Absorption, toxicity and deposition of transition metal based pharmaceuticals following oral administration.

The aim of this dissertation was to study the absorption, and subsequent toxic side effects of transition metal based pharmaceuticals following oral administration to rats. Administration of cisplatin (30mg/kg), carboplatin (37mg/kg) and iproplatin (42mg/kg) by oral gavage resulted in their rapid absorption so that respective peak blood levels of 2.63mug platinum/ml, 1.48mug platinum/ml and 3.13mug platinum/ml were achieved within 2-4 hours. Approximately 3-4% of the dose was excreted in the urine, but the major route of elimination was the faeces (>75%). This indicated that although rapid, absorption was relatively poor. Absorption was enhanced by employing a period of starvation prior to administration. A series of novel platinum (IV) mixed amines were absorbed to a greater extent than cisplatin and its congeners, carboplatin and iproplatin. However, absorption was somewhat slower with peak blood levels being attained some 24 hours after administration. Of the other transition metal complexes studied, auranofin and ruthenium acetylacetonate were particularly well absorbed so that peak blood levels of 12.53mug gold/ml and 6.4mug ruthenium/ml were achieved respectively. Urinary clearance of the ruthenium complex was especially significant with up to 45% of the administered dose being eliminated by this pathway within 48 hours. In vitro everted gut sac and in situ perfusion techniques confirmed the in vivo finding that cisplatin is absorbed from the small intestine more readily than carboplatin. No evidence for active or carrier-mediated transport was found and kinetic studies confirmed that absorption was by passive diffusion. Toxicology studies after oral administration of cisplatin (57 or 30mg/kg) or carboplatin (282mg/kg) indicated that the toxicities associated with the perenteral use of the complexes would also apply to the oral route. This was exemplified by the fact that oral cisplatin was profoundly nephrotoxic, whereas carboplatin was not. In addition, gastro-intestinal toxicity manifested as acute necrotizing enteritis and ulcerogenicity of the stomach was potentiated by the oral route. Studies in the ferret indicated that cisplatin is significantly more emetogenic than carboplatin. Examination of liver morphology indicated changes, such as mitochondrial swelling and vesiculation of the endoplasmic reticulum, that might indicate a higher incidence of hepatotoxic responses associated with administration of platinum complexes by the oral route. Both cisplatin and carboplatin induced a degree of myelosuppression but the most pronounced haematological lesion associated with oral administration was severe erythrocytosis which occurred as a result of a dehydration related decrease in plasma volume. Electrothermal atomic absorption analysis of tissues excised from cisplatin and carboplatin rats indicated that platinum deposition was highest in the kidney. In an attempt to explain the prolonged retention of cisplatin in this organ, the intracellular location of the compound was studied using electron microprobe analysis and subcellular fractionation. The various lysosome populations of the proximal tubule were identified as sites of concentration of platinum and it was hypothesised that sequestration within these organelles might be an important mechanism of detoxification