Effect of time of dosing on the disposition of oral cibenzoline

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Abstract
Single oral doses of cibenzoline were administered to eight healthy volunteers on two different occasions, once at 8.00 am and once at 10.00 pm, in a randomized crossover design with at least one week separating treatments. A fast was maintained for 12 hours prior to and for 2 hours after the morning dose and the subjects did not lie down for at least 12 hours after dosing. A standard dinner was eaten 3 hours prior to the evening dose, and a fast was maintained for 10 hours after dosing; the subjects laid down 2 hours after dosing for at least 6 hours. Blood was collected at specific times for 72 hours and the total volume of urine voided was collected through 72 hours. Cibenzoline concentrations in plasma and urine were measured by HPLC. Cibenzoline absorption was slower in 7 of the 8 volunteers following the evening dose relative to the morning dose. Mean ± S.D. tmax for the evening dose was 2.6 ± 0.5 hours compared to 1.7 ± 0.8 for the morning dose. The corresponding mean ± S.D. Cmax following the morning dose was 446 ± 124 ng ml−1 compared to 402 ± 114 ng ml−1 after the evening dose. The mean ± S.D. AUC was 3328 ± 1101 ng.h.ml−1 after the morning dose and 3561 ± 1430 ng.h.ml−1 after the evening dose. The harmonic mean half‐life was 7.4 hours after both treatments. These data indicated that the total amount of drug absorbed and the elimination rate constant of the drug had not varied between treatments. Plasma concentrations 12 hours after the evening dose were statistically higher than those after the morning dose. The observation was consistent with the statistically higher morning trough concentrations that had been observed previously during a 12‐hour chronic dosing. There was no evidence of diurnal variation in the renal excretion of cibenzoline and the elimination half‐life and total amount of drug recovered in the urine were similar for the two times of administration. It appeared that the only pharmacokinetic difference following the morning or evening dosing was the slightly slower absorption rate at night, which should be of no clinical significance.

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