Influence of ABCB1 (P‐glycoprotein) haplotypes on nortriptyline pharmacokinetics and nortriptyline‐induced postural hypotension in healthy volunteers
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • A single nucleotide polymorphism in ABCB1, which encodes P‐glycoprotein, has retrospectively been associated with symptoms of nortriptyline‐induced postural hypotension in depressed patients. • This finding needs to be replicated in independent studies befo...
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| creator | Jensen, Berit Packert Roberts, Rebecca Lee Vyas, Ritva Bonke, Gitte Jardine, David L. Begg, Evan James |
| description | WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• A single nucleotide polymorphism in ABCB1, which encodes P‐glycoprotein, has retrospectively been associated with symptoms of nortriptyline‐induced postural hypotension in depressed patients.
• This finding needs to be replicated in independent studies before recommendations regarding pharmacogenetic testing can be made.
WHAT THIS STUDY ADDS
• In a prospective study of healthy volunteers homozygous for ABCB1 (1236‐2677‐3435, TTT/TTT or CGC/CGC), a single dose of nortriptyline was administered, plasma exposure was determined and blood pressure and heart rate were monitored during posture change.
• No differences between ABCB1 haplotype groups were found in plasma exposure of nortriptyline and its active metabolites, E‐ and Z‐10‐hydroxynortriptyline. The heart rate response to posture change was increased with nortriptyline, whereas there was no difference in blood pressure response. However, no differences between haplotype groups were observed except that the pre dose heart rate response to standing was greater in the TTT than CGC homozygotes.
• The association between ABCB1 polymorphisms and nortriptyline‐induced postural hypotension found in a previous study could not be confirmed. The results raise the possibility of a predisposition in heart rate response in the TTT homozygotes rather than an effect of nortriptyline.
AIMS To investigate the influence of ABCB1 (1236‐2677‐3435) polymorphisms on nortriptyline pharmacokinetics and nortriptyline‐induced postural hypotension in healthy volunteers.
METHODS Genetic screening of 67 healthy volunteers identified eight CGC homozygotes and nine TTT homozygotes of ABCB1 (1236‐2677‐3435), who were administered a single dose of nortriptyline 25 mg. Plasma exposure of nortriptyline and its active metabolites, E‐ and Z‐10‐hydroxynortriptyline, was determined over 72 h. Heart rate and blood pressure responses to posture change (active standing and passive head‐up tilt) were measured continuously using finger plethysmography.
RESULTS There were no differences in plasma exposure between ABCB1 haplotype groups, as the geometric mean (95% CI) AUC(0,72 h) ratios were 0.98 (0.94, 1.03), 1.02 (0.96, 1.09) and 0.95 (0.80, 1.10) for nortriptyline, E‐ and Z‐10‐hydroxynortriptyline, respectively. The pre dose heart rate response to standing was greater in the TTT than CGC homozygotes (mean (95% CI) difference 7.4 (1.5, 13.4) beats min–1, P = 0.02). At tmax at 8 h post dose, nortriptyline |
| doi_str_mv | 10.1111/j.1365-2125.2011.04126.x |
| format | Article |
| fullrecord | <record><control><sourceid>wiley_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3376438</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>BCP4126</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5036-7f439f4362ea1b116da069952814ce04db56e307a5356c27011c96cc858ef5163</originalsourceid><addsrcrecordid>eNqNkc1u1DAUhS0EokPhFZA3SLBI8LXHnmQBUmfET6VKdAFry-M4jQePHdlJ2-x4BLa8Hk-Cw5SB7rBk-Vr3nOMrfwhhICXk9XpXAhO8oEB5SQlASZZARXn7AC2OjYdoQRgRBaccTtCTlHaEAAPBH6MTCnVdQy0W6Me5b91ovDY4tPhsvVkDfnn589v3Kzfp0McwGOtf4U71LgxTbxIOHvsQh2j7YXLWG9x3Ku6VDl_zZbA6YeWb-5IcZ30zatPgPqRhjMrhbupztk8251mPO6Pc0E34OrjRD8bE9BQ9apVL5tndeYq-vH_3efOxuPj04XxzdlFoTpgoVu2S1XkLahRsAUSjiKhrTitYakOWzZYLw8hKccaFpqv8W7oWWle8Mi0HwU7R20NuP273ptHGD3k-2Ue7V3GSQVl5v-NtJ6_CtWRsJZasygHVIUDHkFI07dELRM645E7OVORMRc645G9c8jZbn__79tH4h08WvLgTqKSVa6Py2qa_Oi5IzRnNujcH3Y11ZvrvAeR6czlX7Bfvt7eZ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Influence