Pharmacokinetics of β‐adrenoceptor blockers in obese and normal volunteers
Aims Obesity can modify the pharmacokinetics of lipophilic drugs. As β‐adrenoceptor blockers (BB) are often prescribed for obese patients suffering from hypertension or coronary heart disease, this study compares the pharmacokinetics of lipophilic β‐adrenoceptor blockers in obese and control subject...
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| Veröffentlicht in: | British journal of clinical pharmacology 1997-06, Vol.43 (6), p.563-570 |
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| creator | Cheymol, Georges Poirier, Jean‐Marie Carrupt, Pierre‐Alain Testa, Bernard Weissenburger, Jacques Levron, Jean‐Claude Snoeck, Eric |
| description | Aims Obesity can modify the pharmacokinetics of lipophilic drugs. As β‐adrenoceptor blockers (BB) are often prescribed for obese patients suffering from hypertension or coronary heart disease, this study compares the pharmacokinetics of lipophilic β‐adrenoceptor blockers in obese and control subjects.
Methods Nine obese (157±24% of ideal body weight (IBW) mean±s.d.) and nine non‐obese healthy volunteers (98±10% IBW), aged 32±9 years, were included in the study. Subjects were randomly given a single i.v. infusion of one of the following racemic β‐adrenoceptor blockers, whose doses (expressed as base per kg of IBW) were: propranolol (0.108 mg), labetalol (0.99 mg) and nebivolol (0.073 mg). The plasma concentrations of unchanged drugs were measured by h.p.l.c. The ionisation constants and lipophilicity parameters of β‐adrenoceptor blockers were assessed.
Results The pharmacokinetic data for the three drugs were qualitatively similar. There was a trend towards a greater total distribution volume (Vss ) in obese patients than in controls. However, Vss expressed per kg body weight was slightly smaller in obese patients. The relationship between Vss and lipophilicity of five β‐adrenoceptor was studied by combining the current results with those previously obtained with a moderately lipophilic drug (bisoprolol) and a hydrophilic one (sotalol). The Vss of the five drugs was positively and well‐correlated (r2=0.90; P |
| doi_str_mv | 10.1046/j.1365-2125.1997.00609.x |
| format | Article |
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Methods Nine obese (157±24% of ideal body weight (IBW) mean±s.d.) and nine non‐obese healthy volunteers (98±10% IBW), aged 32±9 years, were included in the study. Subjects were randomly given a single i.v. infusion of one of the following racemic β‐adrenoceptor blockers, whose doses (expressed as base per kg of IBW) were: propranolol (0.108 mg), labetalol (0.99 mg) and nebivolol (0.073 mg). The plasma concentrations of unchanged drugs were measured by h.p.l.c. The ionisation constants and lipophilicity parameters of β‐adrenoceptor blockers were assessed.
Results The pharmacokinetic data for the three drugs were qualitatively similar. There was a trend towards a greater total distribution volume (Vss ) in obese patients than in controls. However, Vss expressed per kg body weight was slightly smaller in obese patients. The relationship between Vss and lipophilicity of five β‐adrenoceptor was studied by combining the current results with those previously obtained with a moderately lipophilic drug (bisoprolol) and a hydrophilic one (sotalol). The Vss of the five drugs was positively and well‐correlated (r2=0.90; P<0.01) with their distribution coefficient at pH 7.4 (log D7.4 ), but not with their partition coefficients. The linear regression coefficients for lean and obese subjects were very similar.
