryotoxicity (Morrissey et al., 1988).

Developmental toxicity. IRC-JCL mice received a single intraperitoneal injection of 175, 200 or 225 mg/kg bw theophylline on day 12 of gestation. Subsequently, 40% of dams in the high-dose group died, and dyspnoea and convulsions were observed in those in the low- and mid-dose groups. Fetal body weight was decreased with the high and medium doses, and the incidence of resorptions was significantly increased with the high dose. Malformations were observed in all treated groups; these included cleft palate, digital defects and macrognathia. Subcutaneous haematomas were also seen (Fujii & Nishimura, 1969).

ICR mice received an intraperitoneal injection of 100, 150 or 200 mg/kg bw theophylline on one of gestation days 10–13. A dose-related increase in the incidence of resorptions and malformations — mostly cleft palate — was observed, with a peak embryotoxic response in fetuses treated on day 11 (Tucci & Skalko, 1978).

Sprague-Dawley rats were fed theophylline in the diet (average daily dose, 124, 218 or 259 mg/kg bw) on days 6–15 of gestation. In parallel, Swiss CD-1 mice received theophylline in the drinking-water (daily doses, 282, 372 or 396 mg/kg bw) on the same gestation days. Slight maternal toxicity (decreased weight gain) was observed in high-dose rats and in mid- and high-dose mice. In rats, fetal body weight was significantly decreased with the medium and high doses, and live litter size was decreased with the high dose; no malformation was observed. In mice, fetal body weight was significantly decreased in the mid- and high-dose groups, and the incidence of resorptions was increased in the mid-dose group (Lindström et al., 1990).

(iv) Genetic and related effects

The genetic effects of theophylline have been reviewed (Timson, 1975). Additional information on theophylline is included in reviews by Timson (1977) and Tarka (1982).

The results described below are listed in Table 1 on p. 403, with the evaluation of the Working Group, as positive, negative or inconclusive, as defined in the footnotes. The results are tabulated separately for the presence and absence of an exogenous metabolic sytem. The lowest effective dose (LED), in the case of positive results, or the highest ineffective dose (HID), in the case of negative results, are shown, together with the appropriate reference. The studies are summarized briefly below.

Table 1.

Genetic and related effects of theophylline.

As reported in an abstract, theophylline at 3.2 mM displaced 50% of intercalated acridine orange from DNA in vitro (Richardson et al., 1981). In extracts of Escherichia coli, theophylline selectively inhibited some purine nucleoside phosphorylases (Koch & Lamont, 1956). In E. coli, which may not demethylate the drug, theophylline was not incorporated to ‘any great extent’ into DNA (Koch, 1956) and, unlike other inhibitors of DNA synthesis, had little or no effect on λ, prophage induction (Noack & Klaus, 1972). The effects of theophylline on relevant targets other than DNA are discussed in the monograph on caffeine (p. 332).

Theophylline gave negative results in the Bacillus subtilis rec assay [details not given]. It was mutagenic to E. coli chemostat cultures (Novick & Szilard, 1951; Novick, 1956), and this activity could be inhibited by guanosine (Novick & Szilard, 1952). It was also mutagenic to E. coli and in the B. subtilis multigene sporulation test, but not to Salmonella typhimurium.

In Saccharomyces cerevisiae, theophylline promoted sporulation in glucose-containing medium, where it increased the intracellular cAMP level. It had no effect on DNA, RNA or protein synthesis or in medium in which glucose was replaced by potassium acetate (Tsuboi & Yanagishima, 1975).

Theophylline induced mutation in Ophiostoma multiannulatum and Euglena gracilis. It induced chromosomal fragment formation and translocations in Allium cepa root tips, but no chromosomal aberration in Vicia faba root tips.

Theophylline was reported in an abstract to induce aneuploidy in Drosophila melanogaster (Mittler & Mittler, 1968).

