Frank W. Bonner

The tissue disposition and urinary excretion of cadmium, zinc, copper and iron, following repeated parenteral administration of cadmium to rats

The effect of repeated parenteral administration of cadmium (0.75, 1.5 and 3.0 mg/kg) on tissue disposition and urinary excretion of cadmium, zinc, copper and iron has been studied in the male rat. Cadmium, zinc and copper accumulated in liver and kidney, but the concentration of iron did not alter significantly. The kidney weight relative to body weight showed a dose-related increase in weight of 25--65%. Excretion of cadmium in the urine increased directly with dosage and the increase was most significant when kidney damage had probably occurred. Administration of cadmium also resulted in dose-related increases in the urinary excretion of zinc, copper and iron. The cadmium concentration of blood increased with dosage of cadmium, and the plasma concentrations of zinc and copper were also raised but plasma iron concentration was diminished.

The importance of pharmacokinetic and receptor studies in drug safety evaluation

The importance of pharmacokinetic and receptor studies in the preclinical and clinical safety evaluation of candidate drugs is reviewed with reference to a number of recently developed drugs. Different aspects of the relationships between pathways of metabolism, pharmacokinetics, receptor interactions, and drug toxicity are illustrated. The failure of animal toxicity studies to predict drug toxicity in humans, due to species differences in metabolism and pharmacokinetics, is illustrated by reference to the anti-inflammatory antiviral terpenoid carbenoxolone, the antiasthmatic candidate drug FPL 52757, and the cardiotonic drug amrinone. The false prediction of adverse effects in man from toxicity manifested in experimental animals, due to species differences in pharmacokinetics or receptor activities, is exemplified with reference to the antiepileptic valproic acid, the hypolipidemic drug ciprofibrate, the antipeptic ulcer drug, omeprazole, and the progestogen lynestrenol. Finally, the importance of adequate, repeat-dose, clinical pharmacokinetic studies in patients as distinct from healthy volunteers to evaluate any effect of the disease state, in the elderly and the young to examine the effects of age, and in sufficiently large populations to detect genetic anomalies and idiosyncrasies is illustrated by reference to the anti-rheumatoid drug benoxaprofen, the antiangina drug perhexiline, and the diuretic tienilic acid.

The effect of dietary cadmium on zinc, copper and iron levels in the bone of rats

The effect of continuous oral administration of cadium (Cd) (75 ppm) on the concentrations of zinc (ZN), Copper (CU) and iron (Fe) in the bone of rats was investigated. Accumulation of Cd in the femur was low but increased with time. After 8 weeks of Cd exposure, femur Zn and Fe levels were significantly decreased and remained low throughout the period of cadmium treatment. After 48 weeks, Cd exposed animals had Zn and Fe concentrations in the femur of 63% and 51% of controls, respectively. The femur Cu concentration was unchanged at 36 weeks but at 48 weeks it was 76% of control animals.

Cadmium-induced reduction of bone alkaline phosphatase and its prevention by zinc

The dietary exposure of rats to cadmium (75 ppm) for periods of up to 48 weeks caused an accumulation of cadmium in the femur, and an inhibition of the accumulation of zinc in the bone. After 48 weeks of cadmium treatment, there was a decreased activity of alkaline phosphatase in the femur. This effect was prevented by a simultaneous dietary supplement of zinc (300 ppm).

The urinary excretion of enzymes following repeated parenteral administration of cadmium to rats.

Abstract The effect of daily parenteral administration of cadmium (0.75, 1.5, and 3.0 mg/kg) on the urinary excretion of enzymes has been studied in the young male rat. Aspartate amino-transferase, alkaline phosphatase, γ-glutamyl transpeptidase, and leucine aminopeptidase all showed an initial significant increase around the second day of dosage, the intensity of which was dose related. A second phase of enzymuria occurred later, the onset of which was dose related. High-dose-group animals (3.0 mg/kg) exhibited this increase around Day 15, while the median (1.5 mg/kg) and low- (0.75 mg/kg) dose-group animals developed enzymuria around Days 21 and 38, respectively. This second phase of elevated enzyme levels in the urine was persistent, and is believed to represent the development of renal damage.

