Therapeutic receptor-blocking concentrations of neuroleptics

The therapeutic concentrations of antipsychotic drugs in the patient's plasma water or spinal fluid are identical to their blocking potencies in vitro at the dopamine D-2 receptor, with the exception of clozapine which acts at D-2. The variation in K values between laboratories stems from the fact that the apparent K value for any antipsychotic drug depends on the affinity of the competing radioligand for the receptor or the membranes. Clozapine at the D-2 receptor has a K value of 420 nM, using [H-3]nemonapride, 180 nM using [H-3]spiperone and 82 nM using [H-3]raclopride. These K values are related to the tissue/buffer partition coefficients of the ligands. Extrapolating down to either 1 or 0 partition yields the intrinsic K values for the antipsychotic in the absence of any competing ligand. The extrapolated or intrinsic K value for clozapine at D-4 is 1.3 nM, in agreement with the value of 1.1 nM measured directly with [H-3]clozapine at D-4. Clozapine in vivo, however, must compete with endogenous dopamine in the synapse, estimated as 50 nM. Thus, the in vivo concentration of clozapine for 75% occupation of dopamine D-4 receptors can be derived as similar to 14 nM, in agreement with the observed value of 12-20 nM in the plasma water or spinal fluid in treated patients. In L-DOPA psychosis in Parkinson's disease, the clozapine concentration (in the plasma water or spinal fluid) for 75% blockade of dopamine D-4 receptors mag be predicted as similar to 3 nM, in general agreement with the value of similar to 1.2 nM in Parkinson patients who have L-DOPA psychosis. These considerations provide strong support for the conclusion that clozapine primarily targets the D-4 receptor in psychosis. Using the same considerations for haloperidol, it can be shown that the haloperidol therapeutic concentration required for 75% blockade of dopamine D-2 receptors in vivo will be approximately 2-3 nM, in agreement with the observed value in the spinal fluid or plasma water of 1-3 nM.