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Metabolism and Kinetics

  • Chapter
Psychotropic Agents

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 55 / 1))

Abstract

Neuroleptic drugs act principally on the central nervous system. This implies that they are lipophilic compounds which easily penetrate membranes separating single body compartments from one another. As a consequence, their excretion will ordinarily be preceded by biotransformation to more hydrophilic substances, since otherwise binding to tissues and plasma proteins and renal tubular reabsorption would lead to an extremely long persistence in the body. Thus, metabolic transformations become limiting for the elimination of the majority of these drugs.

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References

  • Airoldi, L., Marcucci, F., Mussini, E., Garattini, S.: Distribution of penfluridol in rats and mice. Eur. J. Pharmacol. 25, 291–295 (1974)

    PubMed  CAS  Google Scholar 

  • Akera, T., Brody, T.M.: Inhibition of brain sodium- and potassium-stimulated adenosine triphosphatase activity by chlorpromazine free radical. Mol. Pharmacol. 4, 600–612 (1968)

    PubMed  CAS  Google Scholar 

  • Alfredsson, G., Wiesel, F.-A., Skett, P.: Levels of chlorpromazine and its active metabolites in rat brain and the relationship to central monoamine metabolism and prolactin secretion. Psychopharmacology 53, 13–18 (1977)

    PubMed  CAS  Google Scholar 

  • Allgén, L.-G., Jönsson, B., Nauckhoff, B., Andersen, M.-L., Huus, I., Møller Nielsen, I.: On the elimination of chlorprothixene in rat and man. Experientia 16, 325 (1960)

    PubMed  Google Scholar 

  • Beckett, A.H., Essien, E.E.: Chlorpromazine “hydroxylamines” in red blood cells as major metabolites of chlorpromazine in man. J. Pharm. Pharmacol. 25, 188–189 (1973)

    PubMed  CAS  Google Scholar 

  • Beckett, A.H., Hewick, D.S.: The N-oxidation of chlorpromazine in vitro — the major metabolic route using rat liver microsomes. J. Pharm. Pharmacol. 19, 134–136 (1967)

    CAS  Google Scholar 

  • Beckett, A.H., Beaven, M.A., Robinson, A.E.: Metabolism of chlorpromazine in humans. Biochem. Pharmacol. 12, 779–794 (1963)

    PubMed  CAS  Google Scholar 

  • Beckett, A.H., Gorrod, J.W., Lazarus, C.R.: The in vitro metabolism of [35S]chlorpromazine. Xenobiotica 1, 535–536 (1971)

    PubMed  CAS  Google Scholar 

  • Berman, H.M., Spirtes, M.A.: Gas chromatographic analysis of chlorpromazine and its metabolites formed by hepatic microsomes -I. Influence of magnesium. Biochem. Pharmacol. 20, 2275–2286 (1971)

    PubMed  CAS  Google Scholar 

  • Braun, G.A., Poos, G.I., Soudijn, W.: Distribution, excretion and metabolism of neuroleptics of the butyrophenone type. Part II. Distribution, excretion and metabolism of haloperidol in Sprague-Dawley rats. Eur. J. Pharmacol. 1, 58–62 (1967)

    PubMed  CAS  Google Scholar 

  • Breyer, U.: Urinary metabolites of 10-[3′-(4″-methyl-piperazinyl)-propyl]-phenothiazine (perazine) in psychiatric patients. I. Isolation, identification and determination of metabolites. Biochem. Pharmacol. 18, 777–788 (1969)

    PubMed  CAS  Google Scholar 

  • Breyer, U.: Metabolism of the phenothiazine drug perazine by liver and lung microsomes from various species. Biochem. Pharmacol. 20, 3341–3351 (1971)

    PubMed  CAS  Google Scholar 

  • Breyer, U.: Accumulation and elimination of a novel metabolite during chronic administration of the phenothiazine drug perazine to rats. Biochem. Pharmacol. 21, 1419–1429 (1972)

    PubMed  CAS  Google Scholar 

  • Breyer, U., Gaertner, H.J.: Accumulation and elimination of metabolites in animals and man treated chronically with phenothiazines. Excerpta Med., Int. Congr. Ser. 288, 59–66 (1973)

    Google Scholar 

  • Breyer, U., Schmalzing, G.: Metabolism and disposition of trifluoperazine in the rat. I. A thinlayer chromatographic method for the measurement of trifluoperazine and its metabolites in rat tissues. Drug Metab. Dispos. 5, 97–103 (1977)

    PubMed  CAS  Google Scholar 

  • Breyer, U., Villumsen, K.: Measurement of plasma levels of tricyclic psychoactive drugs and their metabolites by UV reflectance photometry of thin layer chromatograms. Eur. J. Clin. Pharmacol. 9, 457–465 (1976)