of ABCB1 (P‐glycoprotein) haplotypes on nortriptyline pharmacokinetics and nortriptyline‐induced postural hypotension in healthy volunteers</title><source>MEDLINE</source><source>Wiley Online Library Free Content</source><source>Access via Wiley Online Library</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Jensen, Berit Packert ; Roberts, Rebecca Lee ; Vyas, Ritva ; Bonke, Gitte ; Jardine, David L. ; Begg, Evan James</creator><creatorcontrib>Jensen, Berit Packert ; Roberts, Rebecca Lee ; Vyas, Ritva ; Bonke, Gitte ; Jardine, David L. ; Begg, Evan James</creatorcontrib><description>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• A single nucleotide polymorphism in ABCB1, which encodes P‐glycoprotein, has retrospectively been associated with symptoms of nortriptyline‐induced postural hypotension in depressed patients.
• This finding needs to be replicated in independent studies before recommendations regarding pharmacogenetic testing can be made.
WHAT THIS STUDY ADDS
• In a prospective study of healthy volunteers homozygous for ABCB1 (1236‐2677‐3435, TTT/TTT or CGC/CGC), a single dose of nortriptyline was administered, plasma exposure was determined and blood pressure and heart rate were monitored during posture change.
• No differences between ABCB1 haplotype groups were found in plasma exposure of nortriptyline and its active metabolites, E‐ and Z‐10‐hydroxynortriptyline. The heart rate response to posture change was increased with nortriptyline, whereas there was no difference in blood pressure response. However, no differences between haplotype groups were observed except that the pre dose heart rate response to standing was greater in the TTT than CGC homozygotes.
• The association between ABCB1 polymorphisms and nortriptyline‐induced postural hypotension found in a previous study could not be confirmed. The results raise the possibility of a predisposition in heart rate response in the TTT homozygotes rather than an effect of nortriptyline.
AIMS To investigate the influence of ABCB1 (1236‐2677‐3435) polymorphisms on nortriptyline pharmacokinetics and nortriptyline‐induced postural hypotension in healthy volunteers.
METHODS Genetic screening of 67 healthy volunteers identified eight CGC homozygotes and nine TTT homozygotes of ABCB1 (1236‐2677‐3435), who were administered a single dose of nortriptyline 25 mg. Plasma exposure of nortriptyline and its active metabolites, E‐ and Z‐10‐hydroxynortriptyline, was determined over 72 h. Heart rate and blood pressure responses to posture change (active standing and passive head‐up tilt) were measured continuously using finger plethysmography.
RESULTS There were no differences in plasma exposure between ABCB1 haplotype groups, as the geometric mean (95% CI) AUC(0,72 h) ratios were 0.98 (0.94, 1.03), 1.02 (0.96, 1.09) and 0.95 (0.80, 1.10) for nortriptyline, E‐ and Z‐10‐hydroxynortriptyline, respectively. The pre dose heart rate response to standing was greater in the TTT than CGC homozygotes (mean (95% CI) difference 7.4 (1.5, 13.4) beats min–1, P = 0.02). At tmax at 8 h post dose, nortriptyline increased the heart rate response to posture change in all subjects with mean (95% CI) Δ heart rate values of 7.4 (3.6, 11.3) beats min–1 on active standing (P = 0.0009) and 4.8 (2.0, 7.6) beats min–1 on head‐up tilt (P = 0.002), but no difference was observed between haplotype groups. There was no difference in blood pressure response to posture change in either group.
