Physiological pharmacokinetic models are developed for the distribution and disposition of drugs and environmental contaminants. These models provide a plausible set of equations that can be used to extrapolate data from experimental animals to humans, and thereby improve chemotherapy and risk assessment. A pharmacokinetic model developed for topotecan in the Rhesus monkey provides a basis for design and analysis of clinical studies. Important features of the model include reversible opening of the topotecan lactone to an hydroxy acid form, and transport between the plasma and the cerebrospinal fluid. We have collaborated in the further development of a clinical protocol for the administration of AZT into cerebrospinal fluid for the treatment of AIDS dementia. Collaborative research on intraperitoneal drug administration has emphasized macromolecules. Work has been extended on the development of methods using IBZM and SPECT to quantitate D2 receptor densities, affinities, and endogenous dopamine competition for the binding sites. Analyses based on a pharmacokinetic model for IBZM suggest that data scatter from SPECT was sufficiently large that D2 receptor density and dopamine content often appeared correlated. Parameter estimation from PET ligand analysis seems preferable because of favorable counting statistics attainable with late-generation, high-efficiency gamma cameras.
