INFLUENCE OF THE ANTACID MAALOX AND THE H-2-ANTAGONIST CIMETIDINE ON THE PHARMACOKINETICS OF CERIVASTATIN

The possible influence of Maalox 70, an antacid based on magnesium-alu minum hydroxide, and the H-2-antagonist cimetidine, both commonly pres cribed in hypercholesterolemic patients, on the pharmacokinetics of th e new HMG-CoA reductase inhibitor cerivastatin was investigated in 2 s eparate studies in 8 healthy young male subjects each, Cerivastatin pl asma concentration/time profiles were assessed by a specific HPLC assa y; in addition, total immunoreactive drug (cerivastatin plus metabolit es) was determined by RIA. Single oral doses of 200 mu g cerivastatin were administered under fasting conditions without or with 10 ml Maalo x 70 suspension. The mean AUC and C-max ratios (combined dosing/monodo sing) including 90% confidence intervals were 0.92 (0.73 - 1.15) and 0 .89 (0.72 - 1.10) for the HPLC data, and 0.99 (0.85 - 1.14) and 1.03 ( 0.82 - 1.30) for the RIA data, respectively. Thus, no interaction of t he simultaneous administration of Maalox 70 on the pharmacokinetics of cerivastatin was observed. In a similar controlled, randomized nonbli nd 2-way crossover design the influence of the H-2-antagonist and well -known cytochrome P450 enzyme inhibitor cimetidine was investigated. E ight healthy young male volunteers received single oral doses of 200 m u g cerivastatin alone or on the fourth day of a 4-day cimetidine 400 mg b.i.d. pretreatment. The mean AUC and C-max ratios (combined dosing /monodosing) including 90% confidence intervals were 0.98 (0.90 - 1.08 ) and 0.91 (0.78 - 1.07) for the RIA data, and 0.89 (0.82 - 0.96) and 0.93 (0.80 - 1.09) for the HPLC data, respectively, clearly indicating that cimetidine and cerivastatin did not interact pharmacokinetically . These results do not only reflect the apparent insensitivity of ceri vastatin absorption to possible changes in gastric pH, but demonstrate that the metabolic pathways of cerivastatin, involved in its first-pa ss metabolism and elimination, are rather insensitive to cytochrome P4 50 enzyme inhibition induced by cimetidine.