Doses of theophylline greater than 0.3 mg/ml inhibited DNA synthesis in mouse L5178Y lymphoma cells, LS929 mouse fibroblasts and V79 Chinese hamster cells. Theophylline slightly reduced the size of newly synthesized DNA in both unirradiated and ultraviolet-irradiated cells and reversibly inhibited the DNA gap-filling process in ultraviolet-damaged cells (Lehmann, 1973, abstract; Lehmann & Kirk-Bell, 1974). Theophylline also inhibited DNA synthesis in human fibroblastoid EUE cells, and the shape of the dose-response curves and the absence of theophylline-induced DNA strand breaks indicated that theophylline does not directly damage the DNA but acts as a metabolic inhibitor (Slameňová et al., 1986). The results of a study with synchronized HeLa S3 cells exposed to theophylline indicate that the block in DNA replication results from inhibition of histone 1 phosphorylation, which prevents the normal release of chromatin structure between G₁ and S phases (Dolby et al., 1981).

The incidence of 6-thioguanine-resistant mutants in V79 cells was not increased by theophylline.

In the pseudodiploid Chinese hamster cell line, Don-6, theophylline induced a dose-related increase in sister chromatid exchange but did not induce micronuclei. It induced sister chromatid exchange in hamster lung fibroblasts in vitro [details not given]. The induction of sister chromatid exchange is not necessarily due to a directly damaging effect upon DNA, since theophylline can inhibit poly-(ADP-ribose)polymerase (Levi et al., 1978). This activity is associated with the induction of sister chromatid exchange (Morgan & Cleaver, 1982) and may even give rise to false-positive effects, the primary effect upon DNA being due to bromodeoxyuridine (Natarajan et al., 1981).

Theophylline induced sister chromatid exchange in human cells in vitro. Studies on the induction of chromosomal aberrations in human and mammalian cells is equivocal. The apparent lack of mutagenic activity of theophylline may be due to the antimitotic threshold being the same as the mutagenic threshold, so that any mutant cells produced are unable to reproduce (Timson, 1972).

Butcher and Sutherland (1962) reported that theophylline is the most potent naturally occurring phosphodiesterase inhibitor. Inhibition of cyclic 3′,5′-nucleotide phosphodiesterase from beef heart by theophylline is apparently competitive, with a K_i in the order of 0.1 mM. Since theophylline in combination with increasing concentrations of cAMP (up to 500 µg/ml) had no clastogenic effect, Weinstein et al. (1973) argued that inhibition of phosphodiesterase is not involved in clastogenicity in human lymphocytes in culture.

In Chinese hamster ovary CHO-R1 cells, theophylline reduced the expression of parameters associated with transformation, causing an increase in surface fibronectin, cell-substratum adhesive strength and anchorage dependence for growth and a reduction in cell population saturation density (Rajaraman & Faulkner, 1984).

Theophylline inhibited mitosis of mouse ear epidermal cells in the G₂ phase (Marks & Rebien, 1972). In the host-mediated assay with S. typhimurium (G46, nonsense mutation) in Swiss albino mice, theophylline gave negative results. It induced sister chromatid exchange in Chinese hamsters, but did not cause chromosomal aberrations in rat bone marrow in vivo (Renner, 1982). Theophylline did not induce dominant lethal mutations in male Swiss CD-1 mice.

(b) Humans

(i) Absorption, distribution, metabolism and excretion

The metabolism and pharmacokinetics of theophylline in humans have been reviewed (Haley, 1983b; Mungali, 1983; Arnaud, 1984; Stavric, 1988).

Theophylline is readily absorbed after an oral dose. The absorbed fraction of a dose of 7.5 mg/kg bw averaged 99% (Hendeles et al., 1977); however, the absorption of oral theophylline can be delayed by food (Welling et al., 1975; Heimann et al., 1982). Ageing had no effect on the rate or extent of absorption (Cusack et al., 1980; Shin et al., 1988). Peak serum levels are generally achieved within 1.5–2 h (Hendeles et al., 1977; Ogilvie, 1978).

