The metabolism of nifedipine during long-term therapy

The serum concentrations and urinary excretion of nifedipine and 3 of its metabolites have been compared in two groups of hypertensive patients, one receiving prolonged (1-2 years) nifedipine monotherapy, the second receiving the same dosage of nifedipine in conjunction with a variety of other antihypertensive and cardioactive drugs. It was found that prolonged administration of nifedipine was associated with an eight-fold reduction in serum nifedipine concentration, one hour following a 10 mg dose, compared with the levels observed at the same time after an acute 10 mg dose. The serum concentration of the metabolite dehydronifedipinic acid was concomitantly increased, but no evidence for dehydronifedipinolactone, derived from hydroxylation of dehydronifedipinic acid, was found. When the nifedipine was administered as part of polytherapy, there was a marked (p less than 0.001) increase in the serum concentration of the drug as compared with monotherapy, together with a significant (p less than 0.05) increase in the serum concentration of its metabolites. The results suggest that while a significant enhancement of nifedipine metabolism occurs during long-term monotherapy, chronic administration of nifedipine as part of polytherapy appears to be associated with significant inhibition of the initial oxidation of nifedipine to dehydronifedipine, which may be attributable to the actions of the co-administered drugs. The subsequent hydrolysis of dehydronifedipine to dehydronifedipinic acid and the excretion of the latter metabolite appear to be much less affected, but subsequent oxidation of dehydronifedipinic acid may also be inhibited.