abcb1ab P-glycoprotein is involved in the uptake of citalopram and trimipramine into the brain of mice
The phenomenon of a heterogeneous response to the same drug in different patients is well-known. An important reason is that, even at equal concentrations, the bioavailability of a drug depends on the interaction of the drug with the blood–brain barrier (BBB). In part, this is due to the drug-transp...
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description | The phenomenon of a heterogeneous response to the same drug in different patients is well-known. An important reason is that, even at equal concentrations, the bioavailability of a drug depends on the interaction of the drug with the blood–brain barrier (BBB). In part, this is due to the drug-transporting P-glycoprotein (P-gp), a product of the multiple drug resistance gene (ABCB1), which can transport drugs against a concentration gradient across the BBB back into the plasma and thereby reduce the bioavailability in the brain. In the present study, we have examined the uptake of the antidepressants citalopram and trimipramine into the brain of abcb1ab knockout mice compared with controls. One hour after s.c. injection of the drugs, concentrations of the two drugs and of the metabolite d-trimipramine in brain, spleen, kidney, liver and plasma were measured with HPLC. Significantly higher brain concentrations in knockout mice, showing that these drugs are substrates of P-gp and that the presence of P-gp reduces the effective bioavailability of these substances in the brain. The results of our study contradict an earlier report that citalopram is not actively transported from endothelial cells. These results were derived from an in vitro study, showing that due to the complexity of the BBB–drug interaction, it is difficult to transfer results from in vitro studies to the in vivo situation. We hypothesize that inter-individual differences in the activity of the ABCB1 gene can account in part for the great variation in clinical response to antidepressants in psychiatric patients, even at comparable plasma levels. |
doi_str_mv | 10.1016/S0022-3956(03)00022-0 |
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An important reason is that, even at equal concentrations, the bioavailability of a drug depends on the interaction of the drug with the blood–brain barrier (BBB). In part, this is due to the drug-transporting P-glycoprotein (P-gp), a product of the multiple drug resistance gene (ABCB1), which can transport drugs against a concentration gradient across the BBB back into the plasma and thereby reduce the bioavailability in the brain. In the present study, we have examined the uptake of the antidepressants citalopram and trimipramine into the brain of abcb1ab knockout mice compared with controls. One hour after s.c. injection of the drugs, concentrations of the two drugs and of the metabolite d-trimipramine in brain, spleen, kidney, liver and plasma were measured with HPLC. Significantly higher brain concentrations in knockout mice, showing that these drugs are substrates of P-gp and that the presence of P-gp reduces the effective bioavailability of these substances in the brain. The results of our study contradict an earlier report that citalopram is not actively transported from endothelial cells. These results were derived from an in vitro study, showing that due to the complexity of the BBB–drug interaction, it is difficult to transfer results from in vitro studies to the in vivo situation. We hypothesize that inter-individual differences in the activity of the ABCB1 gene can account in part for the great variation in clinical response to antidepressants in psychiatric patients, even at comparable plasma levels.</description><identifier>ISSN: 0022-3956</identifier><identifier>EISSN: 1879-1379</identifier><identifier>DOI: 10.1016/S0022-3956(03)00022-0</identifier><identifier>PMID: 12650738</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Antidepressive Agents, Tricyclic - blood ; Antidepressive Agents, Tricyclic - chemistry ; Antidepressive Agents, Tricyclic - pharmacokinetics ; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics ; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism ; Biological Availability ; Blood-Brain Barrier - drug effects ; Blood–brain barrier ; Brain - metabolism ; Cell Culture Techniques ; Chromatography, High Pressure Liquid ; Citalopram ; Citalopram - blood ; Citalopram - chemistry ; Citalopram - pharmacokinetics ; Female ; Gene Expression - genetics ; Genes, MDR - genetics ; Homozygote ; Kidney - metabolism ; Knock-out mice ; Liver - metabolism ; Male ; Mice ; Mice, Knockout ; Multiple drug resistance ; P-glycoprotein ; Serotonin Uptake Inhibitors - blood ; Serotonin Uptake Inhibitors - chemistry ; Serotonin Uptake Inhibitors - pharmacokinetics ; Spleen - metabolism ; Trimipramine ; Trimipramine - blood ; Trimipramine - chemistry ; Trimipramine - pharmacokinetics</subject><ispartof>Journal of psychiatric research, 2003-05, Vol.37 (3), p.179-185</ispartof><rights>2003 Elsevier Science Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c328t-63e10f73d25d6a4e72ede2689ee02b8d20b74da9fccad0b71aecb505c4253bf53</citedby><cites>FETCH-LOGICAL-c328t-63e10f73d25d6a4e72ede2689ee02b8d20b74da9fccad0b71aecb505c4253bf53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/S0022-3956(03)00022-0$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12650738$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Uhr, Manfred</creatorcontrib><creatorcontrib>Grauer, Markus T.