Pharmacokinetics of anti-AIDS and anti-cancer drugs: Implications on drug delivery and drug interaction

The research studies described in this dissertation focus on the pharmacokinetic principles of drug disposition. In general, tissue distribution and tissue pharmacokinetics, such as drug concentrations and residence time in specific tissues, are the determinants of the desired therapeutic and unwanted adverse effects of a drug. However, due to limitation on tissue accessibility, these studies cannot be readily performed in humans. One of the solutions for this is to use preclinical in vivo animal models to obtain the information need for the development of dosage regimens in humans. The first goal of this dissertation was to determine the tissue pharmacokinetics of paclitaxel, i.e. paclitaxel nanoparticles, an alternative formulation of paclitaxel, one of the important anticancer drugs developed in the past two decades. The data in mice show different tissue distribution of paclitaxel formulated in nanoparticles as compared to the commercial formulation of paclitaxel where paclitaxel is solubilized in cremophor micelles. In general, paclitaxel nanoparticles were preferentially delivered and retained in several organs, i.e. kidney, liver, and small intestine. A comparison of the distribution of paclitaxel containing nanoparticles and a fluorescence-labeled nanoparticles showed that the 7-fold higher accumulation of paclitaxel is mainly due to the preferential partition and retention of paclitaxel in the kidney when it was delivered in nanoparticles as compared to cremophor micelles and to a much smaller extent due to the kidney targeting by the nanoparticles formulation. The second part of my thesis is to investigate the potential pharmacokinetic interaction among drugs. The first study examined the pharmacokinetic interaction between pentamidine and 2',3'-dideoxyinosine (ddI) in rats. The results indicate a pharmacokinetic interaction between these two drugs, which resulted in enhanced ddI accumulation in pancreas in rats, might have also occurred in humans, suggesting the pharmacokinetic interaction as a potential mechanism of the enhanced lethal pancreatic toxicity in AIDS patients who received both pentamidine and ddI. The second study explored the potential pharmacokinetic interaction between paclitaxel and suramin. The results suggest no pharmacokinetic interaction between paclitaxel and suramin for this combination in non-small cell lung cancer patients. In conclusion, pharmacokinetic data such as those described in this thesis may be used to direct the clinical drug development.