Pathway Theophylline Pathway, Pharmacokinetics

Schematic representation of theophylline metabolism in human liver.
Theophylline Pathway, Pharmacokinetics
theophyline coffeine cyp1a2 cyp2e1 xdh cyp1a2 cyp3a4 xdh cyp1a2 cyp3a4
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Theophylline is a methylxanthine drug used in the treatment of asthma and chronic obstructive pulmonary disease (COPD). Its use in asthma is limited because it has a relatively high rate of side effects and low efficacy compared to inhaled corticosteroids or beta adrenergic agonists, however because it is inexpensive it is still widely used in developing countries [Articles:20298368, 19281096]. It is also used as an add-on treatment for hard-to-control asthma [Article:21799015].

In adults approximately 90% of theophylline is metabolized in the liver [Article:6341027]. Theophylline mainly undergoes 8-hydroxylation to 1,3, dimethyluric acid, 13U, (around 60-80% of parent drug) with N-demethylation to form 1-methylxanthine, 1X (8-24%) and 3-methylxanthine, 3X (5-15%) being the alternative routes [Article:8236273]. A small proportion of theophylline (6%) can be N-methylated to form caffeine [Article:6341027]. While 8-hydroxylation can be carried out by expressed CYP1A2, it is not the only enzyme responsible for this pathway in vivo [Article:8236273]. CYP2E1 can also hydroxylate theophylline and polymorphisms in CYP2E1 can influence this reaction (see below for details)[Article:16841220]. In cells without CYPs, xanthine oxidase (XDH) has been suggested as potentially catalyzing this step [Article:8236273]. Although in vitro experiments failed to show involvement of expressed CYP3A4 in the metabolism of theophylline, inhibition experiments in microsomes and drug-drug interactions with several CYP3A4-interacting drugs suggest a minor role for this candidate gene in the production of 1X and 3X [Articles:8786569, 3367304, 2877015].

The N-demethylation of theophylline is carried out by CYP1A2, and the 1X metabolite is further modified by XDH [Article:8236273]. Studies of healthy volunteers show that changes in theophylline metabolism due to inhibition of XDH by febuxostat, do not change dose requirements or plasma drug levels [Article:22541837]. Though urinary metabolites are predominantly 1-methyluric acid (1U) when treated with theophylline plus placebo, and predominantly 1X when treated with theophylline and febuxostat, neither 1U nor IX have any pharmacological effect so there is no clinical consequence of the interaction [Article:22541837]. The 3X metabolite is active although it has about one-tenth the activity of the parent drug drug label.

Theophylline toxicity can occur when CYP1A2 metabolism is impaired by drug-drug interactions. In elderly patients with COPD treated with theophylline, co-prescription of ciprofloxacin, an inhibitor of CYP1A2, was associated with a two-fold increase in risk of hospitalization compared to those co-treated with other antibiotics or no antibiotics [Article:21234553].
Smoking induces the CYP1A2 enzyme and increases clearance of theophylline [Article:3367304]. Reduction in theophylline clearance have also been reported for women in the third trimester of pregnancy, on birth control, and at the 20th day of the menstrual cycle however these are not always consistent and the mechanism for these observations is unknown but may be related to CYP3A4 and hormone metabolism [Articles:3595701, 2191822, 2276390, 10586391].
Theophylline can be endogenously generated during the metabolism of caffeine, however this is a minor pathway (7-8%) in comparison to the major route of caffeine metabolism to paraxanthine (70-80%)[Article:17221922](see Caffeine Pathway, Pharmacokinetics). Conversion of theophylline to caffeine is also a fairly minor reaction, however in neonates the demethylation routes of inactivation of theophylline are not yet active, and hydroxylation is reduced, therefore there is a risk of caffeine intoxication [Article:6341027].

The mechanisms of action of theophylline are not entirely clear, however there is evidence that bronchodilator effects are via inhibition of phosphodiesterase 3, (PDE3) in airway smooth muscle [Article:21799015]. Minor side effects (such as nausea and diarrhea) occur by inhibition of PDE4 [Article:21799015]. Anti-inflammatory activity may occur by antagonism of ADORA2B on mast cells and prevention of activation of NFKB [Article:21799015]. However, it may also antagonize ADORA1 receptors leading to serious side effects, such as cardiac arrhythmias and seizures [Article:21799015]. Theophylline causes reduction in BCL2 which leads to apoptosis in eosinophils and neutrophils in vitro [Article:15313391]. Theophylline can activate histone deacetylases, in a pathway distinct from its inhibition of PDEs and adenosine receptors (ADORAs), acting synergistically with glucocorticoids in the treatment of inflammatory aspects of asthma [Article:12070353]. Several derivative drugs of theophylline are under development for indications including Parkinsons, rheumatoid arthritis and COPD, that aim to enhance the anti-inflammatory actions while reducing the undesirable effects, particularly in cardiac cells [Article:21185259].

There have been few studies of theophylline pharmacogenetics:
In a study of Turkish patients with COPD, the T allele of rs35694136 (also known as -2467delT or CYP1A2*1D) was associated with decreased metabolism of theophylline [Article:20797314]. Patients with the TT and T/del genotypes at this variant also had significantly more severe disease symptoms than those with the del/del genotype [Article:20797314].

Genotypes AA + AG of rs2069514 (also known as -2964G>A or CYP1A2*1C) in CYP1A2 are associated with decreased metabolism of theophylline in Japanese people with Asthma as compared to genotype GG [Article:12732846]. This relationship was confirmed in a study of Korean patients with Asthma [Article:16841220].

In addition five linked SNPs in the CYP2E1 promoter (-1566 T>A, -1295 G>C (rs2031920), -1055 C>T (rs3813867), -1027 T>C, and -807 T>C) were associated with theophylline metabolism [Article:16841220]. Patients carrying a rare haplotype of CYP2E1 (minor alleles for the five linked promoter SNPs) and the minor allele for CYP1A2 polymorphism rs2069514 (-2964 G>A) showed a lower plasma 13U/theophylline ratio than those with homozygous common alleles [Article:16841220]. Two of these CYP2E1 promoter SNPs are part of the CYP2E1*5B allele and affect HNF1 transcription factor binding, regulating CYP2E1 expression in liver cells [Articles:1979861, 1778977, 7529759].

Authors: Caroline F. Thorn.
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
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Therapeutic Categories:
  • Respiratory agents

Entities in the Pathway

Genes (4)

Drugs/Drug Classes (2)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
1-methylxanthine 1-methyl uric acid XDH 22541837, 8236273
theophylline 1,3-dimethyl uric acid CYP1A2, CYP2E1, XDH 12732846, 16841220, 20797314, 21234553, 8236273
theophylline 1-methylxanthine CYP1A2, CYP3A4 2877015, 3367304, 8236273, 8786569
theophylline 3-methylxanthine CYP1A2, CYP3A4 2877015, 3367304, 8236273, 8786569
theophylline caffeine 17221922, 6341027

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