</creatorcontrib><title>abcb1ab P-glycoprotein is involved in the uptake of citalopram and trimipramine into the brain of mice</title><title>Journal of psychiatric research</title><addtitle>J Psychiatr Res</addtitle><description>The phenomenon of a heterogeneous response to the same drug in different patients is well-known. An important reason is that, even at equal concentrations, the bioavailability of a drug depends on the interaction of the drug with the blood–brain barrier (BBB). In part, this is due to the drug-transporting P-glycoprotein (P-gp), a product of the multiple drug resistance gene (ABCB1), which can transport drugs against a concentration gradient across the BBB back into the plasma and thereby reduce the bioavailability in the brain. In the present study, we have examined the uptake of the antidepressants citalopram and trimipramine into the brain of abcb1ab knockout mice compared with controls. One hour after s.c. injection of the drugs, concentrations of the two drugs and of the metabolite d-trimipramine in brain, spleen, kidney, liver and plasma were measured with HPLC. Significantly higher brain concentrations in knockout mice, showing that these drugs are substrates of P-gp and that the presence of P-gp reduces the effective bioavailability of these substances in the brain. The results of our study contradict an earlier report that citalopram is not actively transported from endothelial cells. These results were derived from an in vitro study, showing that due to the complexity of the BBB–drug interaction, it is difficult to transfer results from in vitro studies to the in vivo situation. We hypothesize that inter-individual differences in the activity of the ABCB1 gene can account in part for the great variation in clinical response to antidepressants in psychiatric patients, even at comparable plasma levels.</description><subject>Animals</subject><subject>Antidepressive Agents, Tricyclic - blood</subject><subject>Antidepressive Agents, Tricyclic - chemistry</subject><subject>Antidepressive Agents, Tricyclic - pharmacokinetics</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - genetics</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism</subject><subject>Biological Availability</subject><subject>Blood-Brain Barrier - drug effects</subject><subject>Blood–brain barrier</subject><subject>Brain - metabolism</subject><subject>Cell Culture Techniques</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Citalopram</subject><subject>Citalopram - blood</subject><subject>Citalopram - chemistry</subject><subject>Citalopram - pharmacokinetics</subject><subject>Female</subject><subject>Gene Expression - genetics</subject><subject>Genes, MDR - genetics</subject><subject>Homozygote</subject><subject>Kidney - metabolism</subject><subject>Knock-out mice</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Multiple drug resistance</subject><subject>P-glycoprotein</subject><subject>Serotonin Uptake Inhibitors - blood</subject><subject>Serotonin Uptake Inhibitors - chemistry</subject><subject>Serotonin Uptake Inhibitors - pharmacokinetics</subject><subject>Spleen - metabolism</subject><subject>Trimipramine</subject><subject>Trimipramine - blood</subject><subject>Trimipramine - chemistry</subject><subject>Trimipramine - pharmacokinetics</subject><issn>0022-3956</issn><issn>1879-1379</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkMtKxDAUhoMoOo4-gpKV6KKaS9u0K5HBGwwoqOuQy6lGexmbdGDe3kxn0KWr_Ae-k8P_IXRCySUlNL96IYSxhJdZfk74BRknsoMmtBBlQrkod9HkFzlAh95_Rkgwmu6jA8ryjAheTFCltNFUafycvNcr0y36LoBrsfPYtcuuXoKNAYcPwMMiqC_AXYWNC6qOqGqwai0OvWvcenItRDh0I657FRcj3TgDR2ivUrWH4-07RW93t6-zh2T-dP84u5knhrMiJDkHSirBLctsrlIQDCywvCgBCNOFZUSL1KqyMkbZmKkCozOSmZRlXFcZn6Kzzb-xx_cAPsjGeQN1rVroBi8Fp1QIUUYw24Cm77zvoZKL2EL1K0mJXAuWo2C5ticJl6PgGKbodHtg0A3Yv62t0QhcbwCINZcOeumNg9aAdT2YIG3n_jnxA0U_i7c</recordid><startdate>200305</startdate><enddate>200305</enddate><creator>Uhr, Manfred</creator><creator>Grauer, Markus T.</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>200305</creationdate><title>abcb1ab P-glycoprotein is involved in the uptake of citalopram and trimipramine into the brain of mice</title><author>Uhr, Manfred ; Grauer, Markus T.