Ammonium chloride alters renal tubular cell growth and protein turnover

1. Toxicokinetics of pentachloroanisole (PCA) were studied in F344 rat and B6C3F1 mouse of both sexes by gavage at doses of 10, 20 and 40 mg/kg and by i.v. at 10 mg/kg. 2. PCA was rapidly demethylated to pentachlorophenol (PCP) in both rat and mouse and the resulting PCP plasma concentrations were much higher than that of parent PCA due to the much smaller apparent volume of distribution of PCP. 3. Peak plasma concentrations of PCA and PCP increased with dose in both rat and mouse. 4. Bioavailability of PCA was low in both rat and mouse and was sex independent. 5. The high plasma concentrations and relatively long biological half-life of PCP in both species after both i.v. and oral dosing with PCA indicate possible bioaccumulation of PCP upon multiple oral administrations of PCA.     

Disposition of [14C]avitriptan in rats and humans

Avitriptan is a new 5-HT1-like agonist with abortive antimigraine properties. The study was conducted to characterize the pharmacokinetics, absolute bioavailability, and disposition of avitriptan after intravenous (iv) and oral administrations of [14C]avitriptan in rats and oral administration of [14C]avitriptan in humans. The doses used were 20 mg/kg iv and oral in the rat, 10 mg iv in humans, and 50 mg oral in humans. The drug was rapidly absorbed after oral administration, with peak plasma concentrations occurring at 0.5 hr postdose. Absolute bioavailability was 19.3% in rats and 17.2% in humans. Renal excretion was a minor route of elimination in both species, with the majority of the dose being excreted in the feces. After a single oral dose, urinary excretion accounted for 10% of the administered dose in rats and 18% of the administered dose in humans, with the remainder excreted in the feces. Extensive biliary excretion was observed in rats. Avitriptan was extensively metabolized after oral administration, with the unchanged drug accounting for 32% and 22% of the total radioactivity in plasma in rats and humans, respectively. Plasma terminal elimination half-life was approximately 1 hr in rats and approximately 5 hr in humans. The drug was extensively distributed in rat tissues, with a tendency to accumulate in the pigmented tissues of the eye.     

Teratogenicity study of magnesium chloride hexahydrate in rats

Teratogenicity of magnesium chloride hexahydrate (MgCl2.6H2O) was examined in rats. Magnesium chloride hexahydrate dissolved in distilled water was given to pregnant Wistar rats by gavage once a day from day 6 through 15 of pregnancy at doses of 0, 200, 400 and 800 mg/kg/day. The pregnant rats were sacrificed on day 20 of pregnancy and their fetuses were examined for malformation. Magnesium chloride hexahydrate caused no increased incidences of fetal malformation, and no toxic signs in the pregnant rats and the fetuses. It was concluded that magnesium chloride hexahydrate has no teratogenicity in rats when given by gavage. The no observed adverse effect level was estimated to be over 800 mg/kg/day for both pregnant rats and rat fetuses.     

Pharmacokinetics of a new reversible proton pump inhibitor, YH1885, after intravenous and oral administrations to rats and dogs: hepatic first-pass effect in rats