Conclusions Lipophilic β‐adrenoceptor blockers seem to diffuse less into adipose than into lean tissues. All electrical forms of the drugs (i.e. cations, neutral forms, or zwitterions) present at physiological pH contribute to their tissue distribution, in both obese and lean subjects.Their tissue distribution in obese patients could be restricted by the sum of hydrophobic forces and hydrogen bonds they elicit with macromolecules in lean tissues.</description><identifier>ISSN: 0306-5251</identifier><identifier>EISSN: 1365-2125</identifier><identifier>DOI: 10.1046/j.1365-2125.1997.00609.x</identifier><identifier>PMID: 9205815</identifier><identifier>CODEN: BCPHBM</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Science Ltd</publisher><subject>Adipose Tissue - metabolism ; Adrenergic beta-Antagonists - administration & dosage ; Adrenergic beta-Antagonists - chemistry ; Adrenergic beta-Antagonists - pharmacokinetics ; Adrenergic beta-Antagonists - pharmacology ; Adult ; Antihypertensive agents ; Area Under Curve ; Benzopyrans - administration & dosage ; Benzopyrans - chemistry ; Benzopyrans - pharmacokinetics ; Benzopyrans - pharmacology ; Binding Sites ; Biological and medical sciences ; Bisoprolol - blood ; Bisoprolol - pharmacokinetics ; Bisoprolol - pharmacology ; Blood Chemical Analysis ; Blood Pressure - drug effects ; Cardiac Output - drug effects ; Cardiovascular system ; Chromatography, High Pressure Liquid ; distribution ; Ethanolamines - administration & dosage ; Ethanolamines - chemistry ; Ethanolamines - pharmacokinetics ; Ethanolamines - pharmacology ; Female ; Heart Rate - drug effects ; Humans ; Hydrogen-Ion Concentration ; Infusions, Intravenous ; Labetalol - administration & dosage ; Labetalol - chemistry ; Labetalol - pharmacokinetics ; Labetalol - pharmacology ; lipophilicity ; Male ; Medical sciences ; Nebivolol ; obese subjects ; Obesity - blood ; Obesity - metabolism ; Obesity - physiopathology ; Original ; pharmacokinetics ; Pharmacology. Drug treatments ; Propranolol - administration & dosage ; Propranolol - chemistry ; Propranolol - pharmacokinetics ; Propranolol - pharmacology ; Regression Analysis ; Sotalol - blood ; Sotalol - pharmacokinetics ; Sotalol - pharmacology ; Stereoisomerism ; Tissue Distribution ; β‐adrenoceptor blockers</subject><ispartof>British journal of clinical pharmacology, 1997-06, Vol.43 (6), p.563-570</ispartof><rights>1997 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5309-ce6805f7baf57b8edf53d08800a0d8983bdff516f267d85d5c747a42412498e43</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1046%2Fj.1365-2125.1997.00609.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1046%2Fj.1365-2125.1997.00609.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,776,780,881,1411,1427,27903,27904,45553,45554,46388,46812</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2745394$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9205815$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cheymol, Georges</creatorcontrib><creatorcontrib>Poirier, Jean‐Marie</creatorcontrib><creatorcontrib>Carrupt, Pierre‐Alain</creatorcontrib><creatorcontrib>Testa, Bernard</creatorcontrib><creatorcontrib>Weissenburger, Jacques</creatorcontrib><creatorcontrib>Levron, Jean‐Claude</creatorcontrib><creatorcontrib>Snoeck, Eric</creatorcontrib><title>Pharmacokinetics of β‐adrenoceptor blockers in obese and normal volunteers</title><title>British journal of clinical pharmacology</title><addtitle>Br J Clin Pharmacol</addtitle><description>Aims Obesity can modify the pharmacokinetics of lipophilic drugs. As β‐adrenoceptor blockers (BB) are often prescribed for obese patients suffering from hypertension or coronary heart disease, this study compares the pharmacokinetics of lipophilic β‐adrenoceptor blockers in obese and control subjects.
Methods Nine obese (157±24% of ideal body weight (IBW) mean±s.d.) and nine non‐obese healthy volunteers (98±10% IBW), aged 32±9 years, were included in the study. Subjects were randomly given a single i.v. infusion of one of the following racemic β‐adrenoceptor blockers, whose doses (expressed as base per kg of IBW) were: propranolol (0.108 mg), labetalol (0.99 mg) and nebivolol (0.073 mg). The plasma concentrations of unchanged drugs were measured by h.p.l.c. The ionisation constants and lipophilicity parameters of β‐adrenoceptor blockers were assessed.
Results The pharmacokinetic data for the three drugs were qualitatively similar. There was a trend towards a greater total distribution volume (Vss ) in obese patients than in controls. However, Vss expressed per kg body weight was slightly smaller in obese patients. The relationship between Vss and lipophilicity of five β‐adrenoceptor was studied by combining the current results with those previously obtained with a moderately lipophilic drug (bisoprolol) and a hydrophilic one (sotalol). The Vss of the five drugs was positively and well‐correlated (r2=0.90; P<0.01) with their distribution coefficient at pH 7.4 (log D7.4 ), but not with their partition coefficients. The linear regression coefficients for lean and obese subjects were very similar.
