Pharmacokinetics of m-Chlorophenylpiperazine after Intravenous and Oral Administration in Healthy Male Volunteers: Implication for the Pharmacodynamic Profile

Introduction: Serotonin plays an important role in psychiatric diseases, most notably in depression and anxiety. Seven different major serotonin receptor subtypes have been described. Receptor-selective agonists and antagonists have been searched for to find a suitable drug to test the in vivo receptor sensitivity. Different serotonin receptor subtypes take part in the control of neuroendocrine function. m-Chlorophenylpiperazine (mCPP) acts as an agonist to serotonin 2C, 1A, 1B, and 1D receptor subtypes and is applied in challenge tests. The object of this study was to develop a pharmacokinetic-pharmacodynamic model to describe the effects of mCPP on pituitary hormone secretion. Methods: The hormone and mCPP plasma concentrations were determined after intravenous and oral administration of mCPP to 12 healthy men. The kinetic parameters of mCPP were compared to the drug’s effect on hormonal response. Results: After mCPP treatment, ACTH, cortisol, and prolactin levels were significantly increased compared to placebo. There was also a significant increase in clinical response (anxiety, shivering, dizziness, heightened sensitivity toward light and noise, and fear of losing control). Maximum mCPP concentrations varied 2.3-fold after intravenous infusion and 8-fold after oral administration. The absolute bioavailability ranged from 12 % to 84 %. mCPP’s elimination half-life ranged from 2.4 h to 6.8 h after intravenous infusion and from 2.6 h to 6.1 h after oral application. However, the kinetic data as well as the pharmacodynamic response varied to an extent that precluded pharmacokinetic-pharmacodynamic modeling. The wide interindividual variability in mCPP’s disposition kinetics could not be fully explained by genetic variation of the mCPP-metabolizing enzyme cytochrome P4502D6, which was determined in all probands. Discussion: Other factors contributing to the variability in disposition kinetics could not be ruled out in this study, suggesting that mCPP is not a suitable model drug to test serotonin 2C receptor activity in vivo.

