Abstract:
Oxaliplatin is a third generation platinum anti-tumour agent used for the treatment of metastatic colorectal cancer. However, treatment it is limited by the formation of an acute or chronic peripheral neuropathy. Cimetidine was recently identified to inhibit transport of oxaliplatin through OCT2 in the DRG leading to a reduction in peripheral neurotoxicity. Although, the interaction between cimetidine and oxaliplatin and how it may alter the anti-tumour activity has not been investigated. The aim of this thesis was to understand the interaction between cimetidine and oxaliplatin for the prevention of oxaliplatin-induced neurotoxicity. An HPLC-UV was used to determine the concentrations of cimetidine in mouse plasma extract that were associated with neuroprotective doses. HPLC-UV was also used to evaluate the stability and clearance of oxaliplatin in incubation fluids containing NaCl (150 mM) with or without cimetidine (30 μM, 100 μM and 300 μM) under physiological conditions. (37°C, pH7.4) ICP-MS was used to investigate the effects of cimetidine on platinum tissue accumulation in mice tumours, kidneys and livers. An HPLC-UV method was established and validated for measuring cimetidine in mouse plasma and identified a range of plasma cimetidine concentrations associated with its neuroprotection against oxaliplatin-induced peripheral neurotoxicity. Cimetidine was shown to increase oxaliplatin degradation in vitro but was predicted to have no significant effect on the in vivo clearance of oxaliplatin (≤ 2.5% of total oxaliplatin clearance). Cimetidine did not alter the amount of platinum being accumulated in tumour samples but was shown there was a non-significant increase in platinum levels in the kidney and liver. This work suggests that the neuroprotective concentrations of cimetidine could be achieved in human patients without altering oxaliplatin clearance or affecting its accumulation into the tumour.