Conclusions Lipophilic β‐adrenoceptor blockers seem to diffuse less into adipose than into lean tissues. All electrical forms of the drugs (i.e. cations, neutral forms, or zwitterions) present at physiological pH contribute to their tissue distribution, in both obese and lean subjects.Their tissue distribution in obese patients could be restricted by the sum of hydrophobic forces and hydrogen bonds they elicit with macromolecules in lean tissues.</description><subject>Adipose Tissue - metabolism</subject><subject>Adrenergic beta-Antagonists - administration & dosage</subject><subject>Adrenergic beta-Antagonists - chemistry</subject><subject>Adrenergic beta-Antagonists - pharmacokinetics</subject><subject>Adrenergic beta-Antagonists - pharmacology</subject><subject>Adult</subject><subject>Antihypertensive agents</subject><subject>Area Under Curve</subject><subject>Benzopyrans - administration & dosage</subject><subject>Benzopyrans - chemistry</subject><subject>Benzopyrans - pharmacokinetics</subject><subject>Benzopyrans - pharmacology</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Bisoprolol - blood</subject><subject>Bisoprolol - pharmacokinetics</subject><subject>Bisoprolol - pharmacology</subject><subject>Blood Chemical Analysis</subject><subject>Blood Pressure - drug effects</subject><subject>Cardiac Output - drug effects</subject><subject>Cardiovascular system</subject><subject>Chromatography, High Pressure Liquid</subject><subject>distribution</subject><subject>Ethanolamines - administration & dosage</subject><subject>Ethanolamines - chemistry</subject><subject>Ethanolamines - pharmacokinetics</subject><subject>Ethanolamines - pharmacology</subject><subject>Female</subject><subject>Heart Rate - drug effects</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>Infusions, Intravenous</subject><subject>Labetalol - administration & dosage</subject><subject>Labetalol - chemistry</subject><subject>Labetalol - pharmacokinetics</subject><subject>Labetalol - pharmacology</subject><subject>lipophilicity</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Nebivolol</subject><subject>obese subjects</subject><subject>Obesity - blood</subject><subject>Obesity - metabolism</subject><subject>Obesity - physiopathology</subject><subject>Original</subject><subject>pharmacokinetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Propranolol - administration & dosage</subject><subject>Propranolol - chemistry</subject><subject>Propranolol - pharmacokinetics</subject><subject>Propranolol - pharmacology</subject><subject>Regression Analysis</subject><subject>Sotalol - blood</subject><subject>Sotalol - pharmacokinetics</subject><subject>Sotalol - pharmacology</subject><subject>Stereoisomerism</subject><subject>Tissue Distribution</subject><subject>β‐adrenoceptor blockers</subject><issn>0306-5251</issn><issn>1365-2125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUtuFDEURS0ECp3AEpBqgBCTKp7t8k9CSKHFTwoiAxhbLn9Idartxq4OySxLYC0shEWwEqroVgsmiJEt3XOfPwehCkODoeXPVg2mnNUEE9ZgpUQDwEE113fQ4hDcRQugwGtGGL6PjktZAWCKOTtCR4oAk5gt0PvzC5PXxqbLPvqxt6VKofrx_eftN-Oyj8n6zZhy1Q3JXvpcqj5WqfPFVya6KqapOlRXadjG0U_xA3QvmKH4h_v1BH16_erj8m199uHNu-XpWW0ZBVVbzyWwIDoTmOikd4FRB1ICGHBSSdq5EBjmgXDhJHPMilaYlrSYtEr6lp6gF7u5m2239s76OGYz6E3u1ybf6GR6_XcS-wv9OV1pAi0RUk4DnuwH5PRl68uo132xfhhM9GlbtFCgoBUz-PSfIJZKUC6lUBMqd6jNqZTsw-E-GPRsTa_0LEfPcvRsTf-2pq-n6qM_33Mo7jVN-eN9boo1Q8gm2r4cMCJaRtX8Lc932Nd-8Df_fbx-uTyfNvQX3L61cg</recordid><startdate>199706</startdate><enddate>199706</enddate><creator>Cheymol, Georges</creator><creator>Poirier, Jean‐Marie</creator><creator>Carrupt, Pierre‐Alain</creator><creator>Testa, Bernard</creator><creator>Weissenburger, Jacques</creator><creator>Levron, Jean‐Claude</creator><creator>Snoeck, Eric</creator><general>Blackwell Science Ltd</general><general>Blackwell Science</general><general>Wiley-Blackwell</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>7TS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>199706</creationdate><title>Pharmacokinetics of