    CAS  Google Scholar 

  • Breyer, U., Winne, D.: Absorption and metabolism of the phenothiazine drug perazine in the rat intestinal loop. Biochem. Pharmacol. 26, 1275–1280 (1977)

    CAS  Google Scholar 

  • Breyer, U., Gaertner, H.J., Prox, A.: Formation of identical metabolites from piperazine- and dimethylamino-substituted phenothiazine drugs in man, rat and dog. Biochem. Pharmacol. 23, 313–322 (1974a)

    PubMed  CAS  Google Scholar 

  • Breyer, U., Prox, A., Bertele, R., Gaertner, H.J.: Tissue metabolites of trifluoperazine, fluphenazine, prochlorperazine and perphenazine in the rat: Identification and synthesis. J. Pharm. Sci. 63, 1842–1848 (1974b)

    PubMed  CAS  Google Scholar 

  • Breyer, U., Jahns, J., Irmscher, G., Rassner, H., Rehmer, S.: Kinetics of 35S-perazine in the bile fistula rat. Naunyn Schmiedebergs Arch. Pharmacol. 300, 47–56 (1977)

    PubMed  CAS  Google Scholar 

  • Breyer-Pfaff, U., Kreft, H., Rassner, H., Prox, A.: Formation of sulfone metabolites from chlorpromazine and perazine in man. Drug Metab. Dispos., 6, 114–119 (1978)

    PubMed  CAS  Google Scholar 

  • Brookes, L.G., Forrest, I.S.: In vitro metabolism of 3H-chlorpromazine in various mammals: a preliminary report on 13 species. Exp. Med. Surg. 29, 61–71 (1971)

    PubMed  CAS  Google Scholar 

  • Bruce, R.B., Turnbull, L.B., Newman, J.H., Kinzie, J.M., Morris, P.H., Pinchbeck, F.M.: Butaperazine dimaleate metabolism. Xenobiotica 4, 197–207 (1974)

    PubMed  CAS  Google Scholar 

  • Cassano, G.B., Placidi, G.F.: Penetration and distribution of neuropharmacological agents in the brain. Pharmakopsychiatr. Neuropsychopharmakol. 2, 160–175 (1969)

    CAS  Google Scholar 

  • Christensen, J., Wase, A.W.: Metabolism of S35-chlorpromazine. Fed. Proc. 15, 410 (1956)

    Google Scholar 

  • Coccia, P.F., Westerfeld, W.W.: The metabolism of chlorpromazine by liver microsomal enzyme systems. J. Pharmacol. Exp. Ther. 157, 446–458 (1967)

    PubMed  CAS  Google Scholar 

  • Creese, I., Burt, D.R., Snyder, S.H.: Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192, 481–483 (1976)

    PubMed  CAS  Google Scholar 

  • Cressman, W.A., Plostnieks, J., Johnson, P.C.: Absorption, metabolism and excretion of droperidol by human subjects following intramuscular and intravenous administration. Anesthesiology 38, 363–369 (1973)

    PubMed  CAS  Google Scholar 

  • Curry, S.H., Evans, S.: Assay of 7-hydroxychlorpromazine, and failure to detect more than small quantities, in plasma of responding schizophrenics. Psychopharmacol. Commun. 1, 481–490(1975)

    PubMed  CAS  Google Scholar 

  • Curry, S.H., Marshall, J.H.L.: Plasma levels of chlorpromazine and some of its relatively nonpolar metabolites in psychiatric patients. Life Sci. 7, 9–17 (1968)

    PubMed  CAS  Google Scholar 

  • Curry, S.H., Derr, J.E., Maling, H.M.: The physiological disposition of chlorpromazine in the rat and dog. Proc. Soc. Exp. Biol. Med. 134, 314–318 (1970)

    PubMed  CAS  Google Scholar 

  • Curry, S.H., D’Mello, A., Mould, G.P.: Destruction of chlorpromazine during absorption in the rat in vivo and in vitro. Br. J. Pharmacol. 42, 403–411 (1971)

    PubMed  CAS  Google Scholar 

  • Daly, J.W., Manian, A.A.: The metabolism of hydroxychlorpromazines by rat liver microsomes. Biochem. Pharmacol. 16, 2131–2136 (1967)

    PubMed  CAS  Google Scholar 

  • Daly, J.W., Manian, A.A.: The action of catechol-O-methyltransferase on 7,8-dihydroxychlorpromazine — Formation of 7-hydroxy-8-methoxychlorpromazine and 8-hydroxy-7-methoxychlorpromazine. Biochem. Pharmacol. 18, 1235–1238 (1969)

