Temporal variations in chloroform-induced hepatotoxicity in rats.

There is increasing evidence to show that drug metabolism and effects are modulated by biological rhythms; therefore the possibility that chloroform (CHCl3) induced acute hepatotoxicity may also vary as function of time of administration was investigated in male Sprague--Dawley rats. The animals were given a single intraperitoneal dose of CHCl3 or saline, 0.5 ml/kg, at 09:00 h, 13:00 h, 17:00 h, 21:00 h or 03:00 h and killed 4 h after treatment. The hepatotoxicity induced by CHCl3 was determined by the serum glutamic-pyruvic transaminase (SGPT), serum glutamic-oxaloacetic transaminase (SGOT) and lactic dehydrogenase (LDH) activities and by the glucose-6-phosphatase (G6Pase) activity of the liver. The increases in SGPT, SGOT and LDH were minimal and maximal when the organic solvent was injected at 09:00 h and 21:00 h, respectively, whilst the activity of G6Pase was depressed significantly at 03:00 h and 13:00 h under similar conditions. Starving the rats for 16 h prior to the injection of CHCl3 at 09:00 h increased substantially the hepatotoxicity as measured by the above enzyme activities. These findings may be relevant in the toxicity of CHCl3 in industrial workers exposed to this solvent at various times of the day.

[The effect of cancer on drug metabolism and drug action]. / Influence du cancer sur le métabolisme et les effets des médicaments.

Over the last few years, numerous studies performed mainly in animals with a tumour but also in man with malignant disease have shown that the presence of cancer modifies gastro-intestinal absorption, tissue distribution and transformation of drugs in the liver. Consequently, malignant disease also influences the therapeutic effects and toxic effects of drugs. This effect may occur with several drugs, with or without antineoplastic properties, and appears mainly at an advanced stage of the disease.

Influence of leukaemia on acetaminophen-induced hepatotoxicity in mice.

Since it is known that the metabolism of acetaminophen is involved in its hepatotoxicity and that drug metabolizing enzyme activity is decreased in tumor bearing animals, it was of interest to study the influence of L-1210 leukaemia on acetaminophen hepatotoxicity in BDF-1 male mice. A single oral dose of acetaminophen, 125 mg/kg, was given at the fifth day of the mice survival period (7.7 days) and the animals killed twenty-four hours later. As revealed by serum glutamic-pyruvic transaminase, serum glutamic-oxaloacetic transaminase and lactic dehydrogenase, acetaminophen was less hepatotoxic in leukaemic mice than in control mice by comparison with their own saline group; on the other hand the difference between control and leukaemic mice treated with acetaminophen was significant only for glutamic-pyruvic transaminase. Moreover, we found higher unchanged acetaminophen concentrations in plasma, liver, kidneys, brain and fat of the leukaemic mice as compared to controls, less conjugated metabolites in plasma and liver, decreased in vitro aniline hydroxylation and ethylmorphine N-demethylation. Finally, following acetaminophen administration, reduced hepatic glutathione was depleted to a much lesser extent in the tumor bearing animals than in controls. In conclusion, the L-1210 leukaemia seems to modify the acetaminophen hepatotoxicity and this effect might be explained by decreased acetaminophen biotransformation into toxic metabolites or intermediates.

Increase in the gastrointestinal absorption and in tissue storage of cyclophosphamide in L-1210 leukaemic mice at an advanced stage of the disease.

BDF1 mice were inoculated with 10(6) leukaemic cells and, together with control mice, were given a single oral dose of cyclophosphamide-14C of 100 mg/kg body weight. In the leukaemic mice we observed an increased 14C concentration in the plasma, bone marrow, liver, lungs, spleen, kidney and particularly fat where the level was 2-4 times higher than in control mice. Conversely, during the same period, significantly less 14C was detected in the stomach and small intestine of the leukaemic mice. These results were obtained 6 days after tumour transplantation (median survival time 7.7 days) whereas no differences were observed when the studies were carried out 4 days after tumour transplantation. These findings indicate an increase in the gastrointestinal absorption and in the tissue storage fo cyclophosphamide in L-1210 leukaemic mice at an advanced stage of the disease.

P-aminosalicylate metabolism in cancer patients sensitive and resistant to chemotherapy.

A reduced response of a tumour to chemotherapy may be due to the host's drug metabolism. To test this hypothesis, we measured the metabolism of a model drug, para-aminosalicylate (PAS). Volunteers and cancer patients ingested a single oral dose (2 g) of PAS and we measured the plasma disappearance curve of the drug and its metabolite. In 7 patients suffering from lymphosarcoma, acute or chronic leukaemia and resistant to cancer chemotherapy, we observed low plasma PAS concentrations, an increase in PAS acetylation and an increased number (and a higher frequency) of abnormal liver-function tests. In 14 patients with malignant blood disease, yet responding well to chemotherapy, the metabolism of PAS is similar to that of healthy controls of the same age and sex. The plasma half-life of PAS is similar in sensitive and resistant patients, but slightly longer than in volunteers. Finally, in urine collected 120 min after drug administration, we observed the same results as in plasma. In conclusion, cancer patients resistant to chemotherapy do not metabolize the model drug PAS as volunteers or sensitive patients do, and this might be relevant to the terminal stage of the disease.