TY - JOUR
T1 - Influence of cimetidine, sulfinpyrazone, and cigarette smoking on theobromine metabolism in man
AU - Miners, John O.
AU - Attwood, Janet
AU - Wing, Lindon M.H.
AU - Birkett, Donald J.
PY - 1985/9/1
Y1 - 1985/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0022380439&partnerID=8YFLogxK
M3 - Article
C2 - 2865110
AN - SCOPUS:0022380439
SN - 0090-9556
VL - 13
SP - 598
EP - 601
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 5
ER -