    PubMed  CAS  Google Scholar 

  • De Leenheer, A.P.: Identification and quantitative determination of phenothiazine drugs in urine samples of psychiatric patients. J. Pharm. Sci. 63, 389–394 (1974)

    PubMed  Google Scholar 

  • Dingeil, J.V., Sossi, N.: Studies on the glucuronidation of 7-hydroxychlorpromazine in vitro. Drug Metab. Dispos. 5, 397–404 (1977)

    Google Scholar 

  • Dreyfuss, J., Cohen, A.I.: Identification of 7-hydroxyfluphenazine as major metabolite of fluphenazine-14C in the dog. J. Pharm. Sci. 60, 826–828 (1971)

    PubMed  CAS  Google Scholar 

  • Dreyfuss, J., Ross Jr., J.J., Schreiber, E.C.: Biological disposition and metabolic fate of fluphenazine-14C in the dog and rhesus monkey. J. Pharm. Sci. 60, 821–825 (1971)

    PubMed  CAS  Google Scholar 

  • Dreyfuss, J., Beer, B., Devine, D.D., Roberts, B.F., Schreiber, E.C.: Fluphenazine-induced Parkinsonism in the baboon: Pharmacological and metabolic studies. Neuropharmacology 11, 223–230 (1972)

    PubMed  CAS  Google Scholar 

  • Dreyfuss, J., Ross Jr., J.J., Shaw, J.M., Miller, L, Schreiber, E.C.: Release and elimination of 14C-fluphenazine enanthate and decanoate esters administered in sesame oil to dogs. J. Pharm. Sci. 65, 502–507 (1976 a)

    PubMed  CAS  Google Scholar 

  • Dreyfuss, J., Shaw, J.M., Ross Jr., J.J.: Fluphenazine enanthate and fluphenazine decanoate: Intramuscular injection and esterification as requirements for slow-release characteristics in dogs. J. Pharm. Sci. 65, 1310–1315 (1976b)

    PubMed  CAS  Google Scholar 

  • Ebert, A.G., Hess, S.M.: The distribution and metabolism of fluphenazine enanthate. J. Pharmacol. Exp. Ther. 148, 412–421 (1965)

    PubMed  CAS  Google Scholar 

  • Eckert, H., Hopf, A.: Autoradiographic studies in the distribution of psychoactive drugs in the rat brain. IV. 14C-Thioridazine. Int. Pharmacopsychiatry 4, 98–116 (1970)

    CAS  Google Scholar 

  • Emmerson, J.L., Miya, T.S.: Metabolism of phenothiazine drugs. J. Pharm. Sci. 52, 411–419 (1963)

    CAS  Google Scholar 

  • Fishman, V., Goldenberg, H.: Metabolism of chlorpromazine. IV. Identification of 7-hydroxychlorpromazine and its sulfoxide and desmethyl derivatives. Proc. Soc. Exp. Biol. Med. 112, 501–506 (1963)

    PubMed  CAS  Google Scholar 

  • Fishman, V., Goldenberg, H.: Side-chain degradation and ring hydroxylation of phenothiazine tranquilizers. J. Pharmacol. Exp. Ther. 150, 122–128 (1965)

    PubMed  CAS  Google Scholar 

  • Fishman, V., Heaton, A., Goldenberg, H.: Metabolism of chlorpromazine. III. Isolation and identification of chlorpromazine-N-oxide. Proc. Soc. Exp. Biol. Med. 109, 548–552 (1962)

    PubMed  CAS  Google Scholar 

  • Forrest, I.S., Forrest, F.M.: On the metabolism and action mechanism of the phenothiazine drugs. Exp. Med. Surg. 21, 231–240 (1963)

    PubMed  CAS  Google Scholar 

  • Forrest, I.S., Bolt, A.G., Serra, M.T.: Distribution of chlorpromazine metabolites in selected organs of psychiatric patients chronically dosed up to the time of death. Biochem. Pharmacol. 17, 2061–2070 (1968)

    PubMed  CAS  Google Scholar 

  • Forrest, I.S., Fox, J., Green, D.E., Melikian, A.P., Serra, M.T.: Total excretion of 3H-chlorpromazine and 3H-prochlorperazine in chronically dosed animals: Balance sheet. Adv. Biochem. Psychopharmacol. 9, 347–356 (1974)

    PubMed  CAS  Google Scholar 

  • Forrest, I.S., Green, D.E., Serra, M.T., Soave, O.A.: Chlorpromazine excretion in chronically dosed primates. I. Occurrence of a previously unreported class of chlorpromazine conjugates. Psychopharmacol. Commun. 1, 51–59 (1975)

