Orosomucoid (α1‐acid glycoprotein) plasma concentration and genetic variants: Effects on human immunodeficiency virus protease inhibitor clearance and cellular accumulation
Background and Objective Protease inhibitors are highly bound to orosomucoid (ORM) (α1‐acid glycoprotein), an acute‐phase plasma protein encoded by 2 polymorphic genes, which may modulate their disposition. Our objective was to determine the influence of ORM concentration and phenotype on indinavir,...
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| creator | Colombo, Sara Buclin, Thierry Décosterd, Laurent A. Telenti, Amalio Furrer, Hansjakob Lee, Belle L. Biollaz, Jérôme Eap, Chin B. |
| description | Background and Objective
Protease inhibitors are highly bound to orosomucoid (ORM) (α1‐acid glycoprotein), an acute‐phase plasma protein encoded by 2 polymorphic genes, which may modulate their disposition. Our objective was to determine the influence of ORM concentration and phenotype on indinavir, lopinavir, and nelfinavir apparent clearance (CLapp) and cellular accumulation. Efavirenz, mainly bound to albumin, was included as a control drug.
Methods
Plasma and cells samples were collected from 434 human immunodeficiency virus‐infected patients. Total plasma and cellular drug concentrations and ORM concentrations and phenotypes were determined.
Results
Indinavir CLapp was strongly influenced by ORM concentration (n = 36) (r2 = 0.47 [P = .00004]), particularly in the presence of ritonavir (r2 = 0.54 [P = .004]). Lopinavir CLapp was weakly influenced by ORM concentration (n = 81) (r2 = 0.18 [P = .0001]). For both drugs, the ORM1 S variant concentration mainly explained this influence (r2 = 0.55 [P = .00004] and r2 = 0.23 [P = .0002], respectively). Indinavir CLapp was significantly higher in F1F1 individuals than in F1S and SS patients (41.3, 23.4, and 10.3 L/h [P = .0004] without ritonavir and 21.1, 13.2, and 10.1 L/h [P = .05] with ritonavir, respectively). Lopinavir cellular exposure was not influenced by ORM abundance and phenotype. Finally, ORM concentration or phenotype did not influence nelfinavir (n = 153) or efavirenz (n = 198) pharmacokinetics.
Conclusion
ORM concentration and phenotype modulate indinavir pharmacokinetics and, to a lesser extent, lopinavir pharmacokinetics but without influencing their cellular exposure. This confounding influence of ORM should be taken into account for appropriate interpretation of therapeutic drug monitoring results. Further studies are needed to investigate whether the measure of unbound drug plasma concentration gives more meaningful information than total drug concentration for indinavir and lopinavir.
Clinical Pharmacology & Therapeutics (2006) 80, 307–318; doi: 10.1016/j.clpt.2006.06.006 |
| doi_str_mv | 10.1016/j.clpt.2006.06.006 |
| format | Article |
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Protease inhibitors are highly bound to orosomucoid (ORM) (α1‐acid glycoprotein), an acute‐phase plasma protein encoded by 2 polymorphic genes, which may modulate their disposition. Our objective was to determine the influence of ORM concentration and phenotype on indinavir, lopinavir, and nelfinavir apparent clearance (CLapp) and cellular accumulation. Efavirenz, mainly bound to albumin, was included as a control drug.
Methods
Plasma and cells samples were collected from 434 human immunodeficiency virus‐infected patients. Total plasma and cellular drug concentrations and ORM concentrations and phenotypes were determined.
Results
Indinavir CLapp was strongly influenced by ORM concentration (n = 36) (r2 = 0.47 [P = .00004]), particularly in the presence of ritonavir (r2 = 0.54 [P = .004]). Lopinavir CLapp was weakly influenced by ORM concentration (n = 81) (r2 = 0.18 [P = .0001]). For both drugs, the ORM1 S variant concentration mainly explained this influence (r2 = 0.55 [P = .00004] and r2 = 0.23 [P = .0002], respectively). Indinavir CLapp was significantly higher in F1F1 individuals than in F1S and SS patients (41.3, 23.4, and 10.3 L/h [P = .0004] without ritonavir and 21.1, 13.2, and 10.1 L/h [P = .05] with ritonavir, respectively). Lopinavir cellular exposure was not influenced by ORM abundance and phenotype. Finally, ORM concentration or phenotype did not influence nelfinavir (n = 153) or efavirenz (n = 198) pharmacokinetics.
Conclusion
ORM concentration and phenotype modulate indinavir pharmacokinetics and, to a lesser extent, lopinavir pharmacokinetics but without influencing their cellular exposure. This confounding influence of ORM should be taken into account for appropriate interpretation of therapeutic drug monitoring results. Further studies are needed to investigate whether the measure of unbound drug plasma concentration gives more meaningful information than total drug concentration for indinavir and lopinavir.
Clinical Pharmacology & Therapeutics (2006) 80, 307–318; doi: 10.1016/j.clpt.2006.06.006</description><identifier>ISSN: 0009-9236</identifier><identifier>EISSN: 1532-6535</identifier><identifier>DOI: 10.1016/j.clpt.2006.06.006</identifier><identifier>PMID: 17015049</identifier><identifier>CODEN: CLPTAT</identifier><language>eng</language><publisher>New York, NY: Nature Publishing</publisher><subject>Adult ; Benzoxazines ; Biological and medical sciences ; Cohort Studies ; Female ; Genetic Variation ; HIV Infections - drug therapy ; HIV Infections - metabolism ; HIV Protease Inhibitors - metabolism ; HIV Protease Inhibitors - pharmacokinetics ; Humans ; Indinavir - pharmacokinetics ; Lopinavir ; Male ; Medical sciences ; Middle Aged ; Nelfinavir - pharmacokinetics ; Orosomucoid - genetics ; Orosomucoid - metabolism ; Oxazines - pharmacokinetics ; Pharmacology. Drug treatments ; Phenotype ; Pyrimidinones - pharmacokinetics ; Ritonavir - pharmacokinetics ; Switzerland</subject><ispartof>Clinical pharmacology and therapeutics, 2006-10, Vol.80 (4), p.307-318</ispartof><rights>2006 American Society for Clinical Pharmacology and Therapeutics</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3017-9c22ae4b56ddd802ff0e3294319955b5639cec083997c2882841097c713b15973</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1016%2Fj.clpt.2006.06.006$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1016%2Fj.clpt.2006.06.006$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18213471$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17015049$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Colombo, Sara</creatorcontrib><creatorcontrib>Buclin, Thierry</creatorcontrib><creatorcontrib>Décosterd, Laurent A.</creatorcontrib><creatorcontrib>Telenti, Amalio</creatorcontrib><creatorcontrib>Furrer, Hansjakob</creatorcontrib><creatorcontrib>Lee, Belle L.</creatorcontrib><creatorcontrib>Biollaz, Jérôme</creatorcontrib><creatorcontrib>Eap, Chin B.</creatorcontrib><creatorcontrib>Swiss HIV Cohort Study</creatorcontrib><title>Orosomucoid (α1‐acid glycoprotein) plasma concentration and genetic variants: Effects on human immunodeficiency virus protease inhibitor clearance and cellular accumulation</title><title>Clinical pharmacology and therapeutics</title><addtitle>Clin Pharmacol Ther</addtitle><description>Background and Objective
Protease inhibitors are highly bound to orosomucoid (ORM) (α1‐acid glycoprotein), an acute‐phase plasma protein encoded by 2 polymorphic genes, which may modulate their disposition. Our objective was to determine the influence of ORM concentration and phenotype on indinavir, lopinavir, and nelfinavir apparent clearance (CLapp) and cellular accumulation. Efavirenz, mainly bound to albumin, was included as a control drug.
Methods
Plasma and cells samples were collected from 434 human immunodeficiency virus‐infected patients. Total plasma and cellular drug concentrations and ORM concentrations and phenotypes were determined.
Results
Indinavir CLapp was strongly influenced by ORM concentration (n = 36) (r2 = 0.47 [P = .00004]), particularly in the presence of ritonavir (r2 = 0.54 [P = .004]). Lopinavir CLapp was weakly influenced by ORM concentration (n = 81) (r2 = 0.18 [P = .0001]). For both drugs, the ORM1 S variant concentration mainly explained this influence (r2 = 0.55 [P = .00004] and r2 = 0.23 [P = .0002], respectively). Indinavir CLapp was significantly higher in F1F1 individuals than in F1S and SS patients (41.3, 23.4, and 10.3 L/h [P = .0004] without ritonavir and 21.1, 13.2, and 10.1 L/h [P = .05] with ritonavir, respectively). Lopinavir cellular exposure was not influenced by ORM abundance and phenotype. Finally, ORM concentration or phenotype did not influence nelfinavir (n = 153) or efavirenz (n = 198) pharmacokinetics.
Conclusion
ORM concentration and phenotype modulate indinavir pharmacokinetics and, to a lesser extent, lopinavir pharmacokinetics but without influencing their cellular exposure. This confounding influence of ORM should be taken into account for appropriate interpretation of therapeutic drug monitoring results. Further studies are needed to investigate whether the measure of unbound drug plasma concentration gives more meaningful information than total drug concentration for indinavir and lopinavir.
Clinical Pharmacology & Therapeutics (2006) 80, 307–318; doi: 10.1016/j.clpt.2006.06.006</description><subject>Adult</subject><subject>Benzoxazines</subject><subject>Biological and medical sciences</subject><subject>Cohort Studies</subject><subject>Female</subject><subject>Genetic Variation</subject><subject>HIV Infections - drug therapy</subject><subject>HIV Infections - metabolism</subject><subject>HIV Protease Inhibitors - metabolism</subject><subject>HIV Protease Inhibitors - pharmacokinetics</subject><subject>Humans</subject><subject>Indinavir - pharmacokinetics</subject><subject>Lopinavir</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Nelfinavir - pharmacokinetics</subject><subject>Orosomucoid - genetics</subject><subject>Orosomucoid - metabolism</subject><subject>Oxazines - pharmacokinetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenotype</subject><subject>Pyrimidinones - pharmacokinetics</subject><subject>Ritonavir - pharmacokinetics</subject><subject>Switzerland</subject><issn>0009-9236</issn><issn>1532-6535</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUuOEzEQhi0EYkLgAiyQNyBYJPjRL88CCUXDQ4o0swhrq1LtZhy57WB3D8pujjA3QVyEQ3AS3JNIs0UqyVWlz3-V6ifkJWdLznj1frdEtx-WgrFqOQWrHpEZL6VYVKUsH5MZY0wtlJDVGXmW0i6XhWqap-SM14yXuZiRX5cxpNCPGGxL3_75zf_e3gHm_Ls7YNjHMBjr39G9g9QDxeDR-CHCYIOn4DNmvBks0huIFvyQzulF1xkcEs3A9diDp7bvRx9a01m0xuOB3tg4JnqvDclQ66_t1g4hUnQGIuQR99JonBsdRAqIY5-zaehz8qQDl8yL0zsn3z5dbFZfFuvLz19XH9cLlIzXC4VCgCm2ZdW2bcNE1zEjhSokV6osc1sqNMgaqVSNomlEU3CW05rLLS9VLefkzVE3r_ljNGnQvU3TRuBNGJOuGsUrJVQGxRHEfMgUTaf30fYQD5ozPdmkd3qySU826SlYlT-9OqmP2960D19OvmTg9QmAhOC66So2PXCN4LLIy87JhyP30zpz-I_RenW1Wa2vNlOr4LX8B-qOtM8</recordid><startdate>200610</startdate><enddate>200610</enddate><creator>Colombo, Sara</creator><creator>Buclin, Thierry</creator><creator>Décosterd, Laurent A.</creator><creator>Telenti, Amalio</creator><creator>Furrer, Hansjakob</creator><creator>Lee, Belle L.</creator><creator>Biollaz, Jérôme</creator><creator>Eap, Chin B.</creator><general>Nature Publishing</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>7X8</scope></search><sort><creationdate>200610</creationdate><title>Orosomucoid (α1‐acid glycoprotein) plasma concentration and genetic variants: Effects on human immunodeficiency virus protease inhibitor clearance and cellular accumulation</title><author>Colombo, Sara ; Buclin, Thierry ; Décosterd, Laurent A. ; Telenti, Amalio ; Furrer, Hansjakob ; Lee, Belle L. ; Biollaz, Jérôme ; Eap, Chin B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3017-9c22ae4b56ddd802ff0e3294319955b5639cec083997c2882841097c713b15973</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Adult</topic><topic>Benzoxazines</topic><topic>Biological and medical sciences</topic><topic>Cohort Studies</topic><topic>Female</topic><topic>Genetic Variation</topic><topic>HIV Infections - drug therapy</topic><topic>HIV Infections - metabolism</topic><topic>HIV Protease Inhibitors - metabolism</topic><topic>HIV Protease Inhibitors - pharmacokinetics</topic><topic>Humans</topic><topic>Indinavir - pharmacokinetics</topic><topic>Lopinavir</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Nelfinavir - pharmacokinetics</topic><topic>Orosomucoid - genetics</topic><topic>Orosomucoid - metabolism</topic><topic>Oxazines - pharmacokinetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Phenotype</topic><topic>Pyrimidinones - pharmacokinetics</topic><topic>Ritonavir - pharmacokinetics</topic><topic>Switzerland</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Colombo, Sara</creatorcontrib><creatorcontrib>Buclin, Thierry</creatorcontrib><creatorcontrib>Décosterd, Laurent A.</creatorcontrib><creatorcontrib>Telenti, Amalio</creatorcontrib><creatorcontrib>Furrer, Hansjakob</creatorcontrib><creatorcontrib>Lee, Belle L.</creatorcontrib><creatorcontrib>Biollaz, Jérôme</creatorcontrib><creatorcontrib>Eap, Chin B.</creatorcontrib><creatorcontrib>Swiss HIV Cohort Study</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>MEDLINE - Academic</collection><jtitle>Clinical pharmacology and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Colombo, Sara</au><au>Buclin, Thierry</au><au>Décosterd, Laurent A.</au><au>Telenti, Amalio</au><au>Furrer, Hansjakob</au><au>Lee, Belle L.</au><au>Biollaz, Jérôme</au><au>Eap, Chin B.</au><aucorp>Swiss HIV Cohort Study</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Orosomucoid (α1‐acid glycoprotein) plasma concentration and genetic variants: Effects on human immunodeficiency virus protease inhibitor clearance and cellular accumulation</atitle><jtitle>Clinical pharmacology and therapeutics</jtitle><addtitle>Clin Pharmacol Ther</addtitle><date>2006-10</date><risdate>2006</risdate><volume>80</volume><issue>4</issue><spage>307</spage><epage>318</epage><pages>307-318</pages><issn>0009-9236</issn><eissn>1532-6535</eissn><coden>CLPTAT</coden><abstract>Background and Objective
Protease inhibitors are highly bound to orosomucoid (ORM) (α1‐acid glycoprotein), an acute‐phase plasma protein encoded by 2 polymorphic genes, which may modulate their disposition. Our objective was to determine the influence of ORM concentration and phenotype on indinavir, lopinavir, and nelfinavir apparent clearance (CLapp) and cellular accumulation. Efavirenz, mainly bound to albumin, was included as a control drug.
Methods
Plasma and cells samples were collected from 434 human immunodeficiency virus‐infected patients. Total plasma and cellular drug concentrations and ORM concentrations and phenotypes were determined.
Results
Indinavir CLapp was strongly influenced by ORM concentration (n = 36) (r2 = 0.47 [P = .00004]), particularly in the presence of ritonavir (r2 = 0.54 [P = .004]). Lopinavir CLapp was weakly influenced by ORM concentration (n = 81) (r2 = 0.18 [P = .0001]). For both drugs, the ORM1 S variant concentration mainly explained this influence (r2 = 0.55 [P = .00004] and r2 = 0.23 [P = .0002], respectively). Indinavir CLapp was significantly higher in F1F1 individuals than in F1S and SS patients (41.3, 23.4, and 10.3 L/h [P = .0004] without ritonavir and 21.1, 13.2, and 10.1 L/h [P = .05] with ritonavir, respectively). Lopinavir cellular exposure was not influenced by ORM abundance and phenotype. Finally, ORM concentration or phenotype did not influence nelfinavir (n = 153) or efavirenz (n = 198) pharmacokinetics.
Conclusion
ORM concentration and phenotype modulate indinavir pharmacokinetics and, to a lesser extent, lopinavir pharmacokinetics but without influencing their cellular exposure. This confounding influence of ORM should be taken into account for appropriate interpretation of therapeutic drug monitoring results. Further studies are needed to investigate whether the measure of unbound drug plasma concentration gives more meaningful information than total drug concentration for indinavir and lopinavir.
Clinical Pharmacology & Therapeutics (2006) 80, 307–318; doi: 10.1016/j.clpt.2006.06.006</abstract><cop>New York, NY</cop><pub>Nature Publishing</pub><pmid>17015049</pmid><doi>10.1016/j.clpt.2006.06.006</doi><tpages>12</tpages></addata></record> |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Adult Benzoxazines Biological and medical sciences Cohort Studies Female Genetic Variation HIV Infections - drug therapy HIV Infections - metabolism HIV Protease Inhibitors - metabolism HIV Protease Inhibitors - pharmacokinetics Humans Indinavir - pharmacokinetics Lopinavir Male Medical sciences Middle Aged Nelfinavir - pharmacokinetics Orosomucoid - genetics Orosomucoid - metabolism Oxazines - pharmacokinetics Pharmacology. Drug treatments Phenotype Pyrimidinones - pharmacokinetics Ritonavir - pharmacokinetics Switzerland |
| title | Orosomucoid (α1‐acid glycoprotein) plasma concentration and genetic variants: Effects on human immunodeficiency virus protease inhibitor clearance and cellular accumulation |
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