Effect of P-glycoprotein modulation with cyclosporin A on cerebrospinal fluid penetration of doxorubicin in non-human primates.
OBJECTIVE
P-glycoprotein (Pgp) is a transmembrane drug efflux pump that is expressed in multidrug-resistant cancer cells and in a variety of normal tissues, including brain capillary endothelial cells which comprise the blood-brain barrier. We studied the effects of the Pgp inhibitor, cyclosporin A (CsA), on the cerebrospinal fluid (CSF) penetration of the Pgp substrate, doxorubicin, in non-human primates.


METHODS
The animals received doxorubicin alone (2.0 mg/kg i.v. over 60 min) or doxorubicin (1 mg/kg i.v. over 60 min) and CsA (loading dose 4.0 mg/kg i.v. over 2 h, followed by continuous infusion of 12 mg/kg per day over 48 h). Plasma and CSF were collected over 48 h and the doxorubicin concentration was measured by reverse-phase high-pressure liquid chromatography (HPLC) with fluorescence detection (detection limit 5 nM). A two-compartment model was fitted to the plasma concentration-time data.


RESULTS
Pgp was demonstrated to be present in the epithelium of the choroid plexus by immunohistochemical methods, indicating that CSF drug penetration could be used as a surrogate for blood-brain barrier penetration. Steady state whole blood CsA concentrations, which were measured with a fluorescence-polarization immunoassay (TDX) that detects both CsA and its metabolites, ranged from 551-1315 microg/l at 24 h. The clearance of doxorubicin in four animals was reduced by 34%, 38%, 45% and 49% when given with CsA. The doxorubicin concentration in the CSF was <5 nM in all animals, both after doxorubicin alone and doxorubicin with CsA.


CONCLUSIONS
The Pgp inhibitor, CsA, at a concentration that alters systemic clearance of doxorubicin, does not appear to significantly increase the CSF penetration of doxorubicin.
Warren
K E
KE
Pediatric Oncology Branch, Bldg. 10/Rm. 13N240, 10 Center Drive, National Cancer Institute, Bethesda, MD 20892, USA. warrenk@exchange.nih.gov
Patel
M C
MC
McCully
C M
CM
Montuenga
L M
LM
Balis
F M
FM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000032:analysis / Q000276:immunology; D000970:Antineoplastic Agents / Q000097:blood / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics; D001808:Blood Vessels / Q000737:chemistry; D001921:Brain / Q000098:blood supply; D002831:Choroid Plexus / Q000737:chemistry / Q000166:cytology; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000097:blood / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology; D004847:Epithelial Cells / Q000737:chemistry; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D008657:Metabolic Clearance Rate
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004317:Doxorubicin; D016572:Cyclosporine