The Contribution of cocoa additive to cigarette smoking addiction

RIVM report 650270002 Page 37 of 207
Caffeine
administered immediately after ACM. However, the hepatotoxicity was increased
when it was given before ACM. It is proposed that caffeine interferes with the
metabolism of ACM when administered concomitantly, but induces the microsomal
mixed function oxidase system when used in a pre-treatment regimen, leading to a
more rapid rate of formation of the hepatotoxic arylating ACM biotransformation
product (41).
From the course of the plasma concentration of theophylline, a prolonged half-time of
7.4 to 10.4 h as well as a reduction of the total clearance of 0.71 to 0.37 mL/min/kg
was observed if caffeine and theophylline are administered at the same time. As both
methylxanthines have the same localization of metabolization in the microsomal
enzyme system of the liver a competition by caffeine may be the cause of the delayed
theophylline metabolization. During treatment with theophylline the daily caffeine
consumption should be taken into consideration (42).
The effects of the widely consumed drugs caffeine and phenylpropanolamine are
mediated through activation of the central and sympathetic nervous systems. Greater
increases in both systolic and diastolic blood pressures occurred after the combination
than after either drug alone. Because caffeine levels can be increased greatly when
certain other drugs are co-consumed, these data indicate that phenylpropanolamine
may enhance absorption or inhibit elimination of caffeine and may explain increased
side effects reported after their combined use (43).
The influence of multiple doses of ciprofloxacin on the disposition of caffeine and its
major metabolite, paraxanthine, was investigated in healthy volunteers. Ciprofloxacin
increases the half-life of caffeine and the area under the caffeine concentration-time
curve by reducing total body clearance. This interaction is due at least in part to a
delay in the conversion of caffeine to paraxanthine. Also, caffeine may alter the
kinetics of ciprofloxacin (44).
Grapefruit juice inhibits the biotransformation of several drugs, including caffeine
(23% clearance reduction), which is metabolised by the cytochrome P450 isoform
CYP1A2 (45).
Carbamazepine (CBZ) interacts with the adenosine receptor, which is related to the
inhibition of release of neurotransmitter. The anticonvulsive and sedative effects of
CBZ and its derivates appear due to action on adenosine receptors (A1 and partially
A2) at the therapeutic level, while the methylxanthines, like caffeine have stimulant
and convulsant effects due to occupation on both A1 and A2 adenosine receptors
(46).
In mice chronically administered caffeine decreased the ED50 for morphine-induced
analgesia significantly while the naloxone ED50 for withdrawal jumping was
increased by 2-fold after both types of morphine pre-treatment. Chronic
administration of caffeine increases the potency of acutely administered morphine
and reduces the development of morphine-induced tolerance and dependence. These
effects of caffeine may be independent of adenosine receptor interaction (47).
The interactive effects of caffeine in coffee and cigarette smoking were studied in 15
subjects. Subjective arousal showed antagonistic interaction between caffeine and