Pharmacokinetics and Pharmacodynamic Effects of Aqueous Diltiazem in Healthy Humans

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Abstract
Aqueous diltiazem was given to ten healthy male volunteers in a single oral dose of 2.5 mg/kg body weight. Serum diltiazem levels were measured at various intervals up to 24 hours after administration of the drug as were blood pressure, heart rate, and PR interval. The pharmacokinetics followed a one‐compartment model in six and two‐compartment model in four subjects. The mean distribution half‐life in the latter four subjects was 15.8 ± 3.7 minutes (range, 10.4–18.8 min). In the ten subjects, the peak serum diltiazem level was attained in 20 to 45 minutes (mean, 32.5 ± 9.5 min) and ranged from 136 to 701 ng/mL (mean, 332 ± 180 ng/mL). The elimination half‐life ranged from 2.8 to 4.8 hours (mean, 3.8 ± 0.6 hr). The area under the concentration‐time curve varied from 508 to 2,245 ng‐hr/mL, indicating differing bioavailability. Slight but significant blood pressure reduction was seen only at one to three hours. Changes in heart rate were not significant at any measurement. Transient facial flushing, beginning at ten to 20 minutes after administration, was noted in nine subjects, reflecting the vasodilatory effect of the drug. Significant prolongation (>10%) of PR intervals began at ten minutes in three, at 20 minutes in six, and at 30 minutes in one participant, and progressed to second‐degree Wenckebach atrioventricular (AV) block in six subjects 20 to 60 minutes after administration and third‐degree AV block in one person 45 minutes after dosing. These AV blocks resolved by the third hour without treatment, and PR prolongation resolved by the fifth to seventh hours. Significant PR prolongation was not observed in any subject when the serum diltiazem level was less than 30 ng/mL. In each subject, suppressive effects on the AV node correlated well with the serum diltiazem level. However, there was individual variability in response of the AV node to diltiazem.