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A New in Vivo Method to Study P-Glycoprotein Transport in Tumors and the Blood-Brain Barrier¹

Positron Emission Tomography Center [N. H. H., L. E-F., A. T. M. W., W. V., E. J. F. F.], Department of Medical Oncology [N. H. H., E. G. E. d. V., W. T. A. v. d. G., G. A. P. H.], Groningen University Hospital, 9700 RB Groningen, the Netherlands

Drug resistance is a major cause of chemotherapy failure in cancer treatment. One reason is the overexpression of the drug efflux pump P-glycoprotein (P-gp), involved in multidrug resistance (MDR). In vivo pharmacokinetic analysis of P-gp transport might identify the capacity of modulation by P-gp substrate modulators, such as cyclosporin A. Therefore, P-gp function was measured in vivo with positron emission tomography (PET) and [¹¹C]verapamil as radiolabeled P-gp substrate.

Studies were performed in rats bearing tumors bilaterally, a P-gp-negative small cell lung carcinoma (GLC₄) and its P-gp-overexpressing subline (GLC₄/P-gp). For validation, in vitro and biodistribution studies with [¹¹C]daunorubicin and [¹¹C]verapamil were performed.

[¹¹C]Daunorubicin and [¹¹C]verapamil accumulation were higher in GLC₄ than in GLC₄/P-gp cells. These levels were increased after modulation with cyclosporin A in GLC₄/P-gp. Biodistribution studies showed 159% and 185% higher levels of [¹¹C]daunorubicin and [¹¹C]verapamil, respectively, in GLC₄ than in GLC₄/P-gp tumors. After cyclosporin A, [¹¹C]daunorubicin and [¹¹C]verapamil content in the GLC₄/P-gp tumor was raised to the level of GLC₄ tumors. PET measurements demonstrated a lower [¹¹C]verapamil content in GLC₄/P-gp tumors compared with GLC₄ tumors. Pretreatment with cyclosporin A increased [¹¹C]verapamil levels in GLC₄/P-gp tumors (184%) and in brains (1280%). This pharmacokinetic effect was clearly visualized with PET.

These results show the feasibility of in vivo P-gp function measurement under basal conditions and after modulation in solid tumors and in the brain. Therefore, PET and radiolabeled P-gp substrates may be useful as a clinical tool to select patients who might benefit from the addition of a P-gp modulator to MDR drugs.

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