Circadian phase dependent pharmacokinetics of disopyramide in mice

The focus of the reported work is investigation of disopyramide chronopharmacokinetics in the mouse. Different groups of male NMRI mice maintained under controlled environmental conditions (LD: 0600-1800) received a single intraperitoneal injection of disopyramide (30 mg per kg of body weight) at one of four different fixed time points of a 24-h period, i.e. 1000, 1600, 2200 or 0400. Blood samples were taken 0.5, 1, 2, 3, 4 and 6 hr after drug administration and total and free plasma levels of disopyramide were measured by an immunoenzymatic method. Our data showed statistically significant circadian rhythms in the following pharmacokinetic parameters: highest volume of distribution = 3.91 +/- 0.21 l kg-1 at 2200 (circadian amplitude, half the peak-to-trough difference relative to the 24-hr mean multiplied by 100, is 34%); highest area under concentration curves = 16.06 +/- 1.03 micrograms ml-1 hr-1 at 0400 (circadian amplitude = 43%) and highest clearance = 3.04 +/- 0.19 l hr-1 kg-1 at 2200 (circadian amplitude = 21%). Protein binding of the drug was shown to be circadian time dependent. Alpha and beta phase elimination half-lives were not found to be significantly circadian phase-dependent. Thus circadian changes in disopyramide clearance may represent circadian changes in the drug's volume of distribution.