Influence of cimetidine, sulfinpyrazone, and cigarette smoking on theobromine metabolism in man

John O. Miners, Janet Attwood, Lindon M.H. Wing, Donald J. Birkett

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    21 Citations (Scopus)

    Abstract

    Theobromine metabolism and clearance were investigated at steady-state under chronic oral dosing conditions in eight healthy volunteers, four of whom were cigarette smokers. The subjects were studied before and after separate 1 week pretreatments with cimetidine (1 g/day) and sulfinpyrazone (800 mg/day). Theobromine plasma clearance (CI(TB)) was 33% higher in smokers than in nonsmokers due to induction of all metabolic pathways (3-demethylation, 7-demethylation, and formation of 6-amino-5-(N-methylformylamino)-1-methyluracil (AMMU)). 7-Demethylation was induced by cigarette smoking to a greater extent than the other pathways. Cimetidine pretreatment inhibited theobromine 3-demethylation and AMMU formation resulting in a 27% decrease in CI(TB) in the combined smoker/nonsmoker group. The 7-demethylation pathway was unaffected by cimetidine. In contrast, sulfinpyrazone pretreatment increased CI(TB) by 50% in the whole group by approximately equal induction of each metabolic pathway. The extent of induction due to sulfinpyrazone was 2.4-fold greater in nonsmokers than in smokers. When compared with previous data relating to theophylline, the results suggest that theobromine 3-demethylation is mediated by the same form(s) of cytochrome P-450 involved in theophylline demethylation, while a second form(s) of cytochrome P-450 is involved in theobromine 7-demethylation and theophylline 8-hydroxylation. In addition, since AMMU formation was inhibited by cimetidine and induced by cigarette smoking and sulfinpyrazone, it would appear that the conversion of theobromine to AMMU is also mediated by cytochrome P-450.

    Original languageEnglish
    Pages (from-to)598-601
    Number of pages4
    JournalDrug Metabolism and Disposition
    Volume13
    Issue number5
    Publication statusPublished - 1 Sept 1985

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