Cimetidine-induced reduction in gastrointestinal absorption of antipyrine and rate constants for formation of its metabolites

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Abstract
In 15 normal men, cimetidine taken orally in a dose of 300 mg twice/day for 3 days reduced to similar extents the rate constants for formation (ki) of the 3 principal metabolites of antipyrine (AP): 29.9 .+-. 8.5% (.hivin.X) for 4-hydroxyantipyrine (4-OH-AP); 28.3 .+-. 6.3% for 3-hydroxymethylantipyrine (3-OHM-AP); and 22.4 .+-. 5.6% for N-demethylantipyrine (NDM-AP). AP clearance declined 24.3%; AP salivary t1/2 [half life] rose 33%; and corrected AP apparent volume of distribution was unchanged. In 1 apparently normal subject, ki for formation of 3-OHM-AP and NDM-AP rose after cimetidine even though AP clearance declined 19.7%. This surprising result, which suggests that cimetidine can exert an inductive effect on the hepatic mixed-function oxidases of some subjects, was checked by restudying the individual. Very similar values occurred on repetition. The average increase in ki for NDM-AP and 3-OHM-AP was 172.2 and 34.0%. These unusual results in this subject indicate that at least 2 distinguishable forms of cytochrome P-450 participate in AP metabolism in man. Cimetidine appeared to reduce the amount of AP absorbed from the gut in 10 of 15 normal subjects.

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