Efflux of drugs and solutes from brain: the interactive roles of diffusional transcapillary transport, bulk flow and capillary transporters.

We examined the roles of diffusion, convection and capillary transporters in solute removal from extracellular space (ECS) of the brain. Radiolabeled solutes (eight with passive distribution and four with capillary or cell transporters) were injected into the brains of rats (n=497) and multiple-time point experiments measured the amount remaining in brain as a function of time. For passively distributed compounds, there was a relationship between lipid:water solubility and total brain efflux:diffusional efflux, which dominated when k(p), the transcapillary efflux rate constant, was >10(0) h(-1); when 10(-1)

Isolation of drug delivery from drug effect: problems of optimizing drug delivery parameters.

A recurring question in the treatment of malignant brain tumors has been whether treatment failure is due to inadequate delivery or ineffective drugs. To isolate these issues, we tested a paradigm in which the "therapeutic" agent was a toxin about which there could be no question of efficacy, provided it was delivered in adequate amounts; we used 10% formalin. We infused 10% formalin into 5- to 8-mm subcutaneous RG-2 and D54-MG gliomas at increasing rates until we achieved 100% tumor cell kill. In RG-2 gliomas, infusions of 10 microl/h x 7 days, and 2, 4, 6, and 8 microl/min x 2 h failed to kill tumors, although growth was delayed, while infusion rates of 12 microl/min x 60 min and 48 microl/min x 15 min produced 100% tumor kill. In D54-MG tumors, infusions of 4, 8, and 24 microl/min produced 100% tumor kill. 14C-Formalin autoradiographs showed a heterogeneous distribution after infusions of 2 microl/min x 2 h, whereas infusions of 48 microl/min x 15 min showed a homogeneous distribution within the tumor, but more than 95% of tissue radioactivity was found in tissue surrounding tumor. Drug delivery remains a major issue in brain tumor treatment: Distribution inhomogeneity, rapid efflux, and consequent treatment failures are likely due to high interstitial fluid pressure. Because the infusion rates being used in the treatment of human brain tumors are low and the tumors are larger, treatment failures can be expected on the basis of inadequate drug delivery alone, regardless of the effectiveness of the drug.

Comparative pharmacokinetics of 14C-sucrose in RG-2 rat gliomas after intravenous and convection-enhanced delivery.

We compared tissue and plasma pharmacokinetics of 14C-sucrose in subcutaneous RG-2 rat gliomas after administration by 3 routes, intravenous bolus (i.v.-B; 50 microCi over 30 s), continuous i.v. infusion (i.v.-C, 50 microCi at a constant rate), and convection-enhanced delivery (CED, 5 microCi infused at a rate of 0.5 microl/min), and for 3 experimental durations, 0.5, 2, and 4 h. Plasma, tumor, and other tissue samples were obtained to measure tissue radioactivity. Plasma radioactivity in the CED group increased exponentially and lagged only slightly behind the IV-C group. After 90 min, plasma values were similar in all. Mean tumor radioactivity was 100 to 500 times higher in the CED group at each time point than in the i.v.-B and i.v.-C groups. Tumor radioactivity was homogeneous in the i.v. groups at 0.5 h and inhomogeneous at 1 and 2 h. In CED, radioactivity distribution was inhomogeneous at all 3 time points; highest concentrations were in tissue around tumor and in necrosis, while viable tumor contained the lowest and sometimes negligible amounts of isotope. Systemic tissue radioactivity values were similar in all groups. Efflux of 14C-sucrose from tumors was evaluated in intracerebral tumors (at 0.5, 1, 2, and 4 h) and subcutaneous tumors (at 0 to 0.5 h). Less than 5% of 14C activity remained in intracerebral tumors at each time point. The efflux half-time from the subcutaneous tumors was 7.3 +/- 0.7 min. These results indicate rapid efflux of drug from brain tumor and marked heterogeneity of drug distribution within tumor after CED administration, both of which may be potentially limiting factors in drug delivery by this method.