    PubMed  CAS  Google Scholar 

  • Forsman, A., Fölsch, G., Larsson, M., Öhman, R.: On the metabolism of haloperidol in man. Curr. Ther. Res. 21, 606–617 (1977)

    CAS  Google Scholar 

  • Gaertner, H.J., Breyer, U., Liomin, G.: Metabolism of trifluoperazine, fluphenazine, prochlorperazine and perphenazine in rats: In vitro and urinary metabolites. Biochem. Pharmacol. 23, 303–311 (1974)

    PubMed  CAS  Google Scholar 

  • Gaertner, H.J., Liomin, G., Villumsen, D., Bertele, R., Breyer, U.: Tissue metabolites of trifluoperazine, fluphenazine, prochlorperazine, and perphenazine. Kinetics in chronic treatment. Drug Metab. Dispos. 3, 437–444 (1975)

    PubMed  CAS  Google Scholar 

  • Gauch, R., Michaelis, W.: The metabolism of 8-chloro-11-(4-methyl-l-piperazinyl)-5H-dibenzo[b,e][l,4]diazepine (clozapine) in mice, dogs and human subjects. Farmaco [Prat.] 26, 667–681 (1971)

    CAS  Google Scholar 

  • Goldenberg, H., Fishman, V.: Metabolism of chlorpromazine. V. Confirmation of position 7 as major site of hydroxylation. Biochem. Biophys. Res. Commun. 14, 404–407 (1964)

    PubMed  CAS  Google Scholar 

  • Goldenberg, H., Fishman, V., Heaton, A., Burnett, R.: A detailed evaluation of promazine metabolism. Proc. Soc. Exp. Biol. Med. 115, 1044–1051 (1964)

    PubMed  CAS  Google Scholar 

  • Gorrod, J.W., Lazarus, C.R., Beckett, A.H.: Some aspects of the in vitro oxidation of 35S-chlorpromazine. Adv. Biochem. Psychopharmacol. 9, 191–200 (1974)

    PubMed  CAS  Google Scholar 

  • Goucher, C, Windle, J.J., Levy, L.: Stable enzyme inhibitors and stable free radical species in ultraviolet-irradiated solutions of chlorpromazine. Mol. Pharmacol. 11, 603–612 (1975)

    PubMed  CAS  Google Scholar 

  • Gruenke, L.D., Craig, J.C., Dinovo, E.C., Gottschalk, L.A., Noble, E.P., Biener, R.: Identification of a metabolite of thioridazine and mesoridazine from human plasma. Res. Commun. Chem. Pathol. Pharmacol. 10, 221–225 (1975)

    PubMed  CAS  Google Scholar 

  • Hammar, C.-G., Holmstedt, B., Ryhage, R.: Mass fragmentography. Identification of chlorpromazine and its metabolites in human blood by a new method. Anal. Biochem. 25, 532–548 (1968)

    PubMed  CAS  Google Scholar 

  • Harinath, B.C., Odell, G.V.: Chlorpromazine-N-oxide formation by subcellular liver fractions. Biochem. Pharmacol. 17, 167–171 (1968)

    PubMed  CAS  Google Scholar 

  • Höllt, V., Czlonkowski, A., Herz, A.: The demonstration in vivo of specific binding sites for neuroleptic drugs in mouse brain. Brain Res. 130, 176–183 (1977)

    PubMed  Google Scholar 

  • Idänpään-Heikkilä, J.E., Vapaatalo, H.I., Neuvonen, P.J.: Effect of N-hydroxyethylpromethazine (Aprobit®) on the distribution of 35S-chlorpromazine studied by autoradiography in cats and mice. Psychopharmacologia 13, 1–13 (1968)

    PubMed  Google Scholar 

  • Israili, Z.H., Dayton, P.G., Kiechel, J.R.: Novel routes of drug metabolism. A survey. Drug Metab. Dispos. 5, 411–415 (1977)

    PubMed  CAS  Google Scholar 

  • Janssen, P.A.J., Allewijn, F.T.N.: Pimozide, a chemically novel, highly potent and orally longacting neuroleptic drug. Part II: Kinetic study of the distribution of pimozide and metabolites in brain, liver and blood of the Wistar rat. Arzneim. Forsch. 18, 279–282 (1968)

    CAS  Google Scholar 

  • Janssen, P.A.J., Allewijn, F.T.N.: The distribution of the butyrophenones haloperidol, trifluperidol, moperone, and clofuperol in rats, and its relationship with their neuroleptic activity. Arzneim. Forsch. 19, 199–208 (1969)

    CAS  Google Scholar 

  • Johnson, D.E., Rodriguez, CF., Burchfield, H.P.: Determination by microcoulometric gas chromatography of chlorpromazine metabolites in human urine. Biochem. Pharmacol. 14, 1453–1469 (1965)