β‐adrenoceptor blockers in obese and normal volunteers</title><author>Cheymol, Georges ; Poirier, Jean‐Marie ; Carrupt, Pierre‐Alain ; Testa, Bernard ; Weissenburger, Jacques ; Levron, Jean‐Claude ; Snoeck, Eric</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5309-ce6805f7baf57b8edf53d08800a0d8983bdff516f267d85d5c747a42412498e43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Adipose Tissue - metabolism</topic><topic>Adrenergic beta-Antagonists - administration & dosage</topic><topic>Adrenergic beta-Antagonists - chemistry</topic><topic>Adrenergic beta-Antagonists - pharmacokinetics</topic><topic>Adrenergic beta-Antagonists - pharmacology</topic><topic>Adult</topic><topic>Antihypertensive agents</topic><topic>Area Under Curve</topic><topic>Benzopyrans - administration & dosage</topic><topic>Benzopyrans - chemistry</topic><topic>Benzopyrans - pharmacokinetics</topic><topic>Benzopyrans - pharmacology</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Bisoprolol - blood</topic><topic>Bisoprolol - pharmacokinetics</topic><topic>Bisoprolol - pharmacology</topic><topic>Blood Chemical Analysis</topic><topic>Blood Pressure - drug effects</topic><topic>Cardiac Output - drug effects</topic><topic>Cardiovascular system</topic><topic>Chromatography, High Pressure Liquid</topic><topic>distribution</topic><topic>Ethanolamines - administration & dosage</topic><topic>Ethanolamines - chemistry</topic><topic>Ethanolamines - pharmacokinetics</topic><topic>Ethanolamines - pharmacology</topic><topic>Female</topic><topic>Heart Rate - drug effects</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>Infusions, Intravenous</topic><topic>Labetalol - administration & dosage</topic><topic>Labetalol - chemistry</topic><topic>Labetalol - pharmacokinetics</topic><topic>Labetalol - pharmacology</topic><topic>lipophilicity</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Nebivolol</topic><topic>obese subjects</topic><topic>Obesity - blood</topic><topic>Obesity - metabolism</topic><topic>Obesity - physiopathology</topic><topic>Original</topic><topic>pharmacokinetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Propranolol - administration & dosage</topic><topic>Propranolol - chemistry</topic><topic>Propranolol - pharmacokinetics</topic><topic>Propranolol - pharmacology</topic><topic>Regression Analysis</topic><topic>Sotalol - blood</topic><topic>Sotalol - pharmacokinetics</topic><topic>Sotalol - pharmacology</topic><topic>Stereoisomerism</topic><topic>Tissue Distribution</topic><topic>β‐adrenoceptor blockers</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cheymol, Georges</creatorcontrib><creatorcontrib>Poirier, Jean‐Marie</creatorcontrib><creatorcontrib>Carrupt, Pierre‐Alain</creatorcontrib><creatorcontrib>Testa, Bernard</creatorcontrib><creatorcontrib>Weissenburger, Jacques</creatorcontrib><creatorcontrib>Levron, Jean‐Claude</creatorcontrib><creatorcontrib>Snoeck, Eric</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>Physical Education Index</collection><collection>MEDLINE - Academic</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>Cheymol, Georges</au><au>Poirier, Jean‐Marie</au><au>Carrupt, Pierre‐Alain</au><au>Testa, Bernard</au><au>Weissenburger, Jacques</au><au>Levron, Jean‐Claude</au><au>Snoeck, Eric</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacokinetics of β‐adrenoceptor blockers in obese and normal volunteers</atitle><jtitle>British journal of clinical pharmacology</jtitle><addtitle>Br J Clin Pharmacol</addtitle><date>1997-06</date><risdate>1997</risdate><volume>43</volume><issue>6</issue><spage>563</spage><epage>570</epage><pages>563-570</pages><issn>0306-5251</issn><eissn>1365-2125</eissn><coden>BCPHBM</coden><abstract>Aims Obesity can modify the pharmacokinetics of lipophilic drugs. As β‐adrenoceptor blockers (BB) are often prescribed for obese patients suffering from hypertension or coronary heart disease, this study compares the pharmacokinetics of lipophilic β‐adrenoceptor blockers in obese and control subjects.
