Safety and pharmacokinetics of mifentidine after increasing oral doses in healthy subjects.

Eight healthy men were each given single oral doses of mifentidine 20, 40 and 80 mg, a new H2-receptor antagonist, in a four-way, double-blind, placebo-controlled, cross-over, dose-proportionality study. No significant objective or subjective effects were noted. Mifentidine showed unusual pharmacokinetic behaviour, producing a significant secondary peak in the drug concentration profile. The plasma AUC of mifentidine increased linearly with dose (r = 0.983). The apparent plasma clearance was 38.1 l.h-1, 31.0 l.h-1, and 47.4 l.h-1 for the 20, 40 and 80 mg doses, respectively, and the corresponding terminal plasma half-lives were 10.3 h, 12.0 h, and 8.6 h. About 20% of the parent drug was excreted in urine over 24 h. The renal clearance (9.41 l/h for 20 mg, 9.5 l/h for 40 mg, and 12.8 l/h for 80 mg mifentidine) indicates that some of the drug was excreted by active tubular secretion. The results indicate that mifentidine is safe after single oral doses up to 80 mg. The pharmacokinetics of the 20 and 40 mg doses were similar, but after 80 mg the total body and renal clearances were significantly greater than after the two lower doses. As the terminal plasma half-life of mifentidine is longer than of other available H2-receptor antagonists, it may have clinical implications for once-a-day therapy of peptic ulcer diseases.