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Cyclosporine A (CsA) affects the pharmacodynamics and pharmacokinetics of the atypical antipsychotic amisulpride probably via inhibition of P-glycoprotein (P-gp)

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Summary.

The importance of P-glycoprotein (P-gp) in the pharmacokinetics of amisulpride and the effects of a P-gp inhibitor cyclosporine A (CsA) was investigated both, in vitro and in vivo.

In vitro and in vivo results indicated amisulpride as a substrate of P-gp. Amisulpride was not metabolized by rat liver microsomes. Open field behavior showed time dependent abolishment in locomotion by amisulpride (50 mg kg−1). Co-administration of CsA (50 mg kg−1) resulted in a higher and significantly longer antipsychotic effect (24 h after drug administration). Accordingly, the area under concentration-time curve in serum and brain was higher in CsA co-treated rats (13.5 vs. 29.8 µmol h l−1 for serum and 2.16 vs 2.98 µmol h l−1 for brain tissue) while renal clearance was not affected.

These results pointed to a pharmacokinetic drug interaction between CsA and amisulpride most likely caused by inhibition of P-gp.

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Abbreviations

AMS:

amisulpride

CsA:

cyclosporine A

APO:

apomorphine

References

  • A Abou el Ela S Härtter U Schmitt C Hiemke H Spahn-Langguth P Langguth (2004) ArticleTitleIdentification of P-glycoprotein substrates and inhibitors among psychoactive compounds – implications for pharmacokinetics of selected substrates J Pharm Pharmacol 56 967–975 Occurrence Handle10.1211/0022357043969 Occurrence Handle1:CAS:528:DC%2BD2cXntFeisb4%3D

    Article  CAS  Google Scholar 

  • S Ayesh YM Shao WD Stein (1996) ArticleTitleCo-operative, competitive and non-competitive interactions between modulators of P-glycoprotein Biochim Biophys Acta 1316 8–18 Occurrence Handle8634345

    PubMed  Google Scholar 

  • JM Baron LB Goh Y Denggao CR Wolf T Friedberg (2001a) ArticleTitleModulation of P450 CYP3A4 dependent metabolism by P-glycoprotein: Implication for P450 phenoty** J Pharmacol Exp Ther 296 351–358 Occurrence Handle1:CAS:528:DC%2BD3MXoslarsQ%3D%3D

    CAS  Google Scholar 

  • JM Baron D Höller R Schiffer S Frankenberg M Neis HF Merk FK Jugert (2001b) ArticleTitleExpression of multiple cytochrome P450 enzymes and multidrug resistance-associated transport proteins in human skin keratinocytes J Invest Dermatol 116 541–548 Occurrence Handle1:CAS:528:DC%2BD3M**vFGlsb0%3D Occurrence Handle10.1046/j.1523-1747.2001.01298.x

    Article  CAS  Google Scholar 

  • CV Borlongan CE Stahl T Fujisaki PR Sanberg S Watanabe (1999) ArticleTitleCyclosporine A-induced hyperactivity in rats: is it mediated by immunosuppression, neurotrophism, or both? Cell Transplant 8 153–159 Occurrence Handle10338283 Occurrence Handle1:STN:280:DyaK1M3mvVKjtw%3D%3D

    PubMed  CAS  Google Scholar 

  • P Borst AH Schinkel (1998) P-glycoprotein, a guardian of the brain WM Pardridge (Eds) Introduction to the blood–brain barrier Cambridge University Press Cambridge 198–206

    Google Scholar 

  • AJ Coukell CM Spencer P Benfield (1996) ArticleTitleAmisulpride. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of schizophrenia CNS Drugs 6 237–256 Occurrence Handle1:CAS:528:DyaK28XmtFCht7c%3D Occurrence Handle10.2165/00023210-199606030-00006

    Article  CAS  Google Scholar 

  • KMM Doan JE Humphreys LO Webster SA Wring LJ Shampine CJ Serabjit KK Adkison JW Polli (2002) ArticleTitlePassive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs J Pharmacol Exp Ther 303 1029–1037 Occurrence Handle1:CAS:528:DC%2BD38XptlamtLg%3D Occurrence Handle10.1124/jpet.102.039255

