Three areas of interest dominated the poster topics and discussion in the pharmacokinetics session. The first topic of interest was the pharmacokinetics of DDP analogs, particularly CBDCA and CHIP. CBDCA was studied in 4 animal species in addition to patients, and the correlation among the 5 species was quantitatively good and showed some major differences from DDP. For example, in dog, mouse and rabbit 90–100% of the administered dose was excreted in urine, whereas the urinary excretion of DDP is 50–70% for most species. CBDCA also differed from DDP in the kinetics of filterable platinum. There was no decrease in filterable platinum when CBDCA was incubated in vitro for 8 hours with plasma. During the first several hours after CBDCA administration to animals, filterable platinum and total platinum concentrations were equal and then filterable platinum declined at a greater rate than did total platinum. Filterable platinum was detectable for 4–6 hours after CBDCA administration, in contrast to 1–2 hours after DDP administration. In patients, urinary excretion of platinum after CBDCA was apparently 3 times greater than with DDP, and plasma filterable platinum levels were much more prolonged than with DDP. Protein binding of CBDCA in patients was quite variable, however, with a range of 0–60% bound 2 hours after treatment in 7 patients. In rats the amount of filterable platinum after CBDCA treatment was 80% of control values at the earliest time examined and remained at that level for several hours. This suggests the possibility of a saturable binding site in rat plasma proteins, which might become more obvious if lower doses were studied. Another alternative is that the treatment solution contained a contaminant that was avidly bound to plasma proteins. Plasma half times of total platinum after CBDCA were routinely greater for both elimination and distribution phases than were half times after DDP, but the prolonged final elimination phase appeared to be lacking. Plasma decay curves of total and filterable platinum in patients were complex, with unexplained secondary peaks occurring within the first hour after infusion. Similar peaks have been observed following DDP, however (1). As might be expected, half times were variable from species to species and from one studyto another, depending on the time that the determination was made. This reinforced the need for investigators to always identify the times over which distribution and elimination half times were determined when such calculations are presented. In general, platinum from CBDCA decayed in a bi- or triexponential manner in all species, including humans. Estimates of biliaryexcretion of CBDCA ranged from 0.5% to 14% of the dose in two different studies. Discrepant platinum uptake into RBC also was reported, ranging from essentially no uptake to relating mechanism of CBDCA-induced death to RBC binding by CBDCA. Of particular interest was the retention of platinum in kidneys of CBDCA-treated animals 4 and 6 days after treatment in two different studies. This result was in spite of the lack of CBDCA-induced renal toxicity, and thus forces us to wonder about the wisdom of our assumption that renal toxicity of DDP was related to platinum binding in the kidney.
KeywordsCerebral Spinal Fluid Half Time Total Platinum Elimination Half Time Whole Body Hyperthermia
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