The pharmacokinetics of YH1885 were evaluated after intravenous (iv) and oral administrations of the drug to rats and dogs. The reason for the low extent of bioavailability (F) of YH1885 after oral administration of the drug to rats and the absorption of the drug from various rat gastrointestinal (GI) segments were also investigated. After iv administration of YH1885, 5-20 mg kg(-1), to rats, the pharmacokinetic parameters of YH1885 seem to be independent of the drug at the dose ranges studied. After oral administration of YH1885, 50-200 mg kg(-1), to rats, the area under the plasma concentration-time curve from time zero to 12 or 24 h (AUC(0-12 h) or AUC(0-24 h)) was proportional to the oral dose of the drug, 50-100 mg kg(-1), however, the AUC(0-24 h) value at 200 mg kg(-1) increased with less proportion to the dose increase (324, 689, and 815 microg x min mL(-1) for 50, 100, and 200 mg kg(-1), respectively) due to the poor water solubility of the drug. This was proved by the considerable increase in the percentages of the oral dose remaining in the entire GI tract as unchanged YH1885 at 24 h (11.8, 15.3, and 42.8% for 50, 100, and 200 mg kg(-1), respectively). The F value after oral administration of YH1885 to rats was relatively low; the value was approximately 40% at the oral dose of 50 and 100 mg kg(-1). The reason for the low F in rats was investigated. The liver showed the highest metabolic activity for YH1885 based on an in vitro rat tissue homogenate study; hence, the liver first-pass effect was estimated. The value of AUC after intraportal administration of the drug, 5 mg kg(-1), was approximately 70% (116 versus 163 microg x min mL(-1)) of that after iv administration of the drug, 5 mg kg(-1), to rats; the liver first-pass effect of YH1885 in rats was estimated to be approximately 30%. The total body clearance of YH1885 after iv administration of the drug, 5-20 mg kg(-1), to rats were considerably lower than the cardiac output of rats, indicating that the lung and/or heart first-pass effect of YH1885 could be negligible in rats. After oral administration of YH1885, 50 and 100 mg kg(-1), to rats, the F value was approximately 40%, and approximately 15% of the oral dose was recovered from the entire GI tract as unchanged YH1885 at 24 h, and 30% of the oral dose disappeared with the liver first-pass effect. Therefore, the remainder, approximately 15% of the oral dose, could have disappeared with the small intestine first-pass effect and/or degradation of the drug in the GI tract. YH1885 was absorbed from ileum, duodenum, and jejunum of rat, however, YH1885 was under the detection limit in plasma when the drug was instilled into the rat stomach and large intestine. After iv administration of YH1885, 5-20 mg kg(-1), to dogs, the pharmacokinetic parameters of YH1885 also seemed to be independent of the drug at the dose ranges studied. However, after oral administration of YH1885, 0.5 and 2 g per whole body weight, to dogs, the AUC(0-10 h) values were not significantly different (96.8 versus 98.2 microg x min mL(-1)) and this could be due to the poor water-solubility of the drug. YH1885 was not detected in the urine after both iv and oral administration of the drug to both rats and dogs.     

Diazinon toxicokinetics, tissue distribution and anticholinesterase activity in the rat

The toxicokinetics, tissue distribution, and anticholinesterase (antiChE) activity of diazinon were investigated in the rat. Plasma concentrations most adequately fitted a two-compartment open model after i.v. administration of 10 mg/kg and a one-compartment model after oral administration of 80 mg/kg. Diazinon elimination half-life following i.v. and oral dosing was 4.70 and 2.86 h, respectively. The oral bioavailability was found to be low (35.5%). Hepatic extraction ratios after i.v. administration of 5 or 10 mg/kg were 54.8% and 47.7%, respectively, suggesting that low systemic oral bioavailability can be explained by a first-pass effect in the liver. Diazinon was found to be approximately 89% protein-bound in plasma within the concentration range 0.4-30 ppm. The highest concentration of diazinon after i.v. administration was found in the kidneys, when comparing to liver, kidney, brain. Both red blood cell (RBC) acetylcholinesterase (AChE) and plasma ChE activities were inhibited rapidly (44% and 17% at 10 min, and 36% and 13% min for i.v. and oral administration, respectively), but inhibition of RBC AChE was greater than that of plasma ChE.     

Improvement of impaired glucose tolerance by oral administration of vanadyl sulfate by gavage in streptozotocin-induced diabetic rats

We examined the effect of oral administration of vanadyl sulfate by gavage on the levels of blood glucose and plasma insulin during oral glucose tolerance test (OGTT) in diabetic rats. Diabetes was induced by intravenous injection of streptozotocin at the dose of 32 mg/kg. Nondiabetic control animals were injected with an equal volume of saline. Vanadyl sulfate at a dose of 25, 50, or 75 mg/kg was given orally by gavage for 2 weeks, starting 12 hours after streptozotocin injection. When vanadyl sulfate was given twice a day, half of the one-day-dosage was given in the morning and the remaining half in the evening. Glucose tolerance test with 5 g/kg of glucose was carried out 2 weeks after administration of vanadyl sulfate. The fasting the blood glucose level in the diabetic rats was higher than that in the non-diabetic rats, whereas the plasma insulin level in the diabetic rats was lower. An increase in blood glucose seen in the glucose tolerance test was significantly greater in the diabetic rats than in the non-diabetic rats. The level of plasma insulin was increased by glucose tolerance test in the non-diabetic rats, while it was not changed in diabetic rats. Oral administration of vanadyl sulfate by gavage significantly improved the impaired glucose tolerance in the the diabetic rats in a dose-dependent manner without any change in plasma insulin level. In conclusion, oral administration of vanadyl sulfate by gavage is effective on impaired glucose tolerance in streptozotocin-induced diabetic rats.     