    Article  CAS  Google Scholar 

  • S Döppenschmitt P Langguth CG Regard TB Andersson C Hilgendorf H Spahn-Langguth (1999) ArticleTitleCharacterization of binding properties to human P-glycoprotein: development of a [3H] verapamil radioligand-binding assay J Pharmacol Exp Ther 288 348–357 Occurrence Handle9862789

    PubMed  Google Scholar 

  • P Doze A van Waarde PH Elsingha NH Hendrikse W Vaalburg (2000) ArticleTitleEnhanced cerebral uptake of receptor ligands by modulation of P-glycoprotein function in the blood–brain barrier Synapse 36 66–74 Occurrence Handle10700027 Occurrence Handle1:CAS:528:DC%2BD3cXhslKrsb0%3D Occurrence Handle10.1002/(SICI)1098-2396(200004)36:1<66::AID-SYN7>3.0.CO;2-J

    Article  PubMed  CAS  Google Scholar 

  • J Drewe HA Ball C Beglinger B Peng A Kemmler H Schächinger WE Haefeli (2000) ArticleTitleEffect of P-glycoprotein modulation on the clinical pharmacokinetics and adverse effects of morphine Br J Clin Pharmacol 50 237–246 Occurrence Handle10971308 Occurrence Handle1:CAS:528:DC%2BD3cXnt1KgtbY%3D Occurrence Handle10.1046/j.1365-2125.2000.00226.x

    Article  PubMed  CAS  Google Scholar 

  • AI Esquifino A Arce MA Vicente-Torres PE Gil-Loyzaga (1998) ArticleTitleEffects of acute and chronic administration of cyclosporine on dopamine metabolism in the rat cochlea J Physiol Biochem 54 149–154 Occurrence Handle10217211 Occurrence Handle1:CAS:528:DyaK1M**tFSqurk%3D

    PubMed  CAS  Google Scholar 

  • MM Gottesman I Pastan (1993) ArticleTitleBiochemistry of multidrug resistance mediated by the multidrug transporter Annu Rev Biochem 62 385–427 Occurrence Handle8102521 Occurrence Handle1:CAS:528:DyaK3sXlsFWnsbY%3D Occurrence Handle10.1146/annurev.bi.62.070193.002125

    Article  PubMed  CAS  Google Scholar 

  • S Härtter S Hüwel T Lohmann A Abou el Ela P Langguth C Hiemke H-J Galla (2003) ArticleTitleHow does the benzamide antipsychotic amisulpride get into the brain? – An in vitro approach comparing amisulpride with clozapine Neuropsychopharmacol 28 1916–1922

    Google Scholar 

  • Hanafy A (2001) Transport inhibition and induction as sources for absorption and disposition related drug drug interactions: Talinolol as model substrate for the ABC transporter P-glycoprotein. Thesis, University Halle/Saale, Germany

  • L Jetté GF Murphy R Béliveau (1998) ArticleTitleDrug binding to P-glycoprotein is inhibited in normal tissues following SDZ-PSC 833 treatment Int J Cancer 76 729–737 Occurrence Handle9610733 Occurrence Handle10.1002/(SICI)1097-0215(19980529)76:5<729::AID-IJC19>3.0.CO;2-Z

    Article  PubMed  Google Scholar 

  • M King W Su A Chang A Zuckerman GW Pasternak (2001) ArticleTitleTransport of opioids from the brain to the periphery by P-glycoprotein: peripheral actions of central drugs Nat Neurosci 4 268–274 Occurrence Handle11224543 Occurrence Handle1:CAS:528:DC%2BD3MXhsF2rurg%3D Occurrence Handle10.1038/85115

    Article  PubMed  CAS  Google Scholar 

  • C Lau F Ma Y Wang C Smith (1996) ArticleTitlePharmacokinetics and bioavailability of midazolam after intravenous, subcutaneous, intraperitoneal and oral administration under a chronic food-limited regimen: relating DRL performance to pharmacokinetics Psychopharmacol 126 241–248 Occurrence Handle1:CAS:528:DyaK28XlsFOjurg%3D Occurrence Handle10.1007/BF02246454

    Article  CAS  Google Scholar 

  • SP Letrent GM Pollack KR Brouwer KLR Brouwer (1999) ArticleTitleEffect of a potent and specific P-glycoprotein inhibitor on the blood–brain barrier distribution and antinociceptive effect of morphine in the rat Drug Metab Dispos 27 827–834 Occurrence Handle10383928 Occurrence Handle1:CAS:528:DyaK1MXkt1CjsLc%3D

