Pharmacokinetics of oral sustained release clonidine in humans

Tablet cores of clonidine (Catapres) showing varying rates of in vitro dissolution were administered in a crossover study with intravenous clonidine to determine the rate of absorption into the systemic circulation in humans. Excellent bioavailability (0.87-0.96) was obtained in all 12 subjects for each of the formulations. When peak concentration and time to peak are compared for the standard immediate release cores and the cores designed to be slowly dissolving there was a significant difference (p less than 0.05). Absorption rate plots for each formulation in each subject were obtained using the Loo-Riegelman procedure of comparing the oral pharmacokinetic profile with the intravenous profile. As the release from the cores were formulated to be slower, the in vivo absorption rate of clonidine approached zero order input. Incorporating combinations of sustained release and immediate release cores into a capsule (Perlonget) gave predictable absorption rates, permitting the formulation scientist to control the plasma levels obtained from oral dosing of clonidine. The intravenous pharmacokinetics of clonidine after a 0.2 mg infusion followed a tri-exponential decline with a final phase half-life of 13.6 h (harmonic mean). Following the intravenous infusion 42.3% of the dose was excreted unchanged in the urine with a renal clearance of 10.05 +/- 0.65 1/h (167 ml/min).