Cerebrovascular transport of ( sup 125 I)quinuclidinyl benzilate, ( sup 3 H)cyclofoxy, and ( sup 14 C)iodoantipyrine

The transport rate constants across rat brain capillaries of a muscarinic acetylcholine receptor antagonist, ({sup 125}I)quinuclidinyl benzilate (IQNB), an opiate receptor antagonist, ({sup 3}H)cyclofoxy (CF), and a highly diffusible blood flow indicator, ({sup 14}C)iodoantipyrine (IAP), were determined by the indicator-diffusion technique and a model that includes a distribution of capillary transit times and a homogeneous distribution of the test compound in the tissue parenchyma. The mean influx extraction ratio (E1) of IAP was greater than 0.91, and E1 for CF and IQNB was 0.56-0.79 and 0.34-0.46, respectively. The order of lipid solubility was IQNB greater than IAP greater than CF; the apparent discrepancy (high lipid solubility and low permeability) of IQNB was partly due to intravascular binding to plasma protein and red blood cells. The observed initial tissue distribution volumes (lambda 1, ml/g brain) for IQNB (0.09-0.17), CF (0.51), and IAP (0.71) were compared with those estimated for the unbound free ligand in blood (lambda a, ml/g brain; IQNB = 1.3-2.3, CF = 0.88, and IAP = 1.4). These findings suggest that the binding of lipid-soluble radioligands and drugs to plasma proteins and red blood cells can be a major determinant of transport across the blood-brain barrier and the apparentmore » distribution volume of the ligand in brain tissue.« less