    PubMed  CAS  Google Scholar 

  • DR Luke LJ Brunner K Vadiei (1990) ArticleTitleBioavailability assessment of cyclosporine in the rat. Influence of route of administration Drug Metab Dispos 18 158–162 Occurrence Handle1971566 Occurrence Handle1:CAS:528:DyaK3c**tFSms74%3D

    PubMed  CAS  Google Scholar 

  • JR Murren HJ Durivage AC Buzaid M Reiss SD Flynn D Carter WN Hait (1996) ArticleTitleTrifluperazine as a modulator of multidrug resistance in refractory breast cancer Cancer Chemother Pharmacol 38 65–70 Occurrence Handle8603454 Occurrence Handle1:CAS:528:DyaK28**vVertLw%3D Occurrence Handle10.1007/s002800050449

    Article  PubMed  CAS  Google Scholar 

  • Nonmem Project Group (1998) Nonmem user guide. Beal SL, Sheiner LB (eds) University of California, San Francisco

  • I Pajeva M Wiese (1998) ArticleTitleMolecular modeling of phenothiazines and related drugs as multidrug resistance modifiers: a comparative molecular field analysis study J Med Chem 41 1815–1826 Occurrence Handle9599232 Occurrence Handle1:CAS:528:DyaK1c**s12qu7k%3D Occurrence Handle10.1021/jm970786k

    Article  PubMed  CAS  Google Scholar 

  • L Pani GL Gessa (2002) ArticleTitleThe substituted benzamides and their clinical potential on dysthymia and on the negative symptoms of schizophrenia Mol Psychiatry 7 247–253 Occurrence Handle11920152 Occurrence Handle1:CAS:528:DC%2BD38**vV2ltr0%3D Occurrence Handle10.1038/sj.mp.4001040

    Article  PubMed  CAS  Google Scholar 

  • WM Pardridge (1998) Blood–brain barrier methodology and biology WM Pardridge (Eds) Introduction to the blood–brain barrier Cambridge University Press Cambridge 1–8

    Google Scholar 

  • WM Pardridge (2002) ArticleTitleDrug and gene delivery to the brain: the vasular route Neuron 36 555–558 Occurrence Handle12441045 Occurrence Handle1:CAS:528:DC%2BD38Xpt1Kgsr0%3D Occurrence Handle10.1016/S0896-6273(02)01054-1

    Article  PubMed  CAS  Google Scholar 

  • GH Perrault R Depoortere E Morel DJ Sanger B Scatton (1997) ArticleTitlePsychopharmacological profile of amisulpride: an antipsychotic drug with presynaptic D2/D3 dopamine receptor antagonist activity and limbic selectivity J Pharmacol Exp Ther 280 73–82 Occurrence Handle8996184 Occurrence Handle1:CAS:528:DyaK2sXntVWjtw%3D%3D

    PubMed  CAS  Google Scholar 

  • JW Polli SA Wring JE Humphreys L Huang JB Morgan LO Webster CS Serabjit-Singh (2001) ArticleTitleRational use of in vitro P-glycoprotein assays in drug discovery J Pharmacol Exp Ther 299 620–628 Occurrence Handle11602674 Occurrence Handle1:CAS:528:DC%2BD3MXnvV2qt78%3D

    PubMed  CAS  Google Scholar 

  • VV Rao JL Dahlheimer ME Bardgett AZ Snyder RA Finch AC Sartorelli D Piwnica-Worms (1999) ArticleTitleChoroid plexus epithelial expression of MDR1 P-glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier Proc Natl Acad Sci USA 96 3900–3905 Occurrence Handle10097135 Occurrence Handle1:CAS:528:DyaK1MXjslChsLo%3D Occurrence Handle10.1073/pnas.96.7.3900

    Article  PubMed  CAS  Google Scholar 

  • LL Rubin JM Staddon (1999) ArticleTitleThe cell biology of the blood–brain barrier Annu Rev Neurosci 22 11–28 Occurrence Handle10202530 Occurrence Handle1:CAS:528:DyaK1MXhvFemsr4%3D Occurrence Handle10.1146/annurev.neuro.22.1.11

    Article  PubMed  CAS  Google Scholar 

  • PA Russel DI Williams (1973) ArticleTitleEffects of repeated testing on rats’ locomotor activity in the open-field Anim Behav 21 109–111 Occurrence Handle10.1016/S0003-3472(73)80047-8

