European Neuropsychopharmacology
Volume 20, Issue 8 , Pages 545-552 , August 2010

Effect of hypertriglyceridemia on the pharmacokinetics and blood–brain barrier penetration of clozapine and norclozapine following administration to rats

  • Pavel Gershkovich

      Affiliations

    • Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
    • Corresponding Author InformationCorresponding author. Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall Avenue, Vancouver, BC, Canada V6T 1Z3. Tel.: +1 604 822 6772; fax: +1 604 822 3035.
  • ,
  • Olena Sivak

      Affiliations

    • Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
  • ,
  • Aishwariya Sharma

      Affiliations

    • Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
  • ,
  • Alasdair M. Barr

      Affiliations

    • Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada
  • ,
  • Ric Procyshyn

      Affiliations

    • BC Mental Health and Addictions Research Institute, Vancouver, BC, Canada
  • ,
  • Kishor M. Wasan

      Affiliations

    • Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada

Received 17 October 2009 ,Revised 31 December 2009 ,Accepted 21 January 2010.

References 

  1. Atmaca M, Kuloglu M, Tezcan E, Ustundag B. Serum leptin and triglyceride levels in patients on treatment with atypical antipsychotics. J. Clin. Psychiatry. 2003;64:598–604
  2. Baldessarini RJ, Centorrino F, Flood JG, Volpicelli SA, Huston-Lyons D, Cohen BM. Tissue concentrations of clozapine and its metabolites in the rat. Neuropsychopharmacology. 1993;9:117–124
  3. Baymiller SP, Ball P, McMahon RP, Buchanan RW. Serum glucose and lipid changes during the course of clozapine treatment: the effect of concurrent beta-adrenergic antagonist treatment. Schizophr. Res. 2003;59:49–57
  4. Brocks DR, Wasan KM. The influence of lipids on stereoselective pharmacokinetics of halofantrine: important implications in food-effect studies involving drugs that bind to lipoproteins. J. Pharm. Sci. 2002;91:1817–1826
  5. Brocks DR, Ala S, Aliabadi HM. The effect of increased lipoprotein levels on the pharmacokinetics of cyclosporine A in the laboratory rat. Biopharm. Drug Dispos. 2006;27:7–16
  6. Dehouck B, Fenart L, Dehouck MP, Pierce A, Torpier G, Cecchelli R. A new function for the LDL receptor: transcytosis of LDL across the blood–brain barrier. J. Cell Biol. 1997;138:877–889
  7. Dursun SM, Szemis A, Andrews H, Reveley MA. The effects of clozapine on levels of total cholesterol and related lipids in serum of patients with schizophrenia: a prospective study. J. Psychiatry Neurosci. 1999;24:453–455
  8. Essali A, Al-Haj Haasan N, Li C, Rathbone J. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst. Rev. 2009;1:CD000059
  9. Gershkovich P, Hoffman A. Uptake of lipophilic drugs by plasma derived isolated chylomicrons: linear correlation with intestinal lymphatic bioavailability. Eur. J. Pharm. Sci. 2005;26:394–404
  10. Gershkovich P, Hoffman A. Effect of a high-fat meal on absorption and disposition of lipophilic compounds: the importance of degree of association with triglyceride-rich lipoproteins. Eur. J. Pharm. Sci. 2007;32:24–32
  11. Gershkovich P, Shtainer D, Hoffman A. The effect of a high-fat meal on the pharmacodynamics of a model lipophilic compound that binds extensively to triglyceride-rich lipoproteins. Int. J. Pharm. 2007;333:1–4
  12. Gershkovich P, Fanous J, Qadri B, Yacovan A, Amselem S, Hoffman A. The role of molecular physicochemical properties and apolipoproteins in association of drugs with triglyceride-rich lipoproteins: in-silico prediction of uptake by chylomicrons. J. Pharm. Pharmacol. 2009;61:31–39
  13. Ghaeli P, Dufrense RI. Elevated serum triglycerides on clozapine resolve with risperidone. Pharmacotherapy. 1995;15:382–383
  14. Gupta SK, Benet LZ. High-fat meals increase the clearance of cyclosporine. Pharm. Res. 1990;7:46–48
  15. Gupta SK, Manfro RC, Tomlanovich SJ, Gambertoglio JG, Garovoy MR, Benet LZ. Effect of food on the pharmacokinetics of cyclosporine in healthy subjects following oral and intravenous administration. J. Clin. Pharmacol. 1990;30:643–653
  16. Hamdy DA, Brocks DR. Experimental hyperlipidemia causes an increase in the electrocardiographic changes associated with amiodarone. J. Cardiovasc. Pharmacol. 2009;53:1–8
