Relationship between the clearance of caffeine and its 7-N-demethylation in developing beagle puppies

doi:10.1016/0006-2952(80)90102-1

Biochemical Pharmacology

Volume 29, Issue 13, 1 July 1980, Pages 1909-1914

https://doi.org/10.1016/0006-2952(80)90102-1 Get rights and content

Abstract

Caffeine and eleven of its potential metabolites have been assayed, by high performance liquid chromatography, in the blood and urine of developing beagle puppies. The clearance of caffeine from blood increased from 31.4 ± 6.0 ml · kg⁻¹ · hr⁻¹ at 2 days to 279.1 ± 45.4 ml · kg⁻¹ · hr⁻¹ at of age. This change reflected an increased first-order elimination rate constant since the apparent volume of distribution did not change significantly. Coincident with this increase in clearance, the fraction of a dose of caffeine excreted unchanged in urine decreased 18-fold. The remainder of the dose was metabolized to a series of di- and mono-methylxanthines and urates. In 2-day-old puppies, the caffeine metabolites potentially derived from the paraxanthine, theophylline or theobromine pathway accounted for 42, 33 and 14 per cent, respectively, of the identified products in urine. Between 2 and 22 days of age, the metabolite pattern of caffeine changed substantially, with those metabolites potentially derived from the theophylline pathway (theophylline 1-methylurate, 1–3-dimethylurate and 3-methylxanthine) increasing from 33 to 82 per cent. We suggest, therefore, that the change in caffeine clearance seen during development of the beagle puppy is determined primarily by the rate of maturation of caffeine-7-N-demethylase.

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The 100-fold default uncertainty factor is used to convert a no-observed-adverse-effect level (NOAEL) from a animal toxicity study, to a “safe” value for human intake. The composite uncertainty factor (100) has to allow for interspecies (10-fold) and interindividual (10-fold) differences in toxicokinetics and toxicodynamics. The aim of the current study was to assess the validity of the interspecies default for toxicokinetics (4.0) for each of the test species (dog, rabbit, rat and mouse), using published data for compounds eliminated by CYP1A2 in humans (caffeine, theobromine, theophylline and paraxanthine). An analysis of the published literature showed that the absorption, bioavailability and route of excretion were generally similar between humans and the test species, for each probe substrate. However, interspecies differences in the route of metabolism, and the enzymes involved in this process, were identified. The magnitude of difference in the internal dose, between species, showed that values for the mouse (10.6) and rat (5.4) exceed the 4.0-fold default, whereas the rabbit (2.6) and dog (1.6) were below this value. This work supports the need to replace the generic default factors by a compound-related value derived from specific, relevant, quantitative data; this would result in more relevant and reliable non-cancer risk assessments.
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^☆: This work was supported by the MRC of Canada, Grant MA-5162 and a grant from the International Life Science Institute.

^‡: Present address: Department of Pharmacology, J.H. Miller Health Center, University of Florida, Gainesville, FL 32610, U.S.A.

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Relationship between the clearance of caffeine and its 7-N-demethylation in developing beagle puppies☆

Abstract

J. Pediat.

J. biol. chem.

Life Sci.

J. biol. Chem.

Pediat. Res.

A. Rev. Pharmac. Toxic.

Clin. Pharmac. Ther.

Clin. Pharmac. Ther.