    Article  Google Scholar 

  • J Sachse S Härtter H Weigmann C Hiemke (2003) ArticleTitleAutomated determination of amisulpride by liquid chromatography with column switching and spectrophotometric detection J Chromatogr B 784 405–410 Occurrence Handle1:CAS:528:DC%2BD3sXhtFyqtrg%3D Occurrence Handle10.1016/S1570-0232(02)00808-5

    Article  CAS  Google Scholar 

  • A Sakata I Tamai K Kawazu Y Deguchi T Ohnishi A Saheki AS Tsuji (1994) ArticleTitleIn vivo evidence for ATP-dependent and P-glycoprotein-mediated transport of cyclosporin A at the blood–brain barrier Biochem Pharmacol 48 1989–1992 Occurrence Handle7986214 Occurrence Handle1:CAS:528:DyaK2M**sVGns7c%3D Occurrence Handle10.1016/0006-2952(94)90601-7

    Article  PubMed  CAS  Google Scholar 

  • B Sarkadi EM Price RC Boucher UA Germann GA Scarborough (1992) ArticleTitleExpression of the human multidrug resistance cDNA in insect cells generates a high activity drug-stimulated membrane ATPase J Biol Chem 267 4854–4858 Occurrence Handle1347044 Occurrence Handle1:CAS:528:DyaK38XhsVentbg%3D

    PubMed  CAS  Google Scholar 

  • B Sarkadi I Szasz A Gerloczi G Gardos (1977) ArticleTitleTransport parameters and stoichiometry of active calcium ion extrusion in intact human red cells Biochim Biophys Acta 464 93–107 Occurrence Handle137747 Occurrence Handle1:CAS:528:DyaE2sXktVOnsw%3D%3D Occurrence Handle10.1016/0005-2736(77)90373-X

    Article  PubMed  CAS  Google Scholar 

  • S Scala N Akhmed US Rao K Paull LB Lan B Dickstein JS Lee GH Elgemeie WD Stein SE Bates (1997) ArticleTitleP-glycoprotein substrates and antagonists cluster into two distinct groups Mol Pharmacol 51 1024–1033 Occurrence Handle9187269 Occurrence Handle1:CAS:528:DyaK2sXjvFWlu74%3D

    PubMed  CAS  Google Scholar 

  • B Scatton Y Claustre A Cudennec A Oblin G Perrault DJ Sanger H Schoemaker (1997) ArticleTitleAmisulpride: from animal pharmacology to therapeutic action Int Clin Psychopharmacol 12 IssueIDSuppl 2 S29–S36 Occurrence Handle9218165

    PubMed  Google Scholar 

  • AH Schinkel E Wagenaar CAAM Mol L van Deemter (1996) ArticleTitleP-glycoprotein in the blood–brain barrier of mice influences the brain penetration and pharmacological activity of many drugs J Clin Invest 97 2517–2524 Occurrence Handle8647944 Occurrence Handle1:CAS:528:DyaK28XjsFKjs7Y%3D Occurrence Handle10.1172/JCI118699

    Article  PubMed  CAS  Google Scholar 

  • H Schoemaker Y Claustre D Fage L Rouquier K Chergui O Curet A Oblin F Gonon C Carter J Benavides B Scatton (1997) ArticleTitleNeurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity J Pharmacol Exp Ther 280 83–97 Occurrence Handle8996185 Occurrence Handle1:STN:280:DyaK2s7kvFektQ%3D%3D

    PubMed  CAS  Google Scholar 

  • S Seetheraman MA Barrand L Maskell RJ Scheper (1998) ArticleTitleMultidrug resistance-related transport proteins in isolated human brain microvessels and in cells cultured from these isolates J Neurochem 70 1151–1159 Occurrence Handle10.1046/j.1471-4159.1998.70031151.x

    Article  Google Scholar 

  • LE Shapiro NH Shear (2002) ArticleTitleDrug interactions: proteins, pumps, and P450s J Am Acad Dermatol 47 467–484 Occurrence Handle12271287 Occurrence Handle10.1067/mjd.2002.126823

