Pharmacokinetic-Pharmacodynamic Modeling of Tolerance to the Prolactin-Secreting Effect of Chlorprothixene after Different Modes of Drug Administration1

The objective of this study was the construction of a pharmacokinetic-pharmacodynamic model to describe the effects of chlorprothixene on prolactin secretion and the time-dependent alterations in the concentration-effect relationship due to tolerance development. Prolactin and chlorprothixene serum concentrations were determined in eight healthy men for up to 72 h after the intravenous and oral administration of chlorprothixene. An integrated pharmacokinetic model and a physiological indirect pharmacodynamic/tolerance model were applied to describe the prolactin-secreting effect of chlorprothixene. A threecompartment model served as pharmacokinetic model. The pharmacodynamic and tolerance model accounted for the baseline effect, the effect induced by the drug, and the regulatory mechanism that opposes the effect of the drug. This model adequately characterized the prolactin response after intravenous and oral drug administration of each individual by the sensitivity (dissociation constant), the efficacy (maximal prolactin secretion rate), the extent, and the rate of tolerance development. We speculate that this approach improves the quality of neuroendocrine challenge tests to determine the subject’s sensitivity to drugs and the time course of adaptation. Chlorprothixene is a thioxanthene with antipsychotic properties that is widely used in Europe to treat schizophrenia. Despite long-term use, the pharmacodynamics of antipsychotic drugs are still not totally understood. It is desirable to obtain a detailed pharmacological characterization of these drugs. A pharmacological characterization of dose-effect relationships is primarily confounded by the time delay of several days to weeks between the onset of treatment and the onset of antipsychotic effect. Typical antipsychotic drugs, such as chlorprothixene, block dopamine D2 receptors in the pituitary (lactotroph), compete with the dopamine-induced reduction in prolactin release and consequently cause an increase in prolactin concentration (Moore, 1987). The relationship between prolactin secretion and pathophysiology of schizophrenia or antipsychotic therapy has been extensively studied (Meltzer et al., 1983; Rubin, 1987; Green and Brown, 1988; Nordstrom and Farde, 1998). The results have not been entirely clear cut, and we assume that the discrepancy is mostly due to insufficient data analysis. In this context, the following aspects should be considered: 1) substantial interindividual variability exists in the disposition kinetics of antipsychotic drugs, particularly in the oral bioavailability and systemic clearance; 2) pharmacological response is best described by concentration-effect relationship, which is characterized by the parameters potency (sensitivity to the drug) and efficacy (maximal achievable effect); and 3) virtually all physiological systems, especially endocrine systems, are subject to adaptive selfregulatory processes. Received for publication December 15, 1998. 1 Present address: Department of General Psychiatry, University of Vienna, Austria. 2 Present address: Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany. ABBREVIATIONS: rin.prl, prolactin secretion rate; rin.prl.max, maximal prolactin secretion rate; rin.prl.p, prolactin secretion rate without compensatory increase of T; rin.prl.0, baseline secretion rate of prolactin; rin.prl.50, prolactin secretion rate obtained by 50% inhibition of the prolactin-lowering effects of T; rin.T, secretion rate of T; rin.T.0, baseline secretion rate of T; ccpx, chlorprothixene concentration; cda, dopamine concentration; cprl, prolactin concentration; cprl.p, prolactin concentration that results from rin.prl.p; css.prl.0, cprl at baseline; EC50, dopamine concentration producing 50% rin.prl.max; ET, extent of tolerance; IC50, chlorprothixene concentration required to produce rin.prl.50; IC50.p, IC50 without compensatory increase of T; IC50.n, IC50 with compensatory increase of T; kel.prl, prolactin elimination rate constant; KI, chlorprothixene dissociation constant at the dopamine D2 receptor; ktol, rate of tolerance development; mprl, mass of prolactin; P, proportionality factor; T, EC50-normalized dopamine concentration; Tss.IC50n, T at steady state for ccpx 5 IC50.n; Tss.IC50p, T at steady state for ccpx 5 IC50.p; Tss.0, T at baseline; Vprl, volume of distribution of prolactin. 0022-3565/99/2912-0547$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 291, No. 2 Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 291:547–554, 1999 547 at A PE T Jornals on A uust 0, 2017 jpet.asjournals.org D ow nladed from In brief, the determinants of the response to a drug are the pharmacokinetics of the drug, the pharmacokinetic-pharmacodynamic relationship, and the extent and rate of tolerance development. During the past two decades, there has been tremendous progress in the development of pharmacokineticpharmacodynamic models to relate the time course of the pharmacological effect to the systemic drug concentrations for investigation of the quantitative aspects of these determinants (Holford and Sheiner, 1987). The prolactin secretion serves as a continuous, sensitive, and reproducible pharmacodynamic measure of the dopamine D2 receptor function. Several reports focus on the application of such models in analyzing the effects of drugs on the prolactin secretion (Grevel et al., 1986; Francheteau et al., 1991; Jusko and Ko, 1994; Movin-Osswald and Hammarlund-Udenaes, 1995; Valente et al., 1997). Despite the importance of homeostatic mechanisms in physiology and pharmacology, limited attention has been paid to the kinetic and dynamic relationship of the tolerance development. Cheng and Paalzow (1990) proposed a tolerance model to describe the time-dependent adaptation of dopaminergic activity during constant infusion of haloperidol to rats. A different concept was used by Movin-Osswald and Hammarlund-Udenaes (1995) to model the time-dependent changes in the prolactin response to remoxipride after two consecutive administrations of the same dose. We present here a pharmacokinetic-pharmacodynamic model to describe the concentration-effect relationship of chlorprothixene on the prolactin secretion in healthy subjects and to determine how different routes of administration influence this relationship. The model includes the physiological homeostatic mechanism, which is responsible for tolerance development as an integral part of the pharmacodynamic system. Materials and Methods