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 provide a basis for improvement of chemotherapy and risk assessment. Regional drug administration has been emphasized, with specific work on delivery of drugs to the central nervous system and peritoneal cavity. We have examined the theoretical implications of permeability changes in the brain induced by osmotic or pharmacologic agents, to assess the actual effective change in drug delivery according to appropriate pharmacodynamic metrics (e.g., time above an effective concentration for antimetabolites, or area-under-the-concentration (AUC) curve for alkylating or platinating agents). Route of drug administration was also analyzed to determine the effect of intra-arterial delivery compared with intravenous delivery. Peritoneal drug administration appears to be useful in the treatment of optimal stage III ovarian cancer. Two major problems appear to limit the improved effectiveness of this route for the treatment of ovarian and other cancers growing on serosal surfaces: tissue penetration and adequate exposure of all tumor surfaces. Analysis of these problems and the determination of possible directions toward improved therapy are being examined by means of a spatially distributed description of peritoneal absorption.