    Article  PubMed  Google Scholar 

  • Y Shitara T Itoh H Sato AP Li Y Sugiyama (2003) ArticleTitleInhibition of transporter-mediated hepatic uptake as a mechanism for drug–drug interaction between cerivastatin and cyclosporin A J Pharmacol Exp Ther 304 610–616 Occurrence Handle12538813 Occurrence Handle1:CAS:528:DC%2BD3sXpvVCguw%3D%3D Occurrence Handle10.1124/jpet.102.041921

    Article  PubMed  CAS  Google Scholar 

  • H Spahn-Langguth G Baktir A Radschuweit A Okyar B Terhaag P Ader A Hanafi P Langguth (1998) ArticleTitleP-glycoprotein transporters and the gastrointestinal tract: Evaluation of the potential in vivo relevance of in vitro data employing talinolol as model compound Int J Clin Pharmacol Ther 36 16–24 Occurrence Handle9476144 Occurrence Handle1:CAS:528:DyaK1cXkt1Knsw%3D%3D

    PubMed  CAS  Google Scholar 

  • PA Stewart R Béliveau KA Rogers (1996) ArticleTitleCellular localization of P-glycoprotein in brain versus gonadal capillaries J Histochem Cytochem 44 679–685 Occurrence Handle8675989 Occurrence Handle1:CAS:528:DyaK28Xkt1GqsLo%3D

    PubMed  CAS  Google Scholar 

  • T Terasaki K Hosoya (1999) ArticleTitleThe blood–brain barrier efflux transporters as a detoxifying system for the brain Adv Drug Delivery Rev 36 195–209 Occurrence Handle1:CAS:528:DyaK1MXhvVCgu7c%3D Occurrence Handle10.1016/S0169-409X(98)00088-X

    Article  CAS  Google Scholar 

  • F Thiebaut T Tsuruo H Hamada MM Gottesmann I Pastan MC Willingham (1987) ArticleTitleCellular localization of the multidrug resistance gene product P-glycoprotein in normal human tissue Proc Natl Acad Sci USA 84 7735–7738 Occurrence Handle2444983 Occurrence Handle1:CAS:528:DyaL2sXmtlels7k%3D Occurrence Handle10.1073/pnas.84.21.7735

    Article  PubMed  CAS  Google Scholar 

  • F Tiberghien F Loor (1996) ArticleTitleRanking of P-glycoprotein substrates and inhibitors by a calcein-AM fluorometry screening assay Anti-Cancer Drugs 7 568–578 Occurrence Handle8862725 Occurrence Handle1:CAS:528:DyaK28Xltleru70%3D

    PubMed  CAS  Google Scholar 

  • A Tsuji I Tamai (1997) ArticleTitleBlood-brain barrier function of P-glycoprotein Adv Drug Delivery Rev 25 287–298 Occurrence Handle1:CAS:528:DyaK2sXjsVKht7k%3D Occurrence Handle10.1016/S0169-409X(97)00504-8

    Article  CAS  Google Scholar 

  • M Vasse P Protrais J Costentin JC Schwartz (1985) ArticleTitleUnexpected potentiation by discriminant benzamide derivatives of stereotyped behaviours elicited by dopamine agonists in mice Naunyn Schmiedebergs Arch Pharmacol 329 108–116 Occurrence Handle4040215 Occurrence Handle1:CAS:528:DyaL2MXksVyjtb8%3D Occurrence Handle10.1007/BF00501198

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Psychiatry, University of Mainz, Mainz, Germany

    U. Schmitt, L. J. Guo, C. Hiemke & S. Härtter

  2. Department of Pharmacology, University of Mainz, Mainz, Germany

    A. Abou El-Ela & P. Langguth

  3. SOLVO Biotechnology, Budapest, Hungary

    H. Glavinas & P. Krajcsi

  4. Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary

    P. Krajcsi

  5. Department of Dermatology, University Hospital, RWTH Aachen, Aachen, Germany

    J. M. Baron

  6. Boehringer-Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany

    C. Tillmann & S. Härtter

  7. Department of Pharmacology, Tongji Medical College of Huazhong, University of Science and Technology, Wuhan, The People’s Republic of China

    L. J. Guo

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Schmitt, U., Abou El-Ela, A., Guo, L. et al. Cyclosporine A (CsA) affects the pharmacodynamics and pharmacokinetics of the atypical antipsychotic amisulpride probably via inhibition of P-glycoprotein (P-gp). J Neural Transm 113, 787–801 (2006). https://doi.org/10.1007/s00702-005-0367-4

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