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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 [C-11]verapamil as radiolabeled P-gp substrate. Studies were performed in rats bearing tumors bilaterally, a P-gp-negative small cell lung carcinoma (GLC(4)) and its P-gp-overexpressing subline (GLC(4)/P-gp). For validation, in vitro and biodistribution studies with [C-11]daunorubicin and [C-11]verapamil were performed. [C-11]Daunorubicin and [C-11]verapamil accumulation were higher in GLC(4) than in GLC(4)/P-gp cells. These levels were increased after modulation with cyclosporin A in GLC(4)/P-gp. Biodistribution studies showed 159% and 185% higher levels of [C-11]daunorubicin and [C-11]verapamil, respectively, in GLC(4) than in GLC(4)/P-gp tumors. After cyclosporin A, [C-11]daunorubicin and [C-11]verapamil content in the GLC(4)/P-gp tumor was raised to the level of GLC(4) tumors. PET measurements demonstrated a lower [C-11]verapamil content in GLC(4)/P-gp tumors compared with GLC(4) tumors. Pretreatment with cyclosporin A increased [C-11]verapamil levels in GLC(4)/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.