Pharmacokinetics of a series of bis(methanesulphonamido-arylalkyl)amines in the beagle dog

Abstract

1. The pharmacokinetics of three closely related analogues of dofetilide have been investigated in the beagle dog. These have been compared with those of dofetilide and related to physicochemical properties and structural features of the molecules.

2. Following intravenous administration, the four compounds exhibit elimination half-lives ranging from 4.6 to 19 h. This range is due to changes in both volume of distribution and plasma clearance across the series.

3. In vitro plasma protein binding shows a relationship to lipophilicity within this series. Protein binding increasing from 54% for dofetilide, the least lipophilic compound (logD_7.4 = 0.73), to 92% for the most lipophilic analogue (logD_7.4 = 2.07). There is a trend for a decrease in the volume of distribution with increased plasma protein binding.

4. Plasma clearance values range from 2.4 to 10.2 ml/min/kg and are comprised of renal and non-renal components. Renal clearance ranges from 0.11 to 2.9 ml/min/kg and shows an inverse correlation with the lipophilicity of the compounds. Values for the renal clearance of unbound drug suggest that only the most lipophilic derivative (III), has sufficient membrane affinity to undergo tubular reabsorption.

5. Non-renal clearance of either total or free drug shows no relationship with lipophilicity. Highest values are observed for the two compounds with a methyl substituent on the tertiary amine and lowest values for the two compounds in which the tertiary amine is incorporated into a 7-membered ring. In vitro metabolism in dog liver microsomes also shows increased lability for the two N-methyl compounds. The N-desmethyl metabolite is the major product in both cases.