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Cited by 29Drug Transport and Resistance MechanismsPharmacogenetics and Drug MetabolismDrug Solubulity and Delivery Systems

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Differential roles of P-glycoprotein, multidrug resistance-associated protein 2, and CYP3A on ­saquinavir oral absorption in Sprague-Dawley rats

Usansky, Helen H., Hu, Peidi, Sinko, Patrick J.·2008·Drug Metabolism and Disposition
DOI 10.1124/dmd.107.017483
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Abstract

The objective of this investigation was to differentiate the roles of P-glycoprotein (Pgp), multidrug resistance-associated protein 2 (Mrp2), and CYP3A on saquinavir (SQV) oral absorption. With use of single-pass jejunal perfusion (in situ) and portal vein-cannulated rats (in vivo), SQV absorption was studied under chemical inhibition of Pgp [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2 isoquinolinyl)-ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918)], Mrp2 [(3-(((3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl) ((3-(dimethylamino-3-oxopropyl)thio)methyl)-thio) propanoic acid (MK571)], and/or CYP3A (midazolam). Plasma concentrations of SQV and related metabolites were analyzed by liquid chromatography-tandem mass spectrometry. When given alone, SQV absorption was extremely low both in situ (F(a) = 0.07%) and in vivo [C(max) = 0.068 microg/ml; area under the curve (AUC) = 6.8 microg x min/ml]. Coadministration of GF120918 boosted SQV absorption by more than 20-fold with decreased variation in AUCs (percent coefficient of variation = 30% versus 100%). In contrast, coadministration of MK571 or midazolam increased SQV absorption only 2- to 3-fold without improving the variation in AUCs. SQV oral absorption was not further improved when it was given with GF120918 and midazolam or with GF120918 and MK571. The current results provide, for the first time, direct and explicit evidence that the low oral absorption of SQV is controlled by a secretory transport…

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Metadata

Authors
Usansky, H. H., Hu, P., & Sinko, P. J.
Affiliations
Rutgers, The State University of New Jersey (US)
ORCID
Venue
Drug Metabolism and Disposition
Publisher
Elsevier BV
Published
2008-05
Volume
36
Issue
5
Pages
863-869
ISSN
0090-9556 (ISSN-L)
DOI
10.1124/dmd.107.017483
OpenAlex
W2120336413
Cited by
29
References
0
Citations by year
2023: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 2 · 2014: 1 · 2013: 2 · 2012: 1
FWCI
2.82
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Drug Metabolism and Disposition (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Allergy and Infectious Diseases (R01AI051214)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
Keywords
saquinavir, P-glycoprotein, MRP2, CYP3A, oral absorption, intestinal drug transporters, elacridar, MK571, midazolam, antiretroviral drugs, drug-metabolizing enzymes
MeSH terms
Multidrug Resistance-Associated Protein 2, Administration, Oral, Animals, Biological Availability, Intestinal Absorption, Male, Rats, Sprague-Dawley, HIV Protease Inhibitors, Saquinavir, ATP-Binding Cassette, Sub-Family C Proteins, Rats, Cytochrome P-450 CYP3A

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