Anti-HIV protease inhibitors (PRIs) are frontline drugs in the treatment of AIDS, and are now routinely administered in combination with other anti-HIV drugs including other protease inhibitors, nucleoside (e.g. azidothymidine) and non-nucleoside reverse transcriptase inhibitors (e.g. delavirdine). PRIs are substrates of CYP3A enzymes and of the multidrug resistance (MDR) transporters, MDR1 and MRP2. A significant clinical problem encountered in prescribing PRIs is their propensity to produce clinically significant drug interactions, both inductive and inhibitory, with drugs routinely administered to people with AIDS. To date, the focus of studies on the mechanisms and extent of drug interactions with PRIs has been on the capacity of the PRIs to potently inhibit CYP3A enzymes, both in vitro and in vivo. However, little is known about the mechanisms by which PRIs induce clearance of various drugs, as well as the mechanisms by which they cause induction of their own clearance (autoinduction). Of the PRIs used in the clinic, clinically significant inductive drug interactions and autoinduction have been reported most frequently with ritonavir and nelfinavir. Inductive drug interactions and autoinduction by ritonavir are most surprising as ritonavir inactivates CYP3A enzymes in vitro and potently inhibits CYP3A4/5 in vivo, enzymes responsible for the clearance of ritonavir and other PRIs. Like rifampin, ritonavir appears to be a broad-spectrum inducer of enzymes and transporters. This observation is consistent with ritonavir being an excellent ligand/activator of the human orphan nuclear receptor, hPXR (pregnane X receptor). Surprisingly, nelfinavir is NOT a ligand/activator of hPXR, and yet it is an autoinducer and causes inductive drug interactions. Thus, we have hypothesized that ritonavir and nelfinavir autoinduce and cause inductive drug interactions via different mechanisms. Ritonavir mediates its inductive effects primarily by activating hPXR, while nelfinavir does so via other mechanisms (e.g. activating other orphan nuclear receptors).
The specific aims of this proposal are directed towards testing this hypothesis and towards elucidating the mechanisms and extent of in vitro and in vivo induction by PRIs of CYP enzymes and MDR transporters.
Specific Aims 1. To determine, using human hepatocytes and human intestinal cell lines, the CYP enzymes and MDR transporters that are significantly induced by PRIs. 2. To determine if CYPs and MDR transporters significantly induced by ritonavir and nelfinavir in vitro, are induced to a similar extent in vivo in humans. 3. To determine if known variants of the MDR1 gene determine the in vivo disposition of ritonavir and nelfinavir and, therefore, the in vivo induction by these PRIs of MDR transporters and CYP enzymes. To determine the molecular mechanisms by which CYP enzymes and MDR transporters are induced by ritonavir and nelfinavir.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
2P01GM032165-21
Application #
6701462
Study Section
Special Emphasis Panel (ZGM1-PS-9 (01))
Project Start
2003-08-01
Project End
2008-07-31
Budget Start
Budget End
2004-07-31
Support Year
21
Fiscal Year
2003
Total Cost
$301,185
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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