The Contribution of cocoa additive to cigarette smoking addiction

RIVM report 650270002 Page 15 of 207
Theobromine
After oral intake, theobromine is evenly distributed in body fluids and has been
reported to pass into the breast milk of nursing mothers. The apparent volumes of
distribution and clearance were estimated to be 0.76 l/kg bw and 0.88 ml/min/kg body
weight, respectively (4). The plasma clearance of theobromine is known to be
enhanced in cigarette smokers (21).
Theobromine has a low protein binding capacity in both serum (15 – 21 %) and breast
milk (12 %) (4).
Animal
Transport across the placental membrane into the fetus has been identified for
theobromine in rats (9). Furthermore, the disposition of theobromine in the fetal rat
brain is reported at single doses of 5 or 25 mg/kg caffeine. Unlike the adult, the fetal
rat brain accumulates theobromine when exposed to caffeine doses comparable to
those attainable by normal human consumption (22).
Theobromine was identified in the brain of mice after chronic ingestion of caffeine
(23).
Metabolism
The major metabolite of theobromine in human urine is 7-methylxanthine (34 – 48
%), followed by 3-methylxanthine (20 %) and 7-methyluric acid (7 – 12 %), 6-amino-
5-[N-methylformylamino]-1-methyluracil (6 – 9 %) and 3,7-dimethuluric acid (1 %)
(4). Cytochrome P450 monoxygenase is an enzyme involved in the metabolism of
theobromine (9).
A week of daily theobromine consumption in the form of dark chocolate did not alter
the elimination kinetics or metabolic pattern of theobromine (12).
Excretion
Of the dose in humans, 1 – 18 % is recovered in the urine as unchanged theobromine
(4).
Kinetic parameters
The half-times in plasma and saliva are highly correlated. The mean half-time of
theobromine in human serum ranged from 6.1 to 10 h (4).
In man the disposition of theobromine follows first order kinetics (9).
Critical assessment
Orally, theobromine is readily absorbed and widely distributed in tissues, including
brain. Transplacental transport in rats and human was reported and theobromine was
identified in fetal rat brain. There are no data on pharmacokinetics in animals and
humans from respiratory studies.
Conclusion
Conclusions on potential differences in kinetics between respiratory and oral
administration can neither be drawn based on the pharmacogical and toxicological
data.
TOXICOLOGY
Acute toxicity
Human
Oral human dose of 26 mg/kg bw (TDLo, LOAEL) showed central nervous system