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Methylxanthines pp 33–91Cite as

Pharmacokinetics and Metabolism of Natural Methylxanthines in Animal and Man

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 200))

Abstract

Caffeine, theophylline, theobromine, and paraxanthine administered to animals and humans distribute in all body fluids and cross all biological membranes. They do not accumulate in organs or tissues and are extensively metabolized by the liver, with less than 2% of caffeine administered excreted unchanged in human urine. Dose-independent and dose-dependent pharmacokinetics of caffeine and other dimethylxanthines may be observed and explained by saturation of metabolic pathways and impaired elimination due to the immaturity of hepatic enzyme and liver diseases. While gender and menstrual cycle have little effect on their elimination, decreased clearance is seen in women using oral contraceptives and during pregnancy. Obesity, physical exercise, diseases, and particularly smoking and the interactions of drugs affect their elimination owing to either stimulation or inhibition of CYP1A2. Their metabolic pathways exhibit important quantitative and qualitative differences in animal species and man. Chronic ingestion or restriction of caffeine intake in man has a small effect on their disposition, but dietary constituents, including broccoli and herbal tea, as well as alcohol were shown to modify their plasma pharmacokinetics. Using molar ratios of metabolites in plasma and/or urine, phenotyping of various enzyme activities, such as cytochrome monooxygenases, N-acetylation, 8-hydroxylation, and xanthine oxidase, has become a valuable tool to identify polymorphisms and to understand individual variations and potential associations with health risks in epidemiological surveys.

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Abbreviations

1,3,7DAU:

6-Amino-5(N-formylmethylamino)-1,3-dimethyluracil

1,3,7TMU:

1,3,7-Trimethyluric acid

1,3DMU:

1,3-Dimethyluric acid

1,7DAU:

6-Amino-5-(N-formylmethylamino)-3-methyluracil

1,7DMU:

1,7-Dimethyluric acid

1MU:

1-Methyluric acid

1MX:

1-Methylxanthine

3,7DAU:

6-Amino-5-(N-formylmethylamino)-1-methyluracil

3,7DMU:

3,7-Dimethyluric acid

3MU:

3-Methyluric acid

3MX:

3-Methylxanthine

7MU:

7-Methyluric acid

7MX:

7-Methylxanthine

AAMU:

5-Acetylamino-6-amino-3-methyluracil

AFMU:

5-Acetylamino-6-formylamino-3-methyluracil

AUC:

Area under the concentration versus time curve

C max :

Peak plasma concentration

CYP:

Cytochrome P450

GSH:

Glutathione

IBW:

Ideal body weight

K a :

Absorption rate constant

K e :

Elimination rate constant

K m :

Michaelis–Menten constant

NAT2:

N-Acetyltransferase 2

TBW:

Total body weight

T max :

Time to reach the peak plasma concentration

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Arnaud, M.J. (2011). Pharmacokinetics and Metabolism of Natural Methylxanthines in Animal and Man. In: Methylxanthines. Handbook of Experimental Pharmacology, vol 200. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-13443-2_3

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