    PubMed  CAS  Google Scholar 

  • Jørgensen, A., Fredericson Overø, K., Hansen, V.: Metabolism, distribution and excretion of flupenthixol decanoate in dogs and rats. Acta Pharmacol. Toxicol. 29, 339–358 (1971)

    Google Scholar 

  • Kamm, J.J., Gillette, J.R., Brodie, B.B.: Metabolism of chlorpromazine to chlorpromazine sulfoxide by liver microsomes. Fed. Proc. 17, 382 (1958)

    Google Scholar 

  • Kanig, K., Breyer, U.: Urinary metabolites of 10-[3′-(4″-methyl-piperazinyl)-propyl]-phenothi-azine (perazine) in psychiatric patients. II. Individual metabolite patterns and their changes in the course of treatment. Psychopharmacologia 14, 211–220 (1969)

    PubMed  CAS  Google Scholar 

  • Kaul, P.N., Conway, M.W., Ticku, M.K., Clark, M.L.: Chlorpromazine metabolism II: Determination of nonconjugated metabolites in blood of schizophrenic patients. J. Pharm. Sci. 61, 581–585 (1972)

    PubMed  CAS  Google Scholar 

  • Kawashima, K., Dixon, R., Spector, S.: Development of radioimmunoassay for chlorpromazine. Eur. J. Pharmacol. 32, 195–202 (1975 a)

    PubMed  CAS  Google Scholar 

  • Kawashima, K., Wurzburger, R.I., Spector, S.: Correlation of chlorpromazine levels in rat brain and serum with its hypothermic effect. Psychopharmacol. Commun. 1, 431–436 (1975 b)

    PubMed  CAS  Google Scholar 

  • Khan, A.R.: Some aspects of clopenthixol metabolism in rats and humans. Acta Pharmacol. Toxicol. 27, 202–212 (1969)

    CAS  Google Scholar 

  • Knoll, R., Christ, W., Müller-Oerlinghausen, B., Coper, H.: Formation of chlorpromazine sulphoxide and monodesmethylchlorpromazine by microsomes of small intestine. Naunyn Schmiedebergs Arch. Pharmacol. 297, 195–200 (1977)

    PubMed  CAS  Google Scholar 

  • Krauss, D., Otting, W., Breyer, U.: Identification of a urinary metabolite of perazine as a piperazine-2,5-dione derivative. J. Pharm. Pharmacol. 21, 808–813 (1969)

    PubMed  CAS  Google Scholar 

  • Laduron, P., Leysen, J.: Specific in vivo binding of neuroleptic drugs in rat brain. Biochem. Pharmacol. 26, 1003–1007 (1977)

    PubMed  CAS  Google Scholar 

  • Laduron, P.M., Janssen, P.F.M., Leysen, J.E.: Spiperone: A ligand of choice for neuroleptic receptors. II. Regional distribution and in vivo displacement of neuroleptic drugs. Biochem. Pharmacol. 27, 317–321 (1978 a)

    PubMed  CAS  Google Scholar 

  • Laduron, P.M., Janssen, P.F.M., Leysen, J.E.: Spiperone: A lingand of choice for neuroleptic receptors. III. Subcellular distribution of neuroleptic drugs and their receptors in various rat brain areas. Biochem. Pharmacol. 27, 323–328 (1978 b)

    PubMed  CAS  Google Scholar 

  • Lewi, P.J., Heykants, J.J.P., Allewijn, F.T.N., Dony, J.G.H., Janssen, P.A.J.: Distribution and metabolism of neuroleptic drugs. Part I: Pharmacokinetics of haloperidol. Arzneim. Forsch. 20, 943–948 (1970 a)

    CAS  Google Scholar 

  • Lewi, P.J., Heykants, J.J.P., Janssen, P.A.J.: On the distribution and metabolism of neuroleptic drugs. Part III: Pharmacokinetics of trifluperidol. Arzneim. Forsch. 20, 1701–1705 (1970 b)

    CAS  Google Scholar 

  • Leysen, J.E., Gommeren, W., Laduron, P.M.: Spiperone: A ligand of choice for neuroleptic receptors. I. Kinetics and characteristics of in vitro binding. Biochem. Pharmacol. 27, 307–316 (1978)

    PubMed  CAS  Google Scholar 

  • Lin, T.H., Reynolds, L.W., Rondish, I.M., Van Loon, E.J.: Isolation and characterization of glucuronic acid conjugates of chlorpromazine in human urine. Proc. Soc. Exp. Biol. Med. 102, 602–605 (1959)