  17. Henderson DC, Cagliero E, Gray C, Nasrallah RA, Hayden DL, Schoenfeld DA, et al. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: a five-year naturalistic study. Am. J. Psychiatry. 2000;157:975–981
  18. Humberstone AJ, Porter CJ, Edwards GA, Charman WN. Association of halofantrine with postprandially derived plasma lipoproteins decreases its clearance relative to administration in the fasted state. J. Pharm. Sci. 1998;87:936–942
  19. Leadbetter R, Shutty M, Pavalonis D, Vieweg V, Higgins P, Downs M. Clozapine-induced weight gain: prevalence and clinical relevance. Am. J. Psychiatry. 1992;149:68–72
  20. Mendoza MC, Lindenmayer JP. N-desmethylclozapine: is there evidence for its antipsychotic potential?. Clin. Neuropharmacol. 2009;32:154–157
  21. Pande S, Procyshyn RM, Nazerali M, Attwood D, Chow K. Do triglycerides modulate the effectiveness of clozapine?. Int. Clin. Psychopharmacol. 2002;17:197–199
  22. Patel JP, Fleischer JG, Wasan KM, Brocks DR. The effect of experimental hyperlipidemia on the stereoselective tissue distribution, lipoprotein association and microsomal metabolism of (+/−)-halofantrine. J. Pharm. Sci. 2009;98:2516–2528
  23. Procyshyn RM, Kennedy NB, Marriage S, Wasan KM. Plasma protein and lipoprotein distribution of clozapine. Am. J. Psychiatry. 2001;158:949–951
  24. Procyshyn RM, Wasan KM, Thornton AE, Barr AM, Chen EY, Pomarol-Clotet E, et al. Changes in serum lipids, independent of weight, are associated with changes in symptoms during long-term clozapine treatment. J. Psychiatry Neurosci. 2007;32:331–338
  25. Procyshyn RM, Honer WG, Barr AM. Do serum lipids predict response to clozapine treatment?. J. Psychiatry Neurosci. 2009;34:168
  26. Rosland M, Szeto P, Procyshyn R, Barr AM, Wasan KM. Determination of clozapine and its metabolite, norclozapine in various biological matrices using high-performance liquid chromatography. Drug Dev. Ind. Pharm. 2007;33:1158–1166
  27. Shayeganpour A, Jun AS, Brocks DR. Pharmacokinetics of amiodarone in hyperlipidemic and simulated high fat-meal rat models. Biopharm. Drug Dispos. 2005;26:249–257
  28. Shayeganpour A, Korashy H, Patel JP, El-Kadi AO, Brocks DR. The impact of experimental hyperlipidemia on the distribution and metabolism of amiodarone in rat. Int. J. Pharm. 2008;361:78–86
  29. Spivak B, Lamschtein C, Talmon Y, Guy N, Mester R, Feinberg I, et al. The impact of clozapine treatment on serum lipids in chronic schizophrenic patients. Clin. Neuropharmacol. 1999;22:98–101
  30. Sun L, Lau CE. Intravenous and oral clozapine pharmacokinetics, pharmacodynamics, and concentration–effect relations: acute tolerance. Eur. J. Pharmacol. 2000;398:225–238
  31. Vampini C, Steinmayr M, Bilone F. The increase of plasma levels of triglyceride during clozapine treatment: a case report. Neuropsychopharmacology. 1994;10:249s
  32. Vance JE, Karten B, Hayashi H. Lipid dynamics in neurons. Biochem. Soc. Trans. 2006;34:399–403
  33. Wasan KM. Modifications in plasma lipoprotein concentration and lipid composition regulate the biological activity of hydrophobic drugs. J. Pharmacol. Toxicol. Methods. 1996;36:1–11
  34. Wasan KM, Pritchard PH, Ramaswamy M, Wong W, Donnachie EM, Brunner LJ. Differences in lipoprotein lipid concentration and composition modify the plasma distribution of cyclosporine. Pharm. Res. 1997;14:1613–1620
  35. Wasan KM, Ramaswamy M, Kwong M, Boulanger KD. Role of plasma lipoproteins in modifying the toxic effects of water-insoluble drugs: studies with cyclosporine A. AAPS PharmSci. 2002;4:E30
  36. Wasan KM, Brocks DR, Lee SD, Sachs-Barrable K, Thornton SJ. Impact of lipoproteins on the biological activity and disposition of hydrophobic drugs: implications for drug discovery. Nat. Rev. Drug Discov. 2008;7:84–99
  37. Weigmann H, Hartter S, Fischer V, Dahmen N, Hiemke C. Distribution of clozapine and desmethylclozapine between blood and brain in rats. Eur Neuropsychopharmacol. 1999;9:253–256
  38. Wirshing DA, Boyd JA, Meng LR, Ballon JS, Marder SR, Wirshing WC. The effects of novel antipsychotics on glucose and lipid levels. J. Clin. Psychiatry. 2002;63:856–865
  39. Yamauchi K, Tozuka M, Nakabayashi T, Sugano M, Hidaka H, Kondo Y, et al. Apolipoprotein E in cerebrospinal fluid: relation to phenotype and plasma apolipoprotein E concentrations. Clin. Chem. 1999;45:497–504

PII: S0924-977X(10)00018-0

doi: 10.1016/j.euroneuro.2010.01.002

European Neuropsychopharmacology
Volume 20, Issue 8 , Pages 545-552 , August 2010