A study of the nephrotoxicity of three cephalosporins in rabbits using 1H NMR spectroscopy

Male New Zealand White rabbits received a single intravenous injection of 125 mg/kg cephaloridine, 500 mg/kg cefoperazone or 1000 mg/kg cephalothin. Histological examination of kidneys at 48 h post-dose confirmed the presence of bilateral necrosis of the proximal convoluted tubules in the cephaloridine-treated animals. 1H-NMR urinalysis of cephaloridine-treated rabbits detected drug-related resonances, decreased hippurate and increased glucose at 0-24 h post-dose accompanied by elevated levels of lactate, glycine, citrate, glutamine/glutamate and alanine at 24-48 h post-dose. No histopathological changes were observed following administration of cefoperazone or cephalothin. 1H-NMR spectra of urine collected from these animals showed drug-related resonances and decreased hippurate levels at 0-24 h post-dose, and increased glucose levels at 24-48 h post-dose. Analysis of urine by conventional clinical-chemistry failed to reveal any statistically significant differences between the treatment groups. Under the conditions of this study, the nephrotoxic effects of cephaloridine and the minimal effects of cefoperazone and cephalothin could be clearly distinguished by 1H-NMR urinalysis but not by conventional urinalysis.

A comparison of the effects of three positive inotropic agents (amrinone, milrinone and medorinone) on platelet aggregation in human whole blood

Amrinone, milrinone and medorinone inhibit platelet aggregation in human whole blood. They are particularly potent inhibitors of arachidonic acid induced aggregation, inhibiting by 50% (IC50) at concentrations of 1.5 microM (milrinone), 7.5 microM (medorinone) and 48 microM (amrinone). Each drug was less potent at inhibiting ADP and collagen-induced aggregation. The rank order for inhibition of arachidonic acid - induced aggregation correlated well with the rank order of cyclic AMP phosphodiesterase inhibition for these drugs when compared to the response of a reference cAMP phosphodiesterase inhibitor (CI-930) and a reference cGMP phosphodiesterase inhibitor (M & B 22948). Since inhibition of platelet aggregation in vitro occurred at clinically relevant concentrations, it is evident that these agents have potentially beneficial antithrombotic properties.

The influence of high dietary zinc on tissue disposition and urinary excretion of cadmium, zinc, copper and iron after repeated parenteral administration of cadmium to rats

The administration of a high dietary supplement of zinc sulphate (2000 ppm) to rats for 28 days produced no effect upon growth rate of the animals but caused in increased food intake. The supplement had no effect upon the reduction of growth rate caused by the daily injection of cadmium chloride (1.5 mg/kg). Zinc-supplemented animals showed an increased accumulation of zinc in the liver and kidney, plasma zinc levels were significantly increased and there was an elevated excretion of zinc in the urine compared to control animals. Cadmium-treated, zinc-supplemented animals had a higher concentration of cadmium in the liver compared to animals treated only with cadmium. The high dietary zinc did not interfere with tissue or plasma concentration of copper and iron, nor did it influence the cadmium-induced changes in these metals. There was some indication however of a decreased urinary excretion of copper.

The in vitro effect of amrinone on thromboxane B2 synthesis in human whole blood

Thromboxane B2 production in vitro in human whole blood was inhibited at pharmacological levels of amrinone. There was no observed effect on prostacyclin production as measured by 6-ketoprostaglandin F1 alpha levels. The biochemical basis for the inhibition of platelet aggregation by amrinone and the inter-relationships between arachidonic acid metabolism, c-AMP and Ca2+ levels are discussed.

The acute and subacute effects of cadmium on calcium homeostasis and bone trace metals in the rat

The effect of acute and subacute administration of cadmium chloride on calcium homeostasis and the trace metal content of the bone was investigated in the male rat. A single subcutaneous injection of cadmium chloride (1.5 mg Cd++/kg) produced a decreased plasma concentration of calcium and a decrease in the femur concentration of both calcium and zinc. repeated administration of cadmium chloride (1.5 mg Cd++/kg) daily, for 28 days) caused a marked hypocalciuria that persisted throughout the period of cadmium treatment. There was an accompanying increased excretion of alkaline phosphatase into the urine, and plasma inorganic phosphate was also elevated in these animals. Both of these effects are considered to be evidence of kidney damage. A possible mechanism for this cadmium-induced effect may involve a disturbance of the renal biotransformation of vitamin D, and decreased bioavailability of the essential trace metals due to metallothionein synthesis and excessive loss into the urine.