Clonidine kinetics in man‐evidence for dose dependency and changed pharmacokinetics during chronic therapy.

Abstract

1 Clonidine kinetics were studied in 21 patients with essential hypertension. All received two bolus i.v. injections in the mean dose range of (0.78–3.36 micrograms kg‐1) and one single oral dose (mean dose 1.7–2.3 micrograms kg‐1) on separate occasions. The kinetics were also studied in some of these patients after multiple therapeutic oral dose (mean dose 1.1 or 1.9 micrograms kg‐1) twice daily during a dosage interval after 6–12 months monotherapy with clonidine. The multiple oral dosage was based on the therapeutic response. 2 With increasing i.v. doses the rate constants (alpha, beta) decreased and the plasma clearance was reduced by 74% (9.94–2.61 ml min‐1 kg‐1) indicating dose‐ dependent kinetics. The volume of distribution (Vd beta) did not change with dose in contrast to the volume of the plasma compartment (Vc) which was increased at the highest doses. 3 The single oral dose kinetics agreed with the i.v. kinetics at comparable dose. The bioavailability was 90%. 4 During multiple oral dosing the elimination rate constants decreased compared to the single dose. The plasma clearance increased (7.18 ml min‐1 kg‐1) compared to the corresponding single dose (4.17 ml min‐1 kg‐1). The latter change was probably caused by the decrease in bioavailability to about 65%. 5 The pharmacodynamic properties of the drug could explain the changes in pharmacokinetics with increased dose and during multiple doses. 1981 The British Pharmacological Society