Abstract
Rationale
Accumulating evidence indicates that modulation of the activity of cytochrome P450 (CYP) enzymes and the multidrug resistance transporter P-glycoprotein (P-gp) is responsible for many drug–drug interactions.
Objectives
The potential interaction of risperidone (RISP), which is metabolized by 2D6 and transported across the blood brain barrier (BBB) by P-gp, was studied in combination with bupropion (BUP) and also with sertraline (SERT).
Methods
BUP, SERT, and RISP were administered intraperitoneally into CF1 mice at doses of 100, 10, and 1 μg/g mouse, respectively. Plasma and brain samples were collected at timed intervals from 0.5 to 6 h. A pharmacokinetic analysis was performed using both traditional compartmental modeling and a population pharmacokinetic approach.
Results
BUP increased the RISP plasma (5.9-fold, P<0.01) and brain (2.2-fold, P<0.01) area under the drug concentration vs time curve (AUC), but did not alter the brain-to-plasma concentration ratio. SERT did not significantly change the plasma AUC of RISP and 9-hydroxy-RISP, but increased the brain AUC of RISP and 9-hydroxy-RISP 1.5-fold (P<0.05) and 5-fold (P<0.01), respectively. RISP did not produce significant alterations of plasma or brain concentrations of BUP. It increased the plasma AUC and elimination half-life (T 1/2e) of desmethyl-SERT 12.5-fold (P<0.01) and 107-fold (P<0.01), respectively.
Conclusions
These results suggest that pharmacokinetic interactions exist among these three psychoactive drugs involving inhibition of drug metabolizing enzymes and/or P-gp and other drug transporters present in the BBB. The mechanisms and consequences of these interactions require further study in humans to establish clinical relevance.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Addington D, Addington J, Patten S, Remington G, Moamai J, Labelle A, Beauclair L (2002) Double-blind, placebo-controlled comparison of the efficacy of sertraline as treatment for a major depressive episode in patients with remitted schizophrenia. J Clin Psychopharmacol 22:20–25
Aguilar MA, Rodriguez-Arias M, Mari-Sanmillan MI, Minarro J (1997) Effects of risperidone on conditioned avoidance responding in male mice. Behav Pharmacol 8:669–876
Alfaro CL, Lam YW, Simpson J, Ereshefsky L (2000) CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: intraindividual variability and plasma concentration correlations. J Clin Pharmacol 40:58–66
Bogaards JJ, Bertrand M, Jackson P, Oudshoorn MJ, Weaver RJ, van Bladeren PJ, Walther B (2000) Determining the best animal model for human cytochrome P450 activities: a comparison of mouse, rat, rabbit, dog, micropig, monkey and man. Xenobiotica 30:1131–1152
Boulton DW, DeVane CL, Liston HL, and Markowitz JS (2002) Human recombinant P-glycoprotein specificity for atypical antipsychotics. Life Sci 71:163–169
Bourin M, Colombel MC, Redrobe JP, Nizard J, Hascoet M, Baker GB (1998) Evaluation of efficacies of different classes of antidepressants in the forced swimming test in mice at different ages. Prog Neuropsychopharmacol Biol Psychiatry 22:343–351
Cooper TB, Suckow RF, Glassman A (1984) Determination of bupropion and its major basic metabolites in plasma by liquid chromatography with dual-wavelength ultraviolet detection. J Pharm Sci 73:1104–1107
Coryell W (1996) Psychotic depression. J Clin Psychiatry 57 (Suppl 3):27–31
Cox DS, Scott KR, Gao H, Eddington ND (2002) Effect of P-glycoprotein on the pharmacokinetics and tissue distribution of enaminone anticonvulsants: analysis by population and physiological approaches. J Pharmacol Exp Ther 302:1096–1104
DeVane CL (1998) Translational pharmacokinetics: current issues with newer antidepressants. Depress Anxiety 8 (Suppl 1):64–70
DeVane CL, Liston HL, Markowitz JS (2002) Clinical pharmacokinetics of sertraline. Clin Pharmacokinet 41:1247–1266
Dodd S, Stocky A, Buist A, Burrows GD, Maguire K, Norman TR (2000) Sertraline in paired blood plasma and breast-milk samples from nursing mothers. Hum Psychopharmacol 15:161–264
Eap CB, Bondolfi G, Zullino D, Bryois C, Fuciec M, Savary L, Jonzier-Perey M, Baumann P (2001) Pharmacokinetic drug interaction potential of risperidone with cytochrome p450 isozymes as assessed by the dextromethorphan, the caffeine, and the mephenytoin test. Ther Drug Monit 23:228–231
Fang J, Bourin M, Baker GB (1999) Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4. Naunyn Schmiedebergs Arch Pharmacol 359:147–151
Guzey C, Norstrom A, Spigset O (2002) Change from the CYP2D6 extensive metabolizer to the poor metabolizer phenotype during treatment with bupropion. Ther Drug Monit 24:436–437
