The effect of pretreatment for 3 days with diltiazem 60 mg three times a day on the pharmacokinetics of 500-mg antipyrine and 250-mg trimethadione was studied in six healthy male subjects. Diltiazem decreased the total body clearance from 34.0 +/- 8.0 to 28.6 +/- 6.1 mL/min (P less than .01), and prolonged the elimination half-life from 12.6 +/- 3.0 to 14.3 +/- 2.5 hours (P less than .01) of antipyrine without any changes in volume of distribution. The cumulative renal excretion (% dose) of antipyrine was significantly increased from 2.23 +/- 0.73 to 2.78 +/- 0.83% (P less than .05). Clearances of production for three major antipyrine metabolites, norantipyrine (4.31 +/- 1.64 to 3.50 +/- 1.28 mL/min, P less than .01), 3-hydroxymethylantipyrine (4.67 +/- 1.63 to 3.82 +/- 1.34 mL/min, P less than .01) and 4-hydroxyantipyrine (10.47 +/- 3.41 to 8.16 +/- 2.82 mL/min, P less than .01) were reduced significantly by diltiazem. On the other hand, diltiazem did not produce any significant changes in pharmacokinetic parameters of trimethadione and plasma concentration ratio, oxidative major metabolite of trimethadione to trimethadione itself. These results suggest that other drugs metabolizing the same hepatic oxidative pathways as antipyrine, may be influenced by diltiazem.