The pharmacokinetics of Cis-diamminodichloro-platinum (II) in animals and man : relation to treatment scheduling

Abstract

Summary A detailed knowledge of their patterns of tissue distribution, localisation and retention, as well as a sound understanding of biochemical and toxicological effects, is an essential prerequisite for the optimal exploitation of platinum co-ordination complexes for cancer chemotherapy. At present only limited information on the pharmacokinetics of Cis -diamminodichloro platinum (II) (CDDP) in animals or man is available and even less is known about the handling of other platinum compounds. The biodistribution and retention of CDDP has been studied in mice, rats, rabbits, dogs, sharks and man, but as yet no detailed systematic studies have been reported. The mammalian studies all show a remarkably consistent pattern, the inter-species variations observed probably reflecting differences in urinary excretion during the first 24 hours after intravenous injection. The tissue concentrations of platinum decrease in the order kidney, uterus, liver, skin, adrenal, ovary, spleen, pancreas, lung, muscle, testis, brain. Retention in the total skin mass of man, dog and rat appears to be relatively high and prolonged. In all species the plasma clearance appears to follow a multi-component exponential pattern with 70 to 90 per cent of the injected CDDP being removed from the plasma within 15 mins. The final component of the plasma clearance curves which accounts for less than 7 per cent of the administered dose has a half clearance time of more than 6 days in man and larger animals. The retention of platinum from CDDP in most tissues is broadly biphasic with up to 50 per cent of the tissue content being lost during the first 24 hours followed by a slower removal phase with half-times measured in days. The chemical form and subcellular distribution of platinum from CDDP in the tissues is almost unknown but complex formation with cellular components appears to occur. In all the species studied the urinary excretion of platinum from CDDP during the first 24 hours is rapid, ranging from 20 to 30 per cent in man to over 60 per cent in dogs. Pre-hydration, mannitol or furosemide diuresis, designed to reduce renal toxicity, do not alter plasma or renal clearance rates or total platinum excretion, but such treatment does decrease the initial urinary concentration of the drug. The patterns of tissue uptake and retention, plasma clearance and urinary excretion do not appear to be influenced by the administered dose in the range 0.066 to 3.15 mg CDDP/kg body weight. Studies of the biodistribution of chloroplatinic acid, platinum ethylene-diamine dichloride and sulphato- trans -1,2-diamino cyclohexane platinum (II) in rats show a similar order of tissue concentrations to CDDP, although there are considerable differences in urinary excretion and, possibly, in tissue fixation. An important question in relation to clinical drug scheduling is whether the platinum which is retained in the tissues remains in a cytotoxic form. Comparative studies in animals of the effects of CDDP on DNA synthesis in tumours and normal tissues, and other lines of evidence, suggest that rapid recovery of DNA synthetic capacity can occur in normal tissues even in the presence of high concentrations of platinum indicating that loss of cytotoxicity does occur. Although there is a need for much more information, especially about the handling of multiple doses of CDDP and the nature of the platinum species present in tissues, the present evidence suggests that administration of CDDP at intervals of 5 to 7 days is likely to have a greater anti-tumour effect than single doses given at intervals of 3 weeks or more.