He H, Richardson JS (1995) A pharmacological, pharmacokinetic and clinical overview of risperidone, a new antipsychotic that blocks serotonin 5-HT2 and dopamine D2 receptors. Int Clin Psychopharmacol 10:19–30
Hermann RC, Yang D, Ettner SL et al (2002) Prescription of antipsychotic drugs by office-based physicians in the United Sates, 1989–1997. Psychiatr Serv 53:425–430
Hesse LM, Venkatakrishnan K, Court MH, von Moltke LL, Duan SX, Shader RI, Greenblatt DJ (2000) CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. Drug Metab Dispos 28:1176–1183
Karow A, Lambert M (2003) Polypharmacy in treatment with psychotropic drugs: the underestimated phenomenon. Curr Opin Psychiatry 16:713–718
Kobayashi K, Ishizuka T, Shimada N, Yoshimura Y, Kamijima K, Chiba K (1999) Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro. Drug Metab Dispos 27:763–766
Kotlyar M, Brauer LH, Tracy TS, Hatsukami DK, Harris J, Bronars CA, Adson DE (2005) Inhibition of CYP2D6 activity by bupropion. J Clin Psychopharmacol 25:226–229
Kurt M, Arik AC, Celik S (2000) The effects of sertraline and fluoxetine on anxiety in the elevated plus-maze test in mice. J Basic Clin Physiol Pharmacol 11:173–180
Laizure SC, DeVane CL (1985) Stability of bupropion and its major metabolites in human plasma. Ther Drug Monit 7:447–450
Lane RM (1996) Pharmacokinetic drug interaction potential of selective serotonin reuptake inhibitors. Int Clin Psychopharmacol 11 (Suppl 5):31–61
Liston HL, DeVane CL, Boulton DW, Risch SC, Markowitz JS, Goldman J (2002) Differential time course of cytochrome P450 2D6 enzyme inhibition by fluoxetine, sertraline, and paroxetine in healthy volunteers. J Clin Psychopharmacol 22:169–173
Mahar Doan KM, Humphreys JE, Webster LO, Wring SA, Shampine LJ, Serabjit-Singh CJ, Adkison KK, Polli JW (2002). Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J Pharmacol Exp Ther 303:1029–1037
Mauri MC, Laini V, Cerveri G, Scalvini ME, Volonteri LS, Regispani F, Malvini L, Manfre S, Boscati L, Panza G (2002) Clinical outcome and tolerability of sertraline in major depression: a study with plasma levels. Prog Neuropsychopharmacol Biol Psychiatry 26:597–601
Obach RS, Cox LM, Tremaine LM (2005) Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study. Drug Metab Dispos 33:262–270
Pirraglia PA, Stafford RS, Singer DE (2003) Trends in prescribing of selective serotonin reuptake inhibitors and other newer antidepressant agents in adult primary care. Prim Care Companion J Clin Psychiat 5:153–157
Pollock BG, Sweet RA, Kirshner M, Reynolds CF 3rd (1996) Bupropion plasma levels and CYP2D6 phenotype. Ther Drug Monit 18:581–585
Ronfeld RA, Tremaine LM, Wilner KD (1997) Pharmacokinetics of sertraline and its N-demethyl metabolite in elderly and young male and female volunteers. Clin Pharmacokinet 32 (Suppl 1):22–30
Shad MU, Preskorn SH (1997) A possible bupropion and imipramine interaction. J Clin Psychopharmacol 17:118–119
Shin JG, Soukhova N, Flockhart DA (1999) Effect of antipsychotic drugs on human liver cytochrome P-450 (CYP) isoforms in vitro: preferential inhibition of CYP2D6. Drug Metab Dispos 27:1078–1084
Spina E, Scordo MG, D'Arrigo C (2003) Metabolic drug interactions with new psychotropic agents. Fundam Clin Pharmacol 17:517–538
Spina E, D'Arrigo C, Migliardi G, Morgante L, Zoccali R, Ancione M, Madia A (2004) Plasma risperidone concentrations during combined treatment with sertraline. Ther Drug Monit 26:386–390
Tohen M, Vieta E, Calabrese J et al (2003) Efficacy of olanzapine and olanzapine–bluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 60:1079–1088
Wang JS, Ruan Y, Taylor RM, Donovan JL, Markowitz JS, DeVane CL (2004a) The brain entry of risperidone and 9-hydroxyrisperidone are greatly limited by P-glycoprotein. Int J Neuropsychopharmacol 7:415–419
Wang JS, Taylor R, Ruan Y, Donovan JL, Markowitz JS, DeVane CL (2004b) Olanzapine penetration into brain is greater in transgenic Abcb 1a P-glycoprotein deficient mice than FVB1 (wild-type) animals. Neuropsychopharmacology 29:551–557
Weiss J, Dormann SM, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, Haefeli WE (2003) Inhibition of P-glycoprotein by newer antidepressants. J Pharmacol Exp Ther 305:197–204
Acknowledgements
This work was supported by a grant from Janssen Pharmaceutica and by NIH Grant MH071811-01. None of the authors has conflicting interests that interfere with the integrity of the content of the article.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wang, JS., DeVane, C.L., Gibson, B.B. et al. Population pharmacokinetic analysis of drug–drug interactions among risperidone, bupropion, and sertraline in CF1 mice. Psychopharmacology 183, 490–499 (2006). https://doi.org/10.1007/s00213-005-0209-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-005-0209-y