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

In 15 normal men, Cimetidine taken orally in a dose of 300 mg twice a day for 3 days reduced to similar extents the rate constants for formation (k i ) of the three principal metabolites of antipyrine (AP): 29.9% ± 8.5% (X̄± SD) 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 t½ rose 33%; and corrected AP apparent volume of distribution was unchanged. In one apparently normal subject, however, k i s 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 k i s for NDM‐AP and 3‐OHM‐AP was 172.2% and 34.0%. These unusual results in this subject indicate that at least two 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 our 15 normal subjects. Clinical Pharmacology and Therapeutics (1984) 35, 568–575; doi: 10.1038/clpt.1984.79