Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes.

Article Details

Citation

Choo EF, Leake B, Wandel C, Imamura H, Wood AJ, Wilkinson GR, Kim RB

Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes.

Drug Metab Dispos. 2000 Jun;28(6):655-60.

PubMed ID
10820137 [ View in PubMed
]
Abstract

HIV protease inhibitors have proven remarkably effective in treating HIV-1 infection. However, some tissues such as the brain and testes (sanctuary sites) are possibly protected from exposure to HIV protease inhibitors due to drug entry being limited by the membrane efflux transporter P-glycoprotein, located in the capillary endothelium. Intravenous administration of the novel and potent P-glycoprotein inhibitor LY-335979 to mice (1-50 mg/kg) increased brain and testes concentration of [(14)C]nelfinavir, up to 37- and 4-fold, respectively, in a dose-dependent fashion. Similar effects in brain levels were also observed with (14)C-labeled amprenavir, indinavir, and saquinavir. Because [(14)C]nelfinavir plasma drug levels were only modestly increased by LY-335979, the increase in brain/plasma and testes/plasma ratios of 14- to 17- and 2- to 5-fold, respectively, was due to increased tissue penetration. Less potent P-glycoprotein inhibitors like valspodar (PSC-833), cyclosporin A, and ketoconazole, as well as quinidine and verapamil, had modest or little effect on brain/plasma ratios but increased plasma nelfinavir concentrations due to inhibition of CYP3A-mediated metabolism. Collectively, these findings provide "proof-of-concept" for increasing HIV protease inhibitor distribution into pharmacologic sanctuary sites by targeted inhibition of P-glycoprotein using selective and potent agents and suggest a new therapeutic strategy to reduce HIV-1 viral replication.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
IndinavirP-glycoprotein 1ProteinHumans
Unknown
Substrate
Inhibitor
Inducer
Details
KetoconazoleP-glycoprotein 1ProteinHumans
Unknown
Inhibitor
Details
NelfinavirP-glycoprotein 1ProteinHumans
Unknown
Substrate
Inhibitor
Inducer
Details
QuinidineP-glycoprotein 1ProteinHumans
Unknown
Substrate
Inhibitor
Details
RitonavirP-glycoprotein 1ProteinHumans
Unknown
Substrate
Inhibitor
Inducer
Details
SaquinavirP-glycoprotein 1ProteinHumans
Unknown
Substrate
Inhibitor
Inducer
Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
CyclosporineP-glycoprotein 1IC 50 (nM)1300N/AN/ADetails
IndinavirP-glycoprotein 1IC 50 (nM)44000N/AN/ADetails
KetoconazoleP-glycoprotein 1IC 50 (nM)1200N/AN/ADetails
RitonavirP-glycoprotein 1IC 50 (nM)3800N/AN/ADetails
SaquinavirP-glycoprotein 1IC 50 (nM)6500N/AN/ADetails
VerapamilP-glycoprotein 1IC 50 (nM)2100N/AN/ADetails
Drug Interactions
DrugsInteraction
Azithromycin
Nelfinavir
The serum concentration of Azithromycin can be increased when it is combined with Nelfinavir.
Interactions
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