JAC Advance Access originally published online on February 11, 2003
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Journal of Antimicrobial Chemotherapy (2003) 51, 493-496
© 2003 The British Society for Antimicrobial Chemotherapy
Leading Article |
The mechanisms that control intracellular penetration of the HIV protease inhibitors
Department of Pharmacology & Therapeutics, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK
Keywords: P-glycoprotein, lipophilicity, physiochemical, transport, efflux
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Background |
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Human immunodeficiency virus (HIV) replicates within cells, such as the T4 lymphocyte. Current drug treatment for HIV infection interrupts the viral lifecycle, at the HIV reverse transcriptase and HIV protease steps (Figure 1). Consequently, antiretroviral drugs must enter cells to inhibit viral replication. This article focuses on the penetration of the HIV protease inhibitors (PIs) and some possible mechanisms that control this process.
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Plasma drug concentrations |
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The oral bioavailability and systemic clearance of a drug are the important determinants of plasma concentrations. Following oral administration, the PIs are primarily metabolized by cytochrome P450 (CYP) 3A4, although CYP 2D6 and CYP 2C9 are also involved.1,2 The PIs are also substrates for the transmembrane efflux pump P-glycoprotein (P-gp) in epithelial cells. Thus, extensive first pass metabolism contributes to low and variable bioavailability. To help ensure that adequate drug concentrations are achieved throughout the dosing interval, therapeutic drug monitoring
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Protein binding |
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Intracellular PI concentrations |
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Mechanisms of intracellular accumulation |
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Lipophilicity
Intracellular protein binding
Ion trapping
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Drug transporters |
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P-glycoprotein |
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P-gp distribution
Impact of P-gp on intracellular accumulation
Relationship between P-gp and CYP 3A4
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MRP1 |
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Distribution within the cell |
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Summary |
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Acknowledgements |
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