A PHARMACOKINETIC BASED STUDY TO BETTER UNDERSTAND THE REPORTED COGNITIVE DEFICITS FOR 5-FLUOROURACIL AND METHOTREXATE IN MALE SWISS-WEBSTER MICE

Abstract

Chemotherapy related neurotoxicity is the decrease in cognitive function observed in patients receiving chemotherapy for breast cancer. For cancers with higher survival rates such as breast cancer, quality of life for patients after treatment cessation is a major concern. In studies performed in our laboratory, we reported cognitive deficiencies in male Swiss-Webster mice on administering 75 mg/kg 5-FU with 3.2 mg/kg MTX and these deficits were significantly greater than groups receiving either drug alone or in another higher dose combination. The probable mechanisms for the reported drug-drug interaction (DDI) between 5-FU and MTX could be either pharmacokinetic (PK) or pharmacological. Since the reported study consists of a combination of two drugs, it is imperative to determine if the PK of either drug was altered. On performing the PK based study we established the nature of the DDI to be PK based. We observed statistically significant changes for PK parameters clearance and apparent volume of distribution. Since, 5-FU and MTX are high clearance drugs, uptake transporters responsible for presenting the drugs to the clearing organs are the limiting factors for their clearance. Therefore, for any PK based interactions observed between 5-FU and MTX in the different dose groups a highly probable mechanism would be interactions at the site of uptake transporters. Based on the physicochemical properties of 5-FU and MTX and the results observed form the PK study, we hypothesized transporter-based interactions to be a probable mechanism for the observed DDI. From the transporter based studies we hypothesized 5-FU probably inhibited the uptake of MTX's transport across the blood brain barrier (BBB). To date the transport of MTX and other similar folates has not been characterized extensively. However, MTX is a very close analogue for reduced folates and therefore shares the transporter reduced folate carrier-1 (Rfc-1) expressed abundantly at the BBB, with endogenous reduced folates. Hence we hypothesized the decreased exposure of MTX in the presence of 5-FU would most probably be as a result of inhibition of uptake transporters such as Rfc-1. Finally, we developed a mathematical PK model for MTX to predict appropriately drug concentrations in the plasma and the brain tissue. The utility of the model was to support the hypothesized interactions responsible for the observed PK data. This models utility is to provide the PK component for the future PK-pharmacodynamic models, which would narrow the gap between the reported cognitive deficits and the PK results reported in this dissertation.