At 17 µg/ml, 56% of theophylline was bound reversibly to adult plasma proteins compared to ~36% in cord plasma proteins from full-term infants (Aranda et al., 1976; Ogilvie, 1978). Protein binding was also reduced to 11–13% during the last two trimesters of pregnancy (Frederiksen et al., 1986). Theophylline is not accumulated in specific target organs: it was distributed in erythrocytes (Ogilvie, 1978), saliva (Culig et al., 1982) and breast milk (milk:serum concentration ratio, 0.70; Yurchak & Jusko, 1976), but not extensively in adipose tissue (Rohrbaugh et al., 1982). Theophylline also passed into the amniotic fluid (Sommer et al., 1975; Arwood et al., 1979; Labovitz & Spector, 1982). The presence of a blood-brain barrier reduces theophylline concentrations in the brain, and a cerebrospinal fluid:plasma ratio of 0.68 was reported (Kadlec et al., 1978).

The elimination half-time of theophylline was 15–60 h in premature infants for at least the first two to four weeks postpartum compared to 3.4 h in children aged one to four years (Aranda et al., 1976), while the corresponding values for adults exhibited large variations, between 3 and 11 h (Jenne et al., 1972; Hunt et al., 1976; Chrzanowski et al., 1977). Theophylline clearance increased by 10% per year over the age range 1–15 years (Driscoll et al., 1989). In subjects over 60 years, half-times of 5.4–9.0 h were reported (Nielsen-Kudsk et al., 1978; Fox et al., 1983).

The half-times were decreased from 7 h in nonsmokers to 4 h in smokers, possibly due to induction of theophylline metabolizing enzymes (Jenne et al., 1975; Hunt et al., 1976). Use of oral contraceptives lowered total plasma clearance and prolonged the half-time of theophylline (9–10 h versus 6–7 h), with no change in plasma binding or volume of distribution (Tornatore et al., 1982; Roberts et al., 1983). Cirrhotic patients and patients with acute pulmonary oedema have a prolonged half-time of theophylline (between 23 and 26 h) and decreased plasma clearance (Piafsky et al., 1977a,b; Staib et al., 1980). Plasma binding is also reduced in cirrhotic patients (37% versus 53% in normal subjects) (Piafsky et al., 1977a). The half-time of theophylline was prolonged significantly during exercise (Schlaeffer et al., 1984).

The apparent volumes of distribution of theophylline ranged from 0.44 to 0.51 l/kg bw in adults and children (Ogilvie, 1978), but a value of 0.69 was found in premature newborns (Aranda et al., 1976). The distribution volume and elimination half-time of theophylline were increased in the third trimester of pregnancy (Frederiksen et al., 1986).

Disproportionate increases and decreases in serum theophylline concentrations with changes in oral dosage in adults suggest that the rate of elimination is dose-dependent (Jenne et al., 1972; Ogilvie, 1978; Tang-Liu et al., 1982a). Several studies showed that linear pharmacokinetics is a valid model within the therapeutic range (Mungali et al., 1982; Rovei et al., 1982; Brown et al., 1983). Dose-dependent pharmacokinetics seem to be more frequent in children and in some individual adult patients and are generally seen with plasma theophylline concentrations greater than 15 µg/ml (Weinberger & Ginchansky, 1977). Nonlinearity may be due to metabolic saturation or to the diuretic effect of theophylline (Lesko, 1979, 1986; Tang-Liu et al., 1982b). There is also an age-dependent variation in the elimination of theophylline (Jusko et al., 1979).

Experiments with human liver microsomes showed the involvement of at least two cytochrome P450 isozymes in the metabolism of theophylline (Robson et al., 1988). The pathways were presented in Figure 1.