CONCLUSION The association between ABCB1 polymorphisms and nortriptyline‐induced postural hypotension found in the previous study could not be confirmed. The results raise the possibility of a predisposition in heart rate response in the TTT homozygotes rather than an effect of nortriptyline.</description><identifier>ISSN: 0306-5251</identifier><identifier>EISSN: 1365-2125</identifier><identifier>DOI: 10.1111/j.1365-2125.2011.04126.x</identifier><identifier>PMID: 21999196</identifier><identifier>CODEN: BCPHBM</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>ABCB1 ; Adolescent ; Adult ; Antidepressive Agents, Tricyclic - pharmacokinetics ; Area Under Curve ; ATP Binding Cassette Transporter, Sub-Family B ; ATP-Binding Cassette, Sub-Family B, Member 1 - drug effects ; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics ; Biological and medical sciences ; Blood Pressure - drug effects ; Blood Pressure - genetics ; European Continental Ancestry Group ; Female ; Haplotypes - drug effects ; Haplotypes - genetics ; Heart Rate - genetics ; Humans ; Hypotension, Orthostatic - chemically induced ; Hypotension, Orthostatic - genetics ; Hypotension, Orthostatic - metabolism ; Male ; Medical sciences ; Middle Aged ; nortriptyline ; Nortriptyline - pharmacokinetics ; Pedigree ; Pharmacogenetics ; Pharmacology. Drug treatments ; Polymorphism, Single Nucleotide ; postural hypotension ; Prospective Studies ; P‐glycoprotein ; tricyclic antidepressants ; Young Adult</subject><ispartof>British journal of clinical pharmacology, 2012-04, Vol.73 (4), p.619-628</ispartof><rights>2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society</rights><rights>2015 INIST-CNRS</rights><rights>2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.</rights><rights>2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5036-7f439f4362ea1b116da069952814ce04db56e307a5356c27011c96cc858ef5163</citedby><cites>FETCH-LOGICAL-c5036-7f439f4362ea1b116da069952814ce04db56e307a5356c27011c96cc858ef5163</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1365-2125.2011.04126.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1365-2125.2011.04126.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25609532$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21999196$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jensen, Berit Packert</creatorcontrib><creatorcontrib>Roberts, Rebecca Lee</creatorcontrib><creatorcontrib>Vyas, Ritva</creatorcontrib><creatorcontrib>Bonke, Gitte</creatorcontrib><creatorcontrib>Jardine, David L.</creatorcontrib><creatorcontrib>Begg, Evan James</creatorcontrib><title>Influence of ABCB1 (P‐glycoprotein) haplotypes on nortriptyline pharmacokinetics and nortriptyline‐induced postural hypotension in healthy volunteers</title><title>British journal of clinical pharmacology</title><addtitle>Br J Clin Pharmacol</addtitle><description>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• A single nucleotide polymorphism in ABCB1, which encodes P‐glycoprotein, has retrospectively been associated with symptoms of nortriptyline‐induced postural hypotension in depressed patients.
• This finding needs to be replicated in independent studies before recommendations regarding pharmacogenetic testing can be made.
WHAT THIS STUDY ADDS
• In a prospective study of healthy volunteers homozygous for ABCB1 (1236‐2677‐3435, TTT/TTT or CGC/CGC), a single dose of nortriptyline was administered, plasma exposure was determined and blood pressure and heart rate were monitored during posture change.
• No differences between ABCB1 haplotype groups were found in plasma exposure of nortriptyline and its active metabolites, E‐ and Z‐10‐hydroxynortriptyline. The heart rate response to posture change was increased with nortriptyline, whereas there was no difference in blood pressure response. However, no differences between haplotype groups were observed except that the pre dose heart rate response to standing was greater in the TTT than CGC homozygotes.
• The association between ABCB1 polymorphisms and nortriptyline‐induced postural hypotension found in a previous study could not be confirmed. The results raise the possibility of a predisposition in heart rate response in the TTT homozygotes rather than an effect of nortriptyline.