Methods Nine obese (157±24% of ideal body weight (IBW) mean±s.d.) and nine non‐obese healthy volunteers (98±10% IBW), aged 32±9 years, were included in the study. Subjects were randomly given a single i.v. infusion of one of the following racemic β‐adrenoceptor blockers, whose doses (expressed as base per kg of IBW) were: propranolol (0.108 mg), labetalol (0.99 mg) and nebivolol (0.073 mg). The plasma concentrations of unchanged drugs were measured by h.p.l.c. The ionisation constants and lipophilicity parameters of β‐adrenoceptor blockers were assessed.
Results The pharmacokinetic data for the three drugs were qualitatively similar. There was a trend towards a greater total distribution volume (Vss ) in obese patients than in controls. However, Vss expressed per kg body weight was slightly smaller in obese patients. The relationship between Vss and lipophilicity of five β‐adrenoceptor was studied by combining the current results with those previously obtained with a moderately lipophilic drug (bisoprolol) and a hydrophilic one (sotalol). The Vss of the five drugs was positively and well‐correlated (r2=0.90; P<0.01) with their distribution coefficient at pH 7.4 (log D7.4 ), but not with their partition coefficients. The linear regression coefficients for lean and obese subjects were very similar.
Conclusions Lipophilic β‐adrenoceptor blockers seem to diffuse less into adipose than into lean tissues. All electrical forms of the drugs (i.e. cations, neutral forms, or zwitterions) present at physiological pH contribute to their tissue distribution, in both obese and lean subjects.Their tissue distribution in obese patients could be restricted by the sum of hydrophobic forces and hydrogen bonds they elicit with macromolecules in lean tissues.</abstract><cop>Oxford, UK</cop><pub>Blackwell Science Ltd</pub><pmid>9205815</pmid><doi>10.1046/j.1365-2125.1997.00609.x</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | British journal of clinical pharmacology, 1997-06, Vol.43 (6), p.563-570 |
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| subjects | Adipose Tissue - metabolism Adrenergic beta-Antagonists - administration & dosage Adrenergic beta-Antagonists - chemistry Adrenergic beta-Antagonists - pharmacokinetics Adrenergic beta-Antagonists - pharmacology Adult Antihypertensive agents Area Under Curve Benzopyrans - administration & dosage Benzopyrans - chemistry Benzopyrans - pharmacokinetics Benzopyrans - pharmacology Binding Sites Biological and medical sciences Bisoprolol - blood Bisoprolol - pharmacokinetics Bisoprolol - pharmacology Blood Chemical Analysis Blood Pressure - drug effects Cardiac Output - drug effects Cardiovascular system Chromatography, High Pressure Liquid distribution Ethanolamines - administration & dosage Ethanolamines - chemistry Ethanolamines - pharmacokinetics Ethanolamines - pharmacology Female Heart Rate - drug effects Humans Hydrogen-Ion Concentration Infusions, Intravenous Labetalol - administration & dosage Labetalol - chemistry Labetalol - pharmacokinetics Labetalol - pharmacology lipophilicity Male Medical sciences Nebivolol obese subjects Obesity - blood Obesity - metabolism Obesity - physiopathology Original pharmacokinetics Pharmacology. Drug treatments Propranolol - administration & dosage Propranolol - chemistry Propranolol - pharmacokinetics Propranolol - pharmacology Regression Analysis Sotalol - blood Sotalol - pharmacokinetics Sotalol - pharmacology Stereoisomerism Tissue Distribution β‐adrenoceptor blockers |
| title | Pharmacokinetics of β‐adrenoceptor blockers in obese and normal volunteers |
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