{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T17:26:31Z","timestamp":1790011591589,"version":"4.0.1"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2004,8,1]],"date-time":"2004-08-01T00:00:00Z","timestamp":1091318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2004,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The pharmacokinetics of antipsychotic drugs has become an integral part in understanding their pharmacodynamic activity and clinical effects. In addition to metabolism aspects, carrier-mediated transport, particularly secretion by ABC transporters, has been discussed as potentially relevant for this group of therapeutics. In this study, the psychoactive compounds perphenazine, flupentixol, domperidone, desmethyl clozapine, haloperidol, fluphenazine, fluvoxamine, olanzapine, levome-promazine, perazine, desmethyl perazine, clozapine, quetiapine and amisulpride were characterized in terms of P-glycoprotein (P-gp) affinity and transport. Experimental methods involved a radioligand displacement assay with [3H]talinolol as radioligand and transport \u2014 as well as transport inhibition \u2014 studies of the P-gp substrate [3H]talinolol across Caco-2 cell monolayers. In addition, the physicochemical descriptors log P and \u0394log P were determined to test potential correlations between transporter affinity and lipophilicity parameters. All of the tested antipsychotics showed affinity to P-gp albeit their IC50 values (concentration of competitor that displaced 50% of the bound radioligand) differed by a factor exceeding 1000, when compared using the transport inhibition assay. From the group of P-gp substrates, amisulpride and fluphenazine were selected for in-vivo drug-drug interaction studies in rats to demonstrate the in-vivo relevance of the in-vitro findings. Compounds were administered by intraperitoneal injection either alone or in combination with 50 mg kg\u22121 ciclosporin. The concentration versus time profiles for both drugs were followed in serum as well as in brain tissues. Significant differences between the treatments with the antipsychotic alone versus the combination of antipsychotic with ciclosporin were found for amisulpride. The distribution of amisulpride to the brain was increased and systemic serum levels were likewise increased indicating decreased systemic clearance for the combination regimen. For fluphenazine, systemic levels with and without co-administraton of ciclosporin were comparable while higher brain-to-serum concentration ratios were found after co-administration of ciclosporin. The findings are explained on the basis of the limited contribution of P-gp-mediated transport to the elimination of fluphenazine and to a direct effect with respect to its distribution into the brain.<\/jats:p>","DOI":"10.1211\/0022357043969","type":"journal-article","created":{"date-parts":[[2004,7,19]],"date-time":"2004-07-19T21:51:54Z","timestamp":1090273914000},"page":"967-975","source":"Crossref","is-referenced-by-count":128,"title":["Identification of P-glycoprotein substrates and inhibitors among psychoactive compounds \u2014 implications for pharmacokinetics of selected substrates"],"prefix":"10.1093","volume":"56","author":[{"given":"Amal","family":"Abou El Ela","sequence":"first","affiliation":[{"name":"Institute of Pharmacy, Biopharmaceutics and Pharmaceutical Technology, University of Mainz , Mainz,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"H\u00e4rtter","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Mainz ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Mainz ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Hiemke","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Mainz ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hildegard","family":"Spahn-Langguth","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, Biopharmaceutics and Pharmaceutical Technology, University of Mainz , Mainz,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Langguth","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, Biopharmaceutics and Pharmaceutical Technology, University of Mainz , Mainz,","place":["Germany"]},{"name":"Institute of Pharmacy , Staudingerweg 5, D-55099 Mainz,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2004,8,1]]},"reference":[{"key":"2024103109405637600_cit1","article-title":"Implications of physicochemical parameters for carrier-mediated and passive membrane transport for psychoactive drugs","volume-title":"Ph.D. thesis","author":"El Ela","year":"2003"},{"key":"2024103109405637600_cit2","article-title":"The determination of ionization constant","volume-title":"A Laboratory manual","author":"Albert","year":"1984","edition":"3rd edn."},{"key":"2024103109405637600_cit3","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/S0731-7085(98)00235-0","article-title":"pH-metric log P11. pka determination of water-insoluble drugs in organic solvent-water mixtures","volume":"20","author":"Avdeef","year":"1999","journal-title":"J. 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