    PubMed  CAS  Google Scholar 

  • Lindquist, N.G., Uliberg, S.: The melanin affinity of chloroquine and chlorpromazine studied by whole body autoradiography. Acta Pharmacol. Toxicol. 31, Suppl. 2, 1–32 (1972)

    Google Scholar 

  • Mackay, A.V.P., Healey, A.F., Baker, J.: The relationship of plasma chlorpromazine to its 7-hydroxy and suphoxide metabolites in a large population of chronic schizophrenics. Br. J. Clin. Pharmacol. 1, 425–430 (1974)

    Google Scholar 

  • Mahju, M.A., Maickel, R.P.: Accumulation of phenothiazine tranquilizers in rat brain and plasma after repeated dosage. Biochem. Pharmacol. 18, 2701–2710 (1969)

    PubMed  CAS  Google Scholar 

  • Maickel, R.P., Fedynskyj, N.M., Potter, W.Z., Manian, A.A.: Tissue localization of 7- and 8-hydroxychloropromazines. Toxicol. Appl. Pharmacol. 28, 8–17 (1974)

    PubMed  CAS  Google Scholar 

  • March, J.E., Donato, D., Turano, P., Turner, W.J.: Interpatient variation and significance of plasma levels of chlorpromazine in psychiatric patients. J. Med. (Basel) 3, 146–162 (1972)

    CAS  Google Scholar 

  • Mårtensson, E., Nyberg, G., Axelsson, R., Serck-Hansen, K.: Quantitative determination of thioridazine and nonconjugated thioridazine metabolites in serum and urine of psychiatric patients. Curr. Ther. Res. 18, 687–700 (1975)

    PubMed  Google Scholar 

  • Meier, J.: Bioanalytical assay of clozapine and its N-oxide metabolite and the determination of their blood levels in the dog. Br. J. Pharmacol. 53, 440P (1975)

    PubMed  CAS  Google Scholar 

  • Minder, R., Schnetzer, F., Bickel, M.H.: Hepatic and extrahepatic metabolism of the psychotropic drugs, chlorpromazine, imipramine, and imipramine N-oxide. Naunyn Schmiedebergs Arch. Pharmacol. 268, 334–347 (1971)

    PubMed  CAS  Google Scholar 

  • Mjörndal, T., Wiesel, F.-A., Oreland, L.: Biochemical and behavioral effects of thiothixene: Relation to tissue levels of the drug. Acta Pharmacol. Toxicol. 38, 490–496 (1976)

    Google Scholar 

  • Nybäck, H., Sedvall, G.: Effect of chlorpromazine and some of its metabolites on synthesis and turnover of catecholamines formed from 14C-tyrosine in mouse brain. Psychopharma-cologia 26, 155–160 (1972)

    Google Scholar 

  • Öhman, R., Larsson, M., Nilsson, I.M., Engel, J., Carlsson, A.: Neurometabolic and behavioral effects of haloperidol. Relation to drug levels in serum and in brain. Naunyn Schmiedebergs Arch. Pharmacol. 299, 105–114 (1977)

    PubMed  Google Scholar 

  • Palmer, G.C., Manian, A.A.: Actions of phenothiazine analogues on dopamine-sensitive adenylate cyclase in neuronal and glial-enriched fractions from rat brain. Biochem. Pharmacol. 25, 63–71 (1976)

    PubMed  CAS  Google Scholar 

  • Phillips, B.M., Miya, T.S.: Disposition of S35-prochlorperazine in the rat. J. Pharm. Sci. 53, 1098–1101(1964)

    PubMed  CAS  Google Scholar 

  • Piette, L.H., Forrest, LS.: EPR studies of free radicals in the oxidation of drugs derived from phenothiazine in vitro. Biochim. Biophys. Acta 57, 419–420 (1962)

    PubMed  CAS  Google Scholar 

  • Prema, K., Gopinathan, K.P.: Distribution, induction and purification of a monooxygenase catalyzing sulphoxidation of drugs. Biochem. Pharmacol. 25, 1299–1303 (1976)

    PubMed  CAS  Google Scholar 

  • Raaflaub, J.: Zum Metabolismus des Chlorprothixen. Arzneim. Forsch. 17, 1393–1395 (1967)

    CAS  Google Scholar 

  • Rand, M.J., Jurevics, H.: The pharmacology of Rauwolfia alkaloids. In: Handbuch der experimentellen Pharmakologie, Vol. XXXIX. Berlin, Heidelberg, New York: Springer 1977

    Google Scholar 

  • Rivera-Calimlim, L.: Impaired absorption of chlorpromazine in rats given trihexyphenidyl. Br. J. Pharmacol. 56, 301–305 (1976)

