The influence of structure on the accumulation of caffeine induced by methyl xanthine derivatives.

In rats given caffeine (25 mg kg-1 p.o.) and 1,3,8-trisubstituted xanthine (1,3,8-TSX) derivatives (10 mg kg-1 p.o.) the accumulation of the former in plasma was 300% higher than that in control animals given caffeine alone. The effect on caffeine accumulation appears to be independent of the nature of the N3 substituent and its absence in rats given 1,3-disubstituted xanthines (1,3-DSX) instead of 1,3,8-TSX suggests that the presence of the C8-methyl group in the latter compounds is responsible for the accumulation phenomenon. The results of our previous work imply that these observations in this rat model can be extrapolated to man.

An animal model for the detection of drug-induced inhibition of caffeine metabolism.

Plasma levels of caffeine are increased more than 400% in rats given furafylline (10 mg kg-1 p.o.) and caffeine (25 mg kg-1 p.o.) as compared to rats given caffeine alone. In rats given idrocilamide (100 mg kg-1 p.o.) and caffeine (25 mg kg-1 p.o.) accumulation of xanthine is higher than 600%. The chromatographic separation and analysis of plasma extracts indicates that the N3-demethylation pathway is inhibited. Since furafylline and idrocilamide have been shown to increase blood levels of caffeine by the same mechanisms in humans and to give rise to adverse reactions, the rat would appear to be a suitable model to detect and study the inhibition of the metabolism of caffeine by such drugs and could be usefully included in the usual series of drug interaction studies done routinely during drug development.

Accumulation of caffeine in healthy volunteers treated with furafylline.

The pharmacokinetics and tolerance of repeated oral doses of furafylline were investigated in normal volunteers. In accord with predictions from single dose studies, steady state was achieved on the first day following the administration of 90 mg and maintained by subsequent daily doses of 30 mg. When corrected for body weight there were no significant differences in minimum and maximum plateau levels of furafylline between males (1.2-2.0 micrograms ml-1; mean body weight 67.2 kg) and females (1.6-2.6 micrograms ml-1; mean body weight 54.9 kg). The half-life of elimination was less when the plasma concentration was lower than 600 ng ml-1 than during the stationary phase of treatment. Despite constant plasma levels the repeated administration of furafylline appeared to be associated with the onset of adverse xanthine-like side effects, a finding which was subsequently traced to the presence of, and possible synergism with, accumulating serum levels of caffeine in those volunteers drinking caffeine containing beverages. Subsequent studies showed that a single dose (90 mg) of furafylline results in a rapid accumulation of caffeine given orally (100 mg twice daily) and that this is accompanied by an elimination half-life of some 50 h and an abrupt decrease in metabolite levels. The furafylline-induced accumulation of caffeine was not influenced by the smoking habits of the subjects, implying that the metabolite pathway blocked by furafylline is the demethylation of caffeine in position 3, an implication confirmed by the reduced formation of paraxanthine. This demonstration of an unacceptable level of adverse side effects resulting from a potent inhibiting effect of furafylline on the metabolism of a normal dietary constituent has obvious implications in the interpretation of drug-induced toxicity.

Some pharmacokinetic characteristics of furafylline, a new 1,3,8-trisubstituted xanthine.

After administration of furafylline, a, 1,3,8-trisubstituted xanthine, to beagle dogs at 0.5 and 10 mg kg-1 an elimination half-life 2-10 times longer than that of theophylline was observed. The kinetics were dose-dependent but no phase I metabolites were detected. When the compound was given orally to humans at a dose of 1.3-1.9 mg kg-1 a mean beta elimination half-life of 48.1 +/- 10.8 h was obtained after an initial distribution phase. Evidence of non-linear kinetics for plasma levels below 0.6 microgram ml-1 was also obtained. Other 1,3,8-trisubstituted xanthines, may also have a lower elimination rate than theophylline.

Human metabolism of 7-substituted theophyllines: N3-demethylation and lack of oxidation of proxyphylline.

Proxyphylline metabolism after oral administration to humans was studied. The only metabolic process detected was N3-demethylation, and 1-methyl-7-(2-hydroxypropyl)xanthine was isolated and identified. Proxyphylline was excreted in urine both an unchanged compound (12.7% of dose) and as its metabolic product (30.2% of dose). The latter substance was not found (detection limit = 1 microgram/ml) in the systemic circulation. Thus, it probably does not participate in the pharmacological activity of proxyphylline in vivo, although it was as active as the parent drug in relaxing the guinea pig tracheal chain. Lack of metabolism to uric acid derivatives is explained by the low affinity of both substances toward the enzymes the oxidize xanthine (xanthine oxidase) and methylxanthine derivatives. The presence of the metabolite in urine interferes with some analytical methods developed for estimation of unchanged proxyphylline. Published data on the urinary excretion of this drug need reevaluation.

The pharmacokinetics of a new benzamide drug clebopride, in the rat and the dog.

After intravenous, intramuscular and oral administration of clebopride in the rat and the dog its apparent volume of distribution is high (1.6-3.2 1 kg-1) and it has a longer biological half-life than metoclopramide in both species. High clearance values and concentrations of metabolites in plasma after oral administration indicate that the drug is subjected to an extensive first pass metabolism in the rat. Thus, clebopride administered orally gives relatively low concentrations in the systemic circulation in rats even though it is rapidly absorbed. The metabolic processes appear to become saturated at high doses which is reflected in dose-dependent kinetics. Linear kinetics were observed in the dog, although enterohepatic recycling could occur.