Only 7–12% of theophylline is excreted unchanged in the urine, while several parallel pathways produced 9–18% 3-methylxanthine, 0.3–4% 1-methylxanthine, traces of 3-methyluric acid, 13–26% 1-methyluric acid and the main metabolite, 1,3-dimethyluric acid, at 35–55% (Arnaud, 1984; Birkett et al., 1985). Allopurinol, a xanthine oxidase inhibitor, increased 1-methylxanthine excretion and decreased 1-methyluric acid excretion, demonstrating that the conversion is mediated by xanthine oxidase (Grygiel et al., 1979). Methylation of theophylline into caffeine is the predominant metabolic pathway in neonates because the other enzymatic systems are immature (Bory et al., 1979). Methylation occurs to some extent in adults, but caffeine does not accumulate because it is metabolized further (Tang-Liu & Riegelman, 1981). Patients with decompensated liver cirrhosis have different patterns of urinary metabolites of theophylline than healthy subjects (Staib et al., 1980).

Dietary factors have been shown to modify the elimination of theophylline in children (Feldman et al., 1980) and adults (Anderson et al., 1979). A high protein diet and diets containing charcoal-broiled beef resulted in accelerated elimination of theophylline (Kappas et al., 1978; Feldman et al., 1980). Serum theophylline levels follow a circadian rhythm (for review, see Smolensky & McGovern, 1985), but these effects are less pronounced than interindividual variations (Straughn et al., 1984).

Studies of twins demonstrated that the large interindividual variations in theophylline elimination observed in human subjects are predominantly under genetic control (Miller et al., 1985).

(ii) Toxic effects

The toxicology of theophylline has been reviewed (Ellis, 1983; Haley, 1983a,b; Bukowskyj et al., 1984; Stavric, 1988).

Toxicity can be produced easily owing to its narrow therapeutic index (Labovitz & Spector, 1982; Greenberg et al., 1984; Singer & Kolischenko, 1985). A small percentage of patients taking theophylline therapeutically to control asthma may develop toxicity at serum levels of 20–30 µg/ml. These effects are generally not seen at levels below 15 µg/ml (Stavric, 1988).

Administration of theophylline to premature babies in the preterm period caused sleep disturbances that persisted after the drug had been cleared from the body (Thoman et al., 1985). In a study on long-term effects of theophylline administration in the preterm period, no difference was found at one or two years of age as a function of drug treatment (Nelson et al., 1980). The question of whether theophylline affects learning ability in children remains open (Stavric, 1988).

‘Mild’ toxicity may include headache, gastrointestinal disturbances, hypotension, irritability and insomnia. Symptoms of ‘severe toxicity’ include tachycardia, arrhythmia, cardiac arrest and serious neurological symptoms. Seizures and death have occurred (Helliwell & Berry, 1979; Winek et al., 1980; Woo et al., 1980; Woodcock et al., 1983; Greenberg et al., 1984; Singer & Kolischenko, 1985; Stavric, 1988).

Studies of a possible association between consumption of methylxanthines and benign breast disease are discussed on pp. 347–350.

(iii) Effects on reproduction and prenatal toxicity

No association was seen between use of bronchodilators (theophylline being one of 11 preparations used) and congenital abnormalities in the offspring (Nelson & Forfar, 1971). This finding was corroborated by a study of 117 women who had used the drug (Heinonen, 1982).

(iv) Genetic and related effects

Lymphocytes from a mother given continuous treatment for asthma with theophylline-containing drugs and from her stillborn triploid child both showed increased frequencies of chromatid breaks (14 and 16%, respectively; Halbrecht et al., 1973). Timson (1975) suggested that theophylline may have been involved in the induction of the chromatid breaks. [The Working Group noted that the medication also contained ephedrine, phenobarbital and diphenylhydramine.]

The apparent lack of mutagenic activity of theophylline and other methylxanthines in man may be due to the fact that the antimitotic threshold is the same as the mutagenic threshold, so that any mutant cells produced are unable to reproduce; the net effect is therefore nonmutagenicity (Timson, 1972).

4. Summary of Data Reported and Evaluation

5. References

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Footnotes

1

For description of the italicized terms, see Preamble, pp. 27–31.