References

• 1 Akaike A. Posterior probabilities for choosing a regression model.  Annal Instit Math Stats. 1965;  30 A9-A13
• 2 Aitken R CB. Measurement of feelings using visual analogue scales.  Royal Soc Med. 1969;  62 989-993
• 3 Bagli M, Süverkrüp R, Rao M L, Bode H. Mean input times of three oral chlorprothixene formulations assessed by an enhanced least-square deconvolution method.  J Pharm Sci. 1996;  85 434-439
• 4 Bagli M, Süverkrüp R, Quadflieg R, Höflich G, Kasper S, Möller H J, Langer M, Barlage U, Rao M L. Pharmacokinetic-pharmacodynamic modeling of tolerance to the prolactin-secreting effect of chlorprothixene after different modes of drug administration.  J Pharmacol Exp Ther. 1999;  291 547-554
• 5 Barr L C, Goodman W K, Price L H, McDougle C J, Charney D S. The serotonin hypothesis of obsessive compulsive disorder: Implications of pharmacologic challenge studies.  J Clin Psychiatry. 1992;  53 (4, Suppl.) 17-28
• 6 Bullinger M, Heinisch M, Ludwig M, Geier S. Skalen zur Erfassung des Wohlbefindens: Psychometrische Analysen zum ”Profile of Mood States” (POMS) und zum ”Psychological General Well-Being Index” (PGWB).  Z Diff Diag Psychol. 1990;  11 53-61
• 7 Charney D S, Woods S W, Goodman W K, Heninger G R. Serotonin function in anxiety. II. Effects of the serotonin agonist mCPP in panic disorder patients and healthy subjects.  Psychopharmacology. 1987;  92 14-24
• 8 Cutler D J. Theory of the mean absorption time, an adjunct to conventional bioavailability studies.  J Pharm Pharmacol. 1978;  30 476-478
• 9 Eichelbaum M, Bertilsson L, Sawe J, Zekorn C. Polymorphic oxidation of sparteine and debrisoquine: related pharmacogenetic entities.  Clin Pharmacol Ther. 1982;  31 184-186
• 10 Gabrielson J, Weiner D. Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts and Applications. Stockholm; Swedish Pharmaceutical Press 1994
• 11 Gibaldi M, Perrier D. Pharmacokinetics. 2nd edn New York-Basel; Marcel Dekker 1982
• 12 Gijsman H J, van Gerven J MA, Tieleman M C, Schoemaker R C, Pieters M SM, Ferrari M D, Cohen A F, van Kempen G MJ. Pharmacokinetic and pharmacodynamic profile of oral and intravenous meta-chlorophenylpiperazine in healthy volunteers.  J Clin Psychopharmacol. 1998;  18 289-295
• 13 Hamik A, Peroutka S J. 1-(m-Chlorophenyl)piperazine (mCPP) interactions with neurotransmitter receptors in the human brain.  Biol Psychiatry. 1989;  25 569-575
• 14 Hamilton M. HAMA. Hamilton anxiety scale. In W. Guy (Ed) ECDEU Assessment Manual for Psychopharmacology. Rockville; National Institute of Mental Health 1976a: pp. 193-198
• 15 Hamilton M. HAMD. Hamilton depression scale. In W. Guy (Ed) ECDEU Assessment Manual for Psychopharmacology. Rockville; National Institute of Mental Health 1976b: pp. 179-192
• 16 Kahn R S, Davidson M. Serotonin receptor responsivity in schizophrenia.  Int Clin Pharmacol. 1993;  8 (Suppl. 2) 47-51
• 17 Kahn R S, Wetzler S. m-Chlorophenylpiperazine as a probe of serotonin function.  Biol Psychiatry. 1991;  30 1139-1166
• 18 Kahn R S, Wetzler S, Asnis G M, King M A, Suckow R F, van Praag H M. Effects of m-chlorophenylpiperazine in normal subjects: a dose-response study.  Psychopharmacology. 1990;  100 339-344
• 19 Kahn R S, Wetzler S, Asnis G M, King M A, Suckow R F, van Praag H M. Pituitary hormone responses to meta-chlorophenylpiperazine in panic disorder and healthy control subjects.  Psychiatry Res. 1991;  37 25-34
• 20 Kühn K U, Quednow B B, Bagli M, Meyer K, Feuchtl A, Krüger J, Frahnert C, Maier W, Rao M L. Allelic variants of the serotonin_2C receptor agonist m-chlorophenylpiperazine in healthy male volunteers.  Pharmacopsychiatry. 2002;  35 226-230
• 21 Lappalainen J, Zhang L, Dean M, Oz M, Ozaki N, Yu D H, Virkkunen M, Weight F, Linnoila M. Goldman D. Identification, expression, and pharmacology of Cys 23-Ser23 substitution in the human 5-HT2C receptor gene (HTR2C).  Genomics. 1995;  27 274-279
• 22 Lawlor B A, Sunderland T, Hill J L, Mellow A M, Molchan S E, Mueller E A, Jacobsen F M, Murphy D L. Evidence for a decline with age in behavioral responsivity to the serotonin agonist, m-chlorophenylpiperazine, in healthy human subjects.  Psychiatry Res. 1989;  29 1-10
• 23 Lawlor B A, Sunderland T, Mellow A M, Hill J L, Molchan S E, Murphy D L. Hyperresponsivity to the serotonin agonist, m-chlorophenylpiperazine, in Alzheimer's disease.  Arch Gen Psychiatry. 1989;  46 542-549
• 24 Lewin H A, Stewart-Haynes J A. A simple method for DNA extraction from leukocytes for use in PCR.  Biotechniques. 1992;  13 522-524
• 25 Lohmann P L, Bagli M, Krauss H, Müller D J, Schulze T G, Held T, Fangerau H, Maier W, Rietschel M, Rao M L. CYP2D6 polymorphism and tardive dyskinesia in schizophrenic patients. Pharmacopsychiatry 2003 in press
• 26 Miller R L, DeVane C L. Analysis of trazodone and m-chlorophenylpiperazine in plasma and brain tissue by high-performance liquid chromatography.  J Chromatogr. 1986;  374 388-393
• 27 Murphy D L, Mueller E A, Hill J L, Tolliver T J, Jacobsen F M. Comparative anxiogenic, neuroendocrine, and other physiologic effects of m-chlorophenylpiperazine given intravenously or orally to healthy volunteers.  Psychopharmacology. 1989;  98 275-282
• 28 Riegelmann S, Collier P. The application of statistical moment theory to the evaluation of in vivo dissolution time and absorption time.  J Pharmacokin Biopharm. 1980;  8 509-534
• 29 Rotzinger S, Fang J, Coutts R T, Baker G B. Human CYP2D6 and metabolism of m-chlorophenylpiperazine.  Biol Psychiatry. 1998;  44 1185-1191
• 30 Schwartz P J, Murphy D L, Wehr T A, Garcia-Borreguero D, Oren D A, Moul D E, Ozaki N, Snelbaker A J, Rosenthal N E. Effects of meta-chlorophenylpiperazine infusions in patients with seasonal affective disorder and healthy control subjects.  Arch Gen Psychiatry. 1997;  54 375-385
• 31 Silverstone P H, Cowen P J. The 5-HT₃ agonist, BRL 46 470 does not attenuate m-chlorophenylpiperazine (mCPP)-induced changes in human volunteers.  Biol Psychiatry. 1994;  36 309-316
• 32 Silverstone P H, Rue J E, Franklin M, Hallis K, Camplin G, Laver D, Cowen P J. The effects of administration of mCPP on psychological, cognitive, cardiovascular, hormonal and MHPG measurements in human volunteers.  Int Clin Psychopharmacol. 1994;  9 173-178
• 33 Yamaoka K, Nakagawa T, Uno T. Statistical moments in pharmacokinetics.  J Pharmacokin Biopharm. 1978a;  6 547-558
• 34 Yamaoka K, Nakagawa T, Uno T. Application of the Akaike information criterion AIC in the evaluation of linear pharmacokinetics.  J Pharmacokin Biopharm. 1978b;  6 165-175