Age and cibenzoline disposition

Oral cibenzoline kinetics were followed in 36 healthy subjects aged from 22 to 78 yr divided into groups of six subjects per decade between 20 and 80 yr. Each received a single, oral, 160-mg dose of cibenzoline. Blood and urine samples were collected for 72 hr. Cibenzoline plasma and urine concentrations were measured by HPLC. Maximum plasma cibenzoline concentrations (Cmax) ranged from 283 to 1100 ng/ml and occurred 1 to 2.5 hr after dosing. Apparent oral clearance (ClT) ranged from 401 to 1677 ml/min and the t½ ranged from 5.9 to 13.4 hr. Nonrenal clearance (ClNR) ranged from 65 to 1113 ml/min, renal clearance (ClR) ranged from 165 to 645 ml/min, and 31% to 86% of the dose was recovered unchanged in urine (Xu). The volume of distribution (Vd) was large, ranging from 236 to 948 l. There was a significant relationship between age and the following kinetic parameters: Cmax, Xu, t½ (all of which increased with age), ClT, ClR, ClNR, the terminal elimination rate constant β, and Vd (which decreased with age). Mean ClT was 999 ± 371 ml/min in the 20- to 30-yr age group and was 465 ± 78 ml/min in the 70- to 80-yr age group. The change in ClT with age resulted from a decrease in both ClR and ClNR. Mean t½ varied from 7 hr in the youngest group to 10.5 hr in the oldest group. The age-related changes in cibenzoline kinetics occurred over the entire age range studied and the relationship between age and these kinetic parameters appeared to be linear. Multiple regression analyses showed that ClT, ClR, and Vd were related to sex, age, and serum creatinine concentration, which suggests that these variables may be essential in the clinical individualization of cibenzoline dosing. Clinical Pharmacology and Therapeutics (1984) 36, 613–619; doi:10.1038/clpt.1984.230