Collated from TripSit, Pharmacology. Where sources differ (e.g. dosing), Compare shows them side by side.
Theobromine is the principal bitter alkaloid of the cacao bean. It has been used in various pharmaceutical products as vasodilator, diuretic and as heart stimulant. Theobromine is consumed in cocoa, chocolate and in various forms of chocolate-based foods. It is also present in small amounts in green coffee beans, tea, mate and the kola nut.TS
Oral
Route dataTripSit
| Threshold | Light | Common | Strong | Heavy |
|---|---|---|---|---|
| — | 100–200 mg | 200–300 mg | 300–600 mg | 600 mg+ |
| Onset | 2–3 hours |
|---|---|
| Total | 30–40 hours |
🧬 Receptor activityPH
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| Phosphodiesterase 4 | — | Ki 100000 nM | CHEMBL | TargetPhosphodiesterase 4 Action— AffinityKi 100000 nM SourceCHEMBL |
| Adenosine receptor A3 | — | Ki 103000 nM | CHEMBL | TargetAdenosine receptor A3 Action— AffinityKi 103000 nM SourceCHEMBL |
| Adenosine receptor A1 | — | Ki 105000 nM | CHEMBL | TargetAdenosine receptor A1 Action— AffinityKi 105000 nM SourceCHEMBL |
| Adenosine receptor A2a | — | Ki 250000 nM | CHEMBL | TargetAdenosine receptor A2a Action— AffinityKi 250000 nM SourceCHEMBL |
| Adenosine A2 receptor | — | Ki 250000 nM | CHEMBL | TargetAdenosine A2 receptor Action— AffinityKi 250000 nM SourceCHEMBL |
Mechanism of actionPH
Theobromine stimulates medullary, vagal, vasomotor, and respiratory centers, promoting bradycardia, vasoconstriction, and increased respiratory rate. This action was previously believed to be due primarily to increased intracellular cyclic 3′,5′-adenosine monophosphate (cyclic AMP) following inhibition of phosphodiesterase, the enzyme that degrades cyclic AMP. It is now thought that xanthines such as caffeine and theobromine act as antagonist at adenosine-receptors within the plasma membrane of virtually every cell. As adenosine acts as an autocoid, inhibiting the release of neurotransmitters from presynaptic sites but augmenting the actions of norepinephrine or angiotensin, antagonism of adenosine receptors promotes neurotransmitter release. This explains the stimulatory effects of xanthine derivatives such as theobromine and caffeine. Blockade of the adenosine A1 receptor in the heart leads to the accelerated, pronounced "pounding" of the heart upon caffeine intake.
PharmacodynamicsPH
Theobromine, a xanthine derivative like caffeine and the bronchodilator theophylline, is used as a CNS stimulant, mild diuretic, and respiratory stimulant (in neonates with apnea of prematurity).
Pharmacokinetics
Half-lifePH
The mean half-time of theobromine in human serum ranged from 6.1 to 10 hr.
The disposition half-life of theobromine averaged 7.1 +/- 2.1 hours ...
In dogs, an average plasma half-time of 17.5 hr was reported after single oral doses of theobromine ranging from 15 to 150 mg/kg bw. In rabbits, the mean elimination half-time was 4.3-5.6 hr for doses ranging from 1 to 100 mg/kg bw.
AbsorptionPH
The ratio of brain:blood theobromine concentrations decreased continuously from 0.96 at birth to 0.60 in 30-day-old rats. After 24 hr, no organ accumulation of theobromine or its metabolites could be seen in adult animals.
Theobromine is absorbed and distributed rapidly after oral administration to rats and equilibrates freely between plasma and testicular fluid.
Similar kinetic parameters were observed in male and female rabbits when theobromine was administered intravenously or orally at doses of 1 and 5 mg/kg bw, with complete gastrointestinal absorption. A reduction in the absorption rate constant was seen in rabbits when the dose was increased from 10 to 100 mg/kg bw. In spite of delayed gastrointestinal absorption at high doses, probably due to the low solubility of the compound, the absolute bioavailability of theobromine approached 100%. Labelled theobromine was almost completely absorbed after oral administration (1-6 mg/kg); the peak blood level tended to appear later with larger doses.
When theobromine was given as a single oral dose of 15-50 mg/kg bw to male dogs, peak plasma concentrations, with considerable individual variations, were observed within 3 hr. With a higher dose (150 mg/kg bw), the peak plasma concentrations were attained 14-16 hr later, showing delayed intestinal absorption. In rats, plasma protein binding was very low (8-17%) after oral administration of 1-100 mg/kg bw theobromine.
For more Absorption, Distribution and Excretion (Complete) data for 3,7-Dimethylxanthine (17 total), please visit the HSDB record page.
MetabolismPH
Pregnancy and increased doses of theobromine were shown to modify theobromine metabolism. At a dose of 50 mg/kg bw, pregnant rabbits excreted more unchanged theobromine in the urine (51% versus 35%). Pregnant rats excreted a higher percentage of a 5 mg/kg dose as unchanged theobromine (53%) than non-pregnant rats (39%); this difference disappeared at the saturation dose (100 mg/kg), when unchanged theobromine corresponded to about 60% of the dose in the urine of both pregnant and non-pregnant animals. Rats given 100 mg/kg excreted more unchanged theobromine than those given 1 mg/kg (73% versus 51%), and showed a corresponding relative decrease in excretion of its uracil metabolite, 6-amino-5-(N-methylformylamino)-1-methyluracil (16% versus 28%).
The compounds identified in bile of phenobarbital-treated rats were 3,7-dimethyluric acid (64-76% of biliary radioactivity), dimethylallantoin (5-8%), 6-amino-5-(N-methylformylamino)- 1-methyluracil (10-17%) and theobromine (8-10%). In 3-methylcholanthrene-treated rats, urinary elimination of unchanged theobromine was reduced from 23-27% to only 2%, while excretion of 6-amino-5-(N-methylformylamino)-1- methyluracil was significantly increased. Only 3,7-dimethyluric acid was produced by liver microsomal incubation in control rats while phenobarbital and 3-methylcholanthrene pretreatment enhanced the biotransformation resulting in the production of all metabolites found in vivo as well as unknown polar compounds.
6-Amino-5-(N-methylformylamino)-1-methyluracil is quantitatively the most important theobromine metabolite in rats, accounting for 20-35% of urinary metabolites. The majority of theobromine-derived radioactivity in the feces of rats could be accounted for by 3,7-dimethyluric acid. The most extensive metabolism of theobromine was observed in rabbits and mice; male mice converted theobromine more extensively into this metabolite than did female mice. In contrast, oxidation of theobromine to 3,7-dimethyluric acid was significantly greater in female than in male rats. Rabbits and dogs metabolized theobromine primarily to 7-methylxanthine and 3-methylxanthine, respectively, and dogs excreted small quantities of an unidentified metabolite.
As a metabolite of caffeine, theobromine has been detected in variable amounts in plasma and urine of humans and different animal species.
For more Metabolism/Metabolites (Complete) data for 3,7-Dimethylxanthine (11 total), please visit the HSDB record page.
Theobromine has known human metabolites that include 3,7-Dimethyluric acid, 3-Methylxanthine, and 7-Methylxanthine.
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