RELATIONSHIP BETWEEN PHARMACOKINETICS AND PHARMACODYNAMICS OF TINZAPARIN (LOGIPARIN), A LOW-MOLECULAR-WEIGHT HEPARIN, IN DOGS

1. Pharmacodynamic models relating the plasma concentrations (C) of ra dioactive heparin material to anticoagulant effect (E) have been inves tigated after single i.v. and s.c. doses of H-3-tinzaparin (1 and 4 mg /kg), a radiolabelled low molecular weight heparin, to six dogs. 2. A counterclockwise hysteresis, characterizing the C versus E relationshi p, was observed in all animals after s.c., but not i.v., doses indicat ing a possible delay (lag-time) in the systemic availability of pharma cologically-active heparin material following extra-vascular administr ation. A constant (K(e)) was introduced into the model to account for this hysteresis. 3. At high plasma concentrations of radioactivity (> 10 mug/ml), E was related to C by a sum of two sigmoid E(max) models, whereas, at lower concentrations, this reduced to the well-known sigmo id E(max) model. It was proposed that tinzaparin activates two 'recept ors' having different affinities for the drug. The values of EC50 asso ciated with the activation of a single 'receptor' and of a proposed ad ditional 'receptor' were 3 and 13 mug/ml of heparin material, respecti vely. 4. Heparin material was predominantly eliminated by renal excret ion and underwent widespread tissue distribution. After s.c. administr ation, input of heparin material into systemic plasma was complete wit hin 12h post-dose, and the absorption process was characterized by a b i-exponential function. 5. We conclude that sigmoid E(max) models adeq uately describe the C versus E relationship after s.c. and i.v. doses of H-3-tinzaparin in dogs and that the interindividual variation of th e pharmacodynamic parameters derived from this model was relatively sm all.