    PubMed  CAS  Google Scholar 

  • Rodriguez, C.F., Johnson, D.E.: A new metabolite of chlorpromazine in human urine. Life Sci. 5, 1283–1291 (1966)

    CAS  Google Scholar 

  • Rose, R.M., Dimascio, A., Klerman, G.L.: Non-polar urinary metabolites of chlorpromazine in male schizophrenics. J. Psychiatr. Res. 2, 299–305 (1964)

    CAS  Google Scholar 

  • Sakalis, G., Chan, T.L., Gershon, S., Park, S.: The possible role of metabolites in therapeutic response to chlorpromazine treatment. Psychopharmacologia 32, 279–284 (1973)

    PubMed  CAS  Google Scholar 

  • Sakurai, Y., Nakahara, T., Takahashi, R.: Prediction of response to chlorpromazine treatment in schizophrenics. Psychopharmacologia 44, 195–203 (1975)

    PubMed  CAS  Google Scholar 

  • Salzman, N.P., Brodie, B.B.: Physiological disposition and fate of chlorpromazine and a method for its estimation in biological material. J. Pharmacol. Exp. Ther. 118, 46–54 (1956)

    PubMed  CAS  Google Scholar 

  • Salzman, N.P., Moran, N.C., Brodie, B.B.: Identification and pharmacological properties of a major metabolite of chlorpromazine. Nature 176, 1122–1123 (1955)

    PubMed  CAS  Google Scholar 

  • Sanders, G.T.B.: Distribution of some structurally related pharmacological agents in rat brain. Biochem. Pharmacol. 22, 601–607 (1973)

    PubMed  CAS  Google Scholar 

  • Schmalzing, G.: Metabolism and disposition of trifluoperazine in the rat. II. Kinetics after oral and intravenous administration in acutely and chronically treated animals. Drug Metab. Dispos. 5, 104–115(1977)

    PubMed  CAS  Google Scholar 

  • Schmalzing, G., Breyer, U.: Kinetics of [3H]trifluoperazine in bile fistula rats. Xenobiotica 8, 45–54 (1978)

    PubMed  CAS  Google Scholar 

  • Seeman, P., Lee, T., Chau-Wong, M., Wong, K.: Antipsychotic drug doses and neuroleptic/ dopamine receptors. Nature 261, 717–719 (1976)

    PubMed  CAS  Google Scholar 

  • Sjöstrand, S.E., Cassano, G.B., Hansson, E.: The distribution of 35S-chlorpromazine in mice studied by whole body autoradiography. Arch. Int. Pharmacodyn. Ther. 156, 34–47 (1965)

    PubMed  Google Scholar 

  • Soudijn, W., Van Wijngaarden, I.: The metabolism and excretion of the neuroleptic drug pimozide (R 6238) by the Wistar rat. Life Sci. 8, Part I, 291–295 (1969)

    PubMed  CAS  Google Scholar 

  • Soudijn, W., Van Wijngaarden, I., Allewijn, F.: Distribution, excretion and metabolism of neuroleptics of the butyrophenone type. Part I. Excretion and metabolism of haloperidol and nine related butyrophenone-derivatives in the Wistar rat. Eur. J. Pharmacol. 1, 47–57 (1967)

    PubMed  CAS  Google Scholar 

  • Spano, P.F., Neff, N.H., Macko, E., Costa, E.: Efflux of chlorpromazine and trifluoperazine from the rat brain. J. Pharmacol. Exp. Ther. 174, 20–26 (1970)

    PubMed  CAS  Google Scholar 

  • Spirtes, M.A.: Two types of metabolically produced trifluoperazine N-oxides. Adv. Biochem. Psychopharmacol. 9, 399–404 (1974)

    PubMed  CAS  Google Scholar 

  • Stitzel, R.E.: The biological fate of reserpine. Pharmacol. Rev. 28, 179–205 (1976)

    PubMed  CAS  Google Scholar 

  • Stock, B., Spiteller, G., Heipertz, R.: Austausch aromatisch gebundenen Halogens gegen OH-und SCH3- bei der Metabolisierung des Clozapins im menschlichen Körper. Arzneim. Forsch. 27, 982–990 (1977)

    CAS  Google Scholar 

  • Tinani, H.: Relationships between some physicochemical properties, pharmacokinetic parameters and pharmacological activities of tricyclic neurotropic agents. Thesis, Eidgenössische Technische Hochschule Zürich 1975

    Google Scholar 

  • Turano, P., March, J.E., Turner, W.J., Merlis, S.: Qualitative and quantitative report on chlorpromazine and metabolites in plasma, erythrocytes and erythrocyte washings from chronically medicated schizophrenic patients. J. Med. (Basel) 3, 109–120 (1972)