Dose-dependent vehicle differences in the acute toxicity of bromodichloromethane

Bromodichloromethane (BDCM) is a disinfection by-product of drinking water chlorination and is the second most common trihalomethane (THM) in finished drinking water. THMs have generally been administered to experimental animals in corn oil, rather than drinking water, which can influence the site and magnitude of toxicity. To examine the effects of gavage vehicle on the acute renal and hepatic toxicity of orally administered BDCM, 95-day-old male F344 rats were given single doses of 0, 200, or 400 mg BDCM/kg in corn oil or an aqueous 10% Emulphor solution. Activities of serum hepatoxicity indicators were significantly greater 48 hr after administration of 400 mg BDCM/kg in corn oil compared to the aqueous vehicle, but delivery of the low dose in either dosing vehicle had little effect on serum enzymes. In contrast, significant elevations in urinary renal toxicity indicators were noted at 200 and 400 mg BDCM/kg in both vehicles after 24 hr, indicating that the kidney is more sensitive to low doses of BDCM than the liver. Significantly greater increases were observed in urinary indicators after delivery of 200 mg BDCM/kg in 10% Emulphor compared to corn oil. However, administration of the high dose in corn oil resulted in greater nephrotoxicity than in the aqueous vehicle. Significant interactions between vehicle of administration and BDCM dose observed for both urinary and serum parameters further indicate that vehicle differences noted in BDCM acute toxicity are dose dependent. This observation may be due to pharmacokinetic differences in gastrointestinal rates of absorption of BDCM from corn oil as compared to an aqueous solution.     

Phase I clinical and pharmacological studies of benzylacyclouridine, a uridine phosphorylase inhibitor

Benzylacyclouridine (BAU, IND 039655) is a potent and specific inhibitor of uridine phosphorylase (UrdPase; EC 2.4.2.3). This enzyme plays a major role in regulating uridine homeostasis and also catalyzes the conversion of fluoropyrimidine nucleosides to their respective bases. Inhibition of UrdPase enzyme activity 18-24 h after 5-fluorouracil (5-FU) administration increased plasma levels of uridine and enhanced the therapeutic index of 5-FU by rescuing normal tissues. Moreover, in vitro preclinical studies have also shown that inhibiting UrdPase enzyme activity by BAU prior to administration of 5-FU increased cytotoxicity in a number of human cancer cell lines. A series of preclinical studies was performed in dogs and pigs to evaluate the pharmacological and pharmacodynamic properties of BAU. These data showed a sustained elevation in plasma uridine concentration in both animal models. The rapid degradation of a tracer dose of uridine into uracil was virtually arrested by BAU administered both p.o. or i.v. The t1/2 of BAU was 1.8-3.6 h in dogs, with bioavailability levels of 85% (30 mg/kg) and 42.5% (120 mg/kg). In pigs, the half-life varied from 1.6 to 2.3 h, with a bioavailability of 40% at 120 mg/kg. The drug was distributed into most tissues with a tissue: plasma ratio of approximately 0.7. On the basis of these preclinical studies, we performed a Phase I clinical trial of BAU in patients with advanced cancer. Patients received 200, 400, 800, and 1600 mg/m2 BAU as a single oral dose. Toxicities included grade 2 anemia, grade 1 fever, grade 1 fatigue, grade 1 constipation, and grade 1 elevation in alkaline phosphatase; none of these toxicities were observed to be dose dependent. The maximum tolerated dose and dose-limiting toxicity were not reached at the doses given. BAU plasma concentrations and area under the curve correlated linearly with the oral dose level. The pharmacokinetics of BAU were consistent with a first-order clearance, with average peak concentrations ranging from 19 microM (200 mg/m2) to 99 microM (1600 mg/m2) and tbeta1/2 ranging from 3.0 to 3.9 h at the four dose levels. Compared with baseline plasma uridine, treatment of patients with 200, 400, 800, and 1600 mg/m2 BAU increased peak uridine concentrations by 120, 150, 250, and 175%, respectively. On the basis of this clinical study, the suggested Phase II starting dose of BAU in combination with 5-FU is 800 mg/m2. Studies combining BAU with 5-FU and incorporating appropriate molecular and biochemical end points to assess the effects of this drug combination on tumor and/or surrogate tumor tissue are under way.     

