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Orosomucoid (α 1 ‐acid glycoprotein) plasma concentration and genetic variants: Effects on human immunodeficiency virus protease inhibitor clearance and cellular accumulation
Author(s) -
Colombo Sara,
Buclin Thierry,
Décosterd Laurent A.,
Telenti Amalio,
Furrer Hansjakob,
Lee Belle L.,
Biollaz Jérôme,
Eap Chin B.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2006.06.006
Subject(s) - lopinavir , indinavir , ritonavir , orosomucoid , amprenavir , nelfinavir , pharmacokinetics , efavirenz , chemistry , saquinavir , protease inhibitor (pharmacology) , pharmacology , protease , glycoprotein , virology , biology , human immunodeficiency virus (hiv) , biochemistry , hiv 1 protease , viral load , sida , enzyme , viral disease , antiretroviral therapy
Background and Objective Protease inhibitors are highly bound to orosomucoid (ORM) (α 1 ‐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 (CL app ) 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 CL app was strongly influenced by ORM concentration (n = 36) ( r 2 = 0.47 [ P = .00004]), particularly in the presence of ritonavir ( r 2 = 0.54 [ P = .004]). Lopinavir CL app was weakly influenced by ORM concentration (n = 81) ( r 2 = 0.18 [ P = .0001]). For both drugs, the ORM1 S variant concentration mainly explained this influence ( r 2 = 0.55 [ P = .00004] and r 2 = 0.23 [ P = .0002], respectively). Indinavir CL app 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