    CAS  Google Scholar 

  • Turano, P., Turner, W.J., Manian, A.A.: Thin-layer chromatography of chlorpromazine metabolites. Attempt to identify each of the metabolites appearing in blood, urine and feces of chronically medicated schizophrenics. J. Chromatogr. 75, 277–293 (1973)

    PubMed  CAS  Google Scholar 

  • Usdin, E.: The assay of chlorpromazine and metabolites in blood, urine, and other tissues. CRC Crit. Rev. Clin. Lab. Sci. 2, 347–391 (1971)

    PubMed  CAS  Google Scholar 

  • Van Loon, E.J., Flanagan, T.L., Novick, W.J., Maas, A.R.: Hepatic secretion and urinary excretion of three S35-labeled phenothiazines in the dog. J. Pharm. Sci. 53, 1211–1213 (1964)

    Google Scholar 

  • Walkenstein, S.S., Seifter, J.: Fate, distribution and excretion of 35S-promazine. J. Pharmacol. Exp. Ther. 125, 283–286 (1959)

    PubMed  CAS  Google Scholar 

  • West, N.R, Rosenblum, M.P., Sprince, H., Gold, S., Boehme, D.H., Vogel, W.H.: Assay procedures for thioridazine, trifluoperazine, and their sulfoxides and determination of urinary excretion of these compounds in mental patients. J. Pharm. Sci. 63, 417–419 (1974)

    PubMed  CAS  Google Scholar 

  • West, N.R., Vogel, W.H.: Absorption, distribution and excretion of trifluoperazine in rats. Arch. Int. Pharmacodyn. Ther. 215, 318–335 (1975)

    PubMed  CAS  Google Scholar 

  • Whelpton, R., Curry, S.H.: Methods for study of fluphenazine kinetics in man. J. Pharm. Pharmacol. 28, 869–873 (1976)

    PubMed  CAS  Google Scholar 

  • Wiest, E., Prox, A., Wachsmuth, H., Breyer-Pfaff, U.: Aromatic hydroxydation of chlorprothixene in man and dog. Proceedings of the Fourth International Symposium on Phenothiazines and Related Drugs. Amsterdam: Elsevier, in press 1980

    Google Scholar 

  • Wiles, D.H., Kolakowska, T., McNeilly, A.S., Mandelbrote, B.M., Gelder, M.G.: Clinical significance of plasma chlorpromazine levels. I. Plasma levels of the drug, some of its metabolites and prolactin during acute treatment. Psychol. Med. 6, 407–415 (1976)

    PubMed  CAS  Google Scholar 

  • Wilkinson, G.R., Shand, D.G.: Physiological approach to hepatic drug clearance. Clin. Pharmacol. Ther. 18, 377–390 (1975)

    CAS  Google Scholar 

  • Williams, R.T., Parke, D.V.: The metabolic fate of drugs. Annu. Rev. Pharmacol. 4, 85–114 (1964)

    CAS  Google Scholar 

  • Zehnder, K., Kalberer, F., Kreis, W., Rutschmann, J.: The metabolism of thioridazine (Mellaril®) and one of its pyrrolidine analogues in the rat. Biochem. Pharmacol. 11, 535–550 (1962 a)

    PubMed  CAS  Google Scholar 

  • Zehnder, K., Kalberer, F., Rutschmann, J.: The metabolism of thiethylperazine (Torecan®). Biochem. Pharmacol. 11, 551–556 (1962b)

    PubMed  CAS  Google Scholar 

  • Ziegler, D.M., Mitchell, C.H., Jollow, D.: The properties of a purified hepatic microsomal mixed function amine oxidase. In: Microsomes and Drug Oxidations. London: Academic Press 1969

    Google Scholar 

  • Zingales, I.A.: Detection of chlorpromazine and thioridazine metabolites in human erythrocytes. J. Chromatogr. 44, 547–562 (1969)

    PubMed  CAS  Google Scholar 

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Authors
  1. U. Breyer-Pfaff
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Editors and Affiliations

  1. Institut für Pharmakologie, Bayer AG, Aprather Weg 18a, D-5600, Wuppertal 1, Germany

    F. Hoffmeister

  2. Institut für Arzneimittel des Bundesgesundheitsamtes, StauffenbergstraÜe 13, D-100, Berlin 30, Germany

    G. Stille

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Breyer-Pfaff, U. (1980). Metabolism and Kinetics. In: Hoffmeister, F., Stille, G. (eds) Psychotropic Agents. Handbook of Experimental Pharmacology, vol 55 / 1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-67538-6_13

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  • DOI: https://doi.org/10.1007/978-3-642-67538-6_13

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