A phase I dose-ranging safety and pharmacokinetics study of a novel oral thromboxane synthase inhibitor, FCE 22, 178

A 100- to 3200-mg dose range of FCE 22,178 was studied in this phase I single-dose escalation safety/kinetics study. After oral administration, a rapid drug absorptive phase and a biexponential disposition profile were observed. Mean estimates of the terminal elimination half-life of FCE 22,178, over the doses studied, ranged from 7.6 to 14.4 hours. A disproportionate increase in both maximum peak plasma concentration (Cmax) and area under the curve (AUC0-infinity) was noticed for doses higher than 400 mg. Mean estimates of systemic clearance (CLs/F) over the 100- to 400-mg doses were 0.053 to 0.064 L/hour/kg, and were significantly higher for the three higher dose levels. This nonlinearity appears to be related to the changes in oral bioavailability. Estimates of distribution volume (Vd, lambda z/F) for FCE 22,178 increased from 0.75 L/kg at the 100-mg dose to 3.00 L/kg at the 3200-mg dose, and renal clearance (CLr) also increased with dose. Both observations may be related to an increase in free fraction of FCE 22,178 at higher doses. Urinary excretion of unchanged drug averaged < 10% for all dose levels. The urinary excretion of the glucuronide metabolite (M1) averaged 41 to 70% for doses up to 400 mg, but diminished to 13% at the 3200-mg dose. The disposition of M1 appeared to be formation-rate limited. In addition, the ratio of the formation to the disposition clearance for M1 was relatively stable and apparently dose independent. No drug-related adverse experiences were observed over the studied dose range after single doses at FCE 22,178.     

The metabolism of the hypolipidaemic drug sultosilic acid in rat, dog and man

1. Single oral doses of the hypolipidaemic drug [35S]sultosilic acid to rats (40 mg/kg), dogs (40 mg/kg) and man (7 mg/kg) were well absorbed. During three days, means of 59.2%, 58.8% and 61.8% in urine and 37.7%, 31.9% and 19.7% in faeces, were excreted by these species respectively. Most of the dose was excreted during the first 24 h. 2. Peak plasma levels of 35S were generally reached during 1-2 h after oral doses in rats (12 micrograms equiv./ml), dogs (45 micrograms equiv./ml) and two human subjects (15.2 and 10.3 micrograms equiv./ml). In humans, peak plasma levels of unchanged drug (at 1-1.5 h) were 10.5 and 6.3 micrograms/ml. Plasma concentrations of 35S increased almost proportionately to dose in rats following oral doses of 400 and 1200 mg/kg, although in dogs, concentrations were similar at these two dose levels but several times higher than at 40 mg/kg. 3. Tissue concn. of 35S were generally higher in rats than in dogs. Highest concn. occurred at 3 h in rats and 1 h in dogs. Apart from those in the liver and kidneys, tissue concn. were appreciably lower than the corresponding plasma levels. 4. The major radioactive component in dog urine was sultosilic acid. Rat and human urine contained sultosilic acid and also two more polar major metabolites. In male and female rat urine, the proportions of these excretory products differed and the proportions in male rat urine were similar to those in human urine. Sultosilic acid was also the only component detected in dog plasma, whereas rat and human plasma also contained the two urine metabolites. Dog bile contained a conjugate of sultosilic acid. 5. The two metabolites have been identified by mass spectrometry and nuclear magnetic resonance spectroscopy as products resulting from oxidation of the methyl in the p-toluenesulphonyl group. The structures assigned are the corresponding carboxylic acid and the hydroxymethyl derivatives.     

Road traffic mortality in Victoria: an exploratory investigation into successful strategies

The recovery of radioactivity from plasma, urine and feces was determined in rats after administration of oral and intravenous doses (200 mg/kg) of 14C-labeled sodium gamma-hydroxybutyric acid. Very small portions of the radioactive dose were recovered in the urine (5.5%, oral; 7.1%, intravenous) and feces (1.5% oral; 0.6%, intravenous) collected between 0-48 hours after drug administration. Considerable levels of radioactivity were found in the plasma after oral dosing. The area under the plasma radioactivity time curve after an oral dose was found to be 65% of that observed after an equivalent intravenous dose. This value is much larger than the relative area value (8%) calculated on the basis of free gamma-hydroxybutyric acid. Results of this study strongly indicate that first-pass metabolism, rather than lack of absorption, is responsible for the apparently poor oral bioavailability of gamma-hydroxybutyric acid.     

Assessment of the carcinogenic potential of chlorinated water: experimental studies of chlorine, chloramine, and trihalomethanes

BACKGROUND: Water chlorination has been one of the major disease prevention treatments of this century. While epidemiologic studies suggest an association between cancer in humans and consumption of chlorination byproducts in drinking water, these studies have not been adequate to draw definite conclusions about the carcinogenic potential of the individual byproducts. PURPOSE: The purpose of this study was to investigate the carcinogenic potential of chlorinated or chloraminated drinking water and of four organic trihalomethane byproducts of chlorination (chloroform, bromodichloromethane, chlorodibromomethane, and bromoform) in rats and mice. METHODS: Bromodichloromethane, chlorodibