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Biotransformation of caffeine in human liver microsomes from foetuses, neonates, infants and adults.
Author(s) -
Cazeneuve C.,
Pons G.,
Rey E.,
Treluyer JM,
Cresteil T.,
Thiroux G.,
D'Athis P.,
Olive G.
Publication year - 1994
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.1994.tb05706.x
Subject(s) - biotransformation , microsome , caffeine , medicine , microsoma , physiology , fetus , pharmacology , pregnancy , chemistry , biology , biochemistry , enzyme , genetics
1. Caffeine metabolism was studied in human liver microsomes from foetuses (n = 10), neonates (n = 10), infants (n = 9) and adults (n = 5). Caffeine and its metabolites, 1‐3‐7‐trimethyluric acid, paraxanthine, theophylline and theobromine, were assayed by h.p.l.c. Methoxyresorufin‐O‐demethylase activity (MEROD) was determined and immunoquantifiable levels of CYP1A2 were measured. 2. The formation of the dimethylxanthines by N‐3, N‐7 or N‐1‐demethylation was significantly less in foetuses, neonates and infants than in adults, as shown previously in vivo. The formation of 1‐3‐7‐trimethyluric acid (C‐ 8‐hydroxylation) was not significantly different between age groups. The production of total dimethylxanthines, paraxanthine and theophylline increased significantly with age within the neonate‐infant group over at least the 0‐300 day range (rs = 0.739, 0.667, 0.682, respectively). These data differ from those reported in vivo which suggested that N‐3 and N‐7‐demethylations matured at about 120 days. The difference in maturational profiles of each metabolic pathway suggests that the reactions depend on different isoenzymes. The delay in the maturation of N‐1 compared with N‐3 and N‐7‐demethylation is in agreement with previous in vivo data. 3. In the neonate‐infant group, only N‐3‐demethylation correlated with both MEROD activity (rs = 0.681; P < 0.05) and CYP1A2 microsomal concentration (rs = 0.454; P approximately 0.05), suggesting that, as in adults, this reaction depends on CYP1A2. 4. In the foetal samples, the production of total dimethylxanthines, paraxanthine and theobromine decreased significantly (rs = ‐0.879, ‐0.767, ‐0.708, respectively) with increasing gestational age.(ABSTRACT TRUNCATED AT 250 WORDS)