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c328t-63e10f73d25d6a4e72ede2689ee02b8d20b74da9fccad0b71aecb505c4253bf53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Antidepressive Agents, Tricyclic - blood</topic><topic>Antidepressive Agents, Tricyclic - chemistry</topic><topic>Antidepressive Agents, Tricyclic - pharmacokinetics</topic><topic>ATP-Binding Cassette, Sub-Family B, Member 1 - genetics</topic><topic>ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism</topic><topic>Biological Availability</topic><topic>Blood-Brain Barrier - drug effects</topic><topic>Blood–brain barrier</topic><topic>Brain - metabolism</topic><topic>Cell Culture Techniques</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Citalopram</topic><topic>Citalopram - blood</topic><topic>Citalopram - chemistry</topic><topic>Citalopram - pharmacokinetics</topic><topic>Female</topic><topic>Gene Expression - genetics</topic><topic>Genes, MDR - genetics</topic><topic>Homozygote</topic><topic>Kidney - metabolism</topic><topic>Knock-out mice</topic><topic>Liver - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Multiple drug resistance</topic><topic>P-glycoprotein</topic><topic>Serotonin Uptake Inhibitors - blood</topic><topic>Serotonin Uptake Inhibitors - chemistry</topic><topic>Serotonin Uptake Inhibitors - pharmacokinetics</topic><topic>Spleen - metabolism</topic><topic>Trimipramine</topic><topic>Trimipramine - blood</topic><topic>Trimipramine - chemistry</topic><topic>Trimipramine - pharmacokinetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Uhr, Manfred</creatorcontrib><creatorcontrib>Grauer, Markus T.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of psychiatric research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Uhr, Manfred</au><au>Grauer, Markus T.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>abcb1ab P-glycoprotein is involved in the uptake of citalopram and trimipramine into the brain of mice</atitle><jtitle>Journal of psychiatric research</jtitle><addtitle>J Psychiatr Res</addtitle><date>2003-05</date><risdate>2003</risdate><volume>37</volume><issue>3</issue><spage>179</spage><epage>185</epage><pages>179-185</pages><issn>0022-3956</issn><eissn>1879-1379</eissn><abstract>The phenomenon of a heterogeneous response to the same drug in different patients is well-known. An important reason is that, even at equal concentrations, the bioavailability of a drug depends on the interaction of the drug with the blood–brain barrier (BBB). In part, this is due to the drug-transporting P-glycoprotein (P-gp), a product of the multiple drug resistance gene (ABCB1), which can transport drugs against a concentration gradient across the BBB back into the plasma and thereby reduce the bioavailability in the brain. In the present study, we have examined the uptake of the antidepressants citalopram and trimipramine into the brain of abcb1ab knockout mice compared with controls. One hour after s.c. injection of the drugs, concentrations of the two drugs and of the metabolite d-trimipramine in brain, spleen, kidney, liver and plasma were measured with HPLC. Significantly higher brain concentrations in knockout mice, showing that these drugs are substrates of P-gp and that the presence of P-gp reduces the effective bioavailability of these substances in the brain. The results of our study contradict an earlier report that citalopram is not actively transported from endothelial cells. These results were derived from an in vitro study, showing that due to the complexity of the BBB–drug interaction, it is difficult to transfer results from in vitro studies to the in vivo situation. We hypothesize that inter-individual differences in the activity of the ABCB1 gene can account in part for the great variation in clinical response to antidepressants in psychiatric patients, even at comparable plasma levels.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>12650738</pmid><doi>10.1016/S0022-3956(03)00022-0</doi><tpages>7</tpages></addata></record> |
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subjects | Animals Antidepressive Agents, Tricyclic - blood Antidepressive Agents, Tricyclic - chemistry Antidepressive Agents, Tricyclic - pharmacokinetics ATP-Binding Cassette, Sub-Family B, Member 1 - genetics ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism Biological Availability Blood-Brain Barrier - drug effects Blood–brain barrier Brain - metabolism Cell Culture Techniques Chromatography, High Pressure Liquid Citalopram Citalopram - blood Citalopram - chemistry Citalopram - pharmacokinetics Female Gene Expression - genetics Genes, MDR - genetics Homozygote Kidney - metabolism Knock-out mice Liver - metabolism Male Mice Mice, Knockout Multiple drug resistance P-glycoprotein Serotonin Uptake Inhibitors - blood Serotonin Uptake Inhibitors - chemistry Serotonin Uptake Inhibitors - pharmacokinetics Spleen - metabolism Trimipramine Trimipramine - blood Trimipramine - chemistry Trimipramine - pharmacokinetics |
title | abcb1ab P-glycoprotein is involved in the uptake of citalopram and trimipramine into the brain of mice |
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