Mutual kinetic interaction between 5-fluorouracil and bromodeoxyuridine or iododeoxyuridine in dogs.

The pharmacokinetics of 5-fluorouracil (FUra) were studied alone and in the presence of either bromodeoxyuridine (BrdUrd) or iododeoxyuridine (IdUrd) in five mixed breed hounds. FUra was administered intravenously over 1 min as a 5 mg/kg dose in all three treatments. BrdUrd or IdUrd was infused intravenously at 2.5 mg/hr.kg x 6 hr and FUra was given 3 hr into the 6-hr infusion of thymidine analog. Serial blood samples were obtained for 3 hr prior to and after FUra dosing. Plasma concentrations of FUra, BrdUrd and bromouracil (BrUra), and IdUrd and iodouracil (IUra) were measured by reversed-phase HPLC. Concomitant administration of BrdUrd or IdUrd resulted in substantial changes in the kinetics of FUra. In particular, the total plasma clearance of FUra was decreased and area under the plasma concentration-time curve was increased. There were also significant changes in the volume of distribution steady-state, and in the mean residence time and half-life of FUra. The data show that FUra had little or no effect on the disposition of BrdUrd or IdUrd. In contrast, FUra had a significant effect on the disposition of BrUra and IUra going to form catabolic products. The observed pharmacokinetic interaction in dogs is probably due to a competition between BrUra (or IUra) and FUra for the rate-limiting catabolic enzyme, dihydropyrimidine dehydrogenase. This kinetic interaction was mutual and of a smaller magnitude for FUra + BrdUrd than for FUra + IdUrd.

Microscopic analysis of arterial microsphere distribution in rabbit liver and hepatic VX2 tumor.

Microspheres conjugated to radioisotopes and chemotherapeutic agents are playing an important investigative and clinical role in the management of metastatic neoplasms. The purpose of our investigation was to histologically assess the basis for regional intra-arterial microsphere therapy, by comparing the spatial distribution of microspheres in the tumor and liver of experimental models of hepatic metastases. Three New Zealand white rabbits with hepatic VX2 tumor implants were arterially injected with hepatic doses of either 15 or 30 million blue-dyed, polystyrene microspheres (27 microns-diameter). Microscopic examination of random liver and tumor samples revealed that 6-12 times as many microspheres were embolized within tumor than in normal liver (p less than 0.002). The majority of microspheres aggregated into clusters of various size within liver and tumor vasculature, though analysis of cluster sizes illustrated an exponentially skewed distribution toward isolated microspheres. Approximately eight times as many clusters were observed in tumor than in liver (p less than 0.008). Finally, a morphometric analysis was used to quantitate the minimal distances separating microsphere clusters, the intercluster distance (ICD). Analysis of over three thousand intercluster measurements revealed a median ICD approximately five times lower in tumor than in liver (p less than 1 x 10(-8)). This microquantitative analysis provides a fundamental description of how regional intra-arterial microsphere therapy allows the targeted delivery of microspheres to neoplastic tissue, to potentially improve the therapeutic index in the treatment of hepatic metastases.