AIMS To investigate the influence of ABCB1 (1236‐2677‐3435) polymorphisms on nortriptyline pharmacokinetics and nortriptyline‐induced postural hypotension in healthy volunteers.
METHODS Genetic screening of 67 healthy volunteers identified eight CGC homozygotes and nine TTT homozygotes of ABCB1 (1236‐2677‐3435), who were administered a single dose of nortriptyline 25 mg. Plasma exposure of nortriptyline and its active metabolites, E‐ and Z‐10‐hydroxynortriptyline, was determined over 72 h. Heart rate and blood pressure responses to posture change (active standing and passive head‐up tilt) were measured continuously using finger plethysmography.
RESULTS There were no differences in plasma exposure between ABCB1 haplotype groups, as the geometric mean (95% CI) AUC(0,72 h) ratios were 0.98 (0.94, 1.03), 1.02 (0.96, 1.09) and 0.95 (0.80, 1.10) for nortriptyline, E‐ and Z‐10‐hydroxynortriptyline, respectively. The pre dose heart rate response to standing was greater in the TTT than CGC homozygotes (mean (95% CI) difference 7.4 (1.5, 13.4) beats min–1, P = 0.02). At tmax at 8 h post dose, nortriptyline increased the heart rate response to posture change in all subjects with mean (95% CI) Δ heart rate values of 7.4 (3.6, 11.3) beats min–1 on active standing (P = 0.0009) and 4.8 (2.0, 7.6) beats min–1 on head‐up tilt (P = 0.002), but no difference was observed between haplotype groups. There was no difference in blood pressure response to posture change in either group.
CONCLUSION The association between ABCB1 polymorphisms and nortriptyline‐induced postural hypotension found in the previous study could not be confirmed. The results raise the possibility of a predisposition in heart rate response in the TTT homozygotes rather than an effect of nortriptyline.</description><subject>ABCB1</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Antidepressive Agents, Tricyclic - pharmacokinetics</subject><subject>Area Under Curve</subject><subject>ATP Binding Cassette Transporter, Sub-Family B</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - drug effects</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - genetics</subject><subject>Biological and medical sciences</subject><subject>Blood Pressure - drug effects</subject><subject>Blood Pressure - genetics</subject><subject>European Continental Ancestry Group</subject><subject>Female</subject><subject>Haplotypes - drug effects</subject><subject>Haplotypes - genetics</subject><subject>Heart Rate - genetics</subject><subject>Humans</subject><subject>Hypotension, Orthostatic - chemically induced</subject><subject>Hypotension, Orthostatic - genetics</subject><subject>Hypotension, Orthostatic - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>nortriptyline</subject><subject>Nortriptyline - pharmacokinetics</subject><subject>Pedigree</subject><subject>Pharmacogenetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Polymorphism, Single Nucleotide</subject><subject>postural hypotension</subject><subject>Prospective Studies</subject><subject>P‐glycoprotein</subject><subject>tricyclic antidepressants</subject><subject>Young Adult</subject><issn>0306-5251</issn><issn>1365-2125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1u1DAUhS0EokPhFZA3SLBI8LXHnmQBUmfET6VKdAFry-M4jQePHdlJ2-x4BLa8Hk-Cw5SB7rBk-Vr3nOMrfwhhICXk9XpXAhO8oEB5SQlASZZARXn7AC2OjYdoQRgRBaccTtCTlHaEAAPBH6MTCnVdQy0W6Me5b91ovDY4tPhsvVkDfnn589v3Kzfp0McwGOtf4U71LgxTbxIOHvsQh2j7YXLWG9x3Ku6VDl_zZbA6YeWb-5IcZ30zatPgPqRhjMrhbupztk8251mPO6Pc0E34OrjRD8bE9BQ9apVL5tndeYq-vH_3efOxuPj04XxzdlFoTpgoVu2S1XkLahRsAUSjiKhrTitYakOWzZYLw8hKccaFpqv8W7oWWle8Mi0HwU7R20NuP273ptHGD3k-2Ue7V3GSQVl5v-NtJ6_CtWRsJZasygHVIUDHkFI07dELRM645E7OVORMRc645G9c8jZbn__79tH4h08WvLgTqKSVa6Py2qa_Oi5IzRnNujcH3Y11ZvrvAeR6czlX7Bfvt7eZ</recordid><startdate>201204</startdate><enddate>201204</enddate><creator>Jensen, Berit Packert</creator><creator>Roberts, Rebecca Lee</creator><creator>Vyas, Ritva</creator><creator>Bonke, Gitte</creator><creator>Jardine, David L.</creator><creator>Begg, Evan James</creator><general>Blackwell Publishing Ltd</general><general>Blackwell</general><general>Blackwell Science Inc</general><scope>IQODW</scope><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>5PM</scope></search><sort><creationdate>201204</creationdate><title>Influence of ABCB1 (P‐glycoprotein) haplotypes on nortriptyline pharmacokinetics and nortriptyline‐induced postural hypotension in healthy volunteers</title><author>Jensen, Berit Packert ; Roberts, Rebecca Lee ; Vyas, Ritva ; Bonke, Gitte ; Jardine, David L. ; Begg, Evan James</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5036-7f439f4362ea1b116da069952814ce04db56e307a5356c27011c96cc858ef5163</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>ABCB1</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Antidepressive Agents, Tricyclic - pharmacokinetics</topic><topic>Area Under Curve</topic><topic>ATP Binding Cassette Transporter, Sub-Family B</topic><topic>ATP-Binding Cassette, Sub-Family B, Member 1 - drug effects</topic><topic>ATP-Binding Cassette, Sub-Family B, Member 1 - genetics</topic><topic>Biological and medical sciences</topic><topic>Blood Pressure - drug effects</topic><topic>Blood Pressure - genetics</topic><topic>European Continental Ancestry Group</topic><topic>Female</topic><topic>Haplotypes - drug effects</topic><topic>Haplotypes - genetics</topic><topic>Heart Rate - genetics</topic><topic>Humans</topic><topic>Hypotension, Orthostatic - chemically induced</topic><topic>Hypotension, Orthostatic - genetics</topic><topic>Hypotension, Orthostatic - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>nortriptyline</topic><topic>Nortriptyline - pharmacokinetics</topic><topic>Pedigree</topic><topic>Pharmacogenetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Polymorphism, Single Nucleotide</topic><topic>postural hypotension</topic><topic>Prospective Studies</topic><topic>P‐glycoprotein</topic><topic>tricyclic antidepressants</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jensen, Berit Packert</creatorcontrib><creatorcontrib>Roberts, Rebecca Lee</creatorcontrib><creatorcontrib>Vyas, Ritva</creatorcontrib><creatorcontrib>Bonke, Gitte</creatorcontrib><creatorcontrib>Jardine, David L.</creatorcontrib><creatorcontrib>Begg, Evan James</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jensen, Berit Packert</au><au>Roberts, Rebecca Lee</au><au>Vyas, Ritva</au><au>Bonke, Gitte</au><au>Jardine, David L.</au><au>Begg, Evan James</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Influence of ABCB1 (P‐glycoprotein) haplotypes on nortriptyline pharmacokinetics and nortriptyline‐induced postural hypotension in healthy volunteers</atitle><jtitle>British journal of clinical pharmacology</jtitle><addtitle>Br J Clin Pharmacol</addtitle><date>2012-04</date><risdate>2012</risdate><volume>73</volume><issue>4</issue><spage>619</spage><epage>628</epage><pages>619-628</pages><issn>0306-5251</issn><eissn>1365-2125</eissn><coden>BCPHBM</coden><abstract>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• A single nucleotide polymorphism in ABCB1, which encodes P‐glycoprotein, has retrospectively been associated with symptoms of nortriptyline‐induced postural hypotension in depressed patients.
• This finding needs to be replicated in independent studies before recommendations regarding pharmacogenetic testing can be made.
WHAT THIS STUDY ADDS
• In a prospective study of healthy volunteers homozygous for ABCB1 (1236‐2677‐3435, TTT/TTT or CGC/CGC), a single dose of nortriptyline was administered, plasma exposure was determined and blood pressure and heart rate were monitored during posture change.
• No differences between ABCB1 haplotype groups were found in plasma exposure of nortriptyline and its active metabolites, E‐ and Z‐10‐hydroxynortriptyline. The heart rate response to posture change was increased with nortriptyline, whereas there was no difference in blood pressure response. However, no differences between haplotype groups were observed except that the pre dose heart rate response to standing was greater in the TTT than CGC homozygotes.
• The association between ABCB1 polymorphisms and nortriptyline‐induced postural hypotension found in a previous study could not be confirmed. The results raise the possibility of a predisposition in heart rate response in the TTT homozygotes rather than an effect of nortriptyline.
AIMS To investigate the influence of ABCB1 (1236‐2677‐3435) polymorphisms on nortriptyline pharmacokinetics and nortriptyline‐induced postural hypotension in healthy volunteers.
METHODS Genetic screening of 67 healthy volunteers identified eight CGC homozygotes and nine TTT homozygotes of ABCB1 (1236‐2677‐3435), who were administered a single dose of nortriptyline 25 mg. Plasma exposure of nortriptyline and its active metabolites, E‐ and Z‐10‐hydroxynortriptyline, was determined over 72 h. Heart rate and blood pressure responses to posture change (active standing and passive head‐up tilt) were measured continuously using finger plethysmography.
RESULTS There were no differences in plasma exposure between ABCB1 haplotype groups, as the geometric mean (95% CI) AUC(0,72 h) ratios were 0.98 (0.94, 1.03), 1.02 (0.96, 1.09) and 0.95 (0.80, 1.10) for nortriptyline, E‐ and Z‐10‐hydroxynortriptyline, respectively. The pre dose heart rate response to standing was greater in the TTT than CGC homozygotes (mean (95% CI) difference 7.4 (1.5, 13.4) beats min–1, P = 0.02). At tmax at 8 h post dose, nortriptyline increased the heart rate response to posture change in all subjects with mean (95% CI) Δ heart rate values of 7.4 (3.6, 11.3) beats min–1 on active standing (P = 0.0009) and 4.8 (2.0, 7.6) beats min–1 on head‐up tilt (P = 0.002), but no difference was observed between haplotype groups. There was no difference in blood pressure response to posture change in either group.
CONCLUSION The association between ABCB1 polymorphisms and nortriptyline‐induced postural hypotension found in the previous study could not be confirmed. The results raise the possibility of a predisposition in heart rate response in the TTT homozygotes rather than an effect of nortriptyline.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>21999196</pmid><doi>10.1111/j.1365-2125.2011.04126.x</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | British journal of clinical pharmacology, 2012-04, Vol.73 (4), p.619-628 |
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| source | MEDLINE; Wiley Online Library Free Content; Access via Wiley Online Library; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | ABCB1 Adolescent Adult Antidepressive Agents, Tricyclic - pharmacokinetics Area Under Curve ATP Binding Cassette Transporter, Sub-Family B ATP-Binding Cassette, Sub-Family B, Member 1 - drug effects ATP-Binding Cassette, Sub-Family B, Member 1 - genetics Biological and medical sciences Blood Pressure - drug effects Blood Pressure - genetics European Continental Ancestry Group Female Haplotypes - drug effects Haplotypes - genetics Heart Rate - genetics Humans Hypotension, Orthostatic - chemically induced Hypotension, Orthostatic - genetics Hypotension, Orthostatic - metabolism Male Medical sciences Middle Aged nortriptyline Nortriptyline - pharmacokinetics Pedigree Pharmacogenetics Pharmacology. Drug treatments Polymorphism, Single Nucleotide postural hypotension Prospective Studies P‐glycoprotein tricyclic antidepressants Young Adult |
| title | Influence of ABCB1 (P‐glycoprotein) haplotypes on nortriptyline pharmacokinetics and nortriptyline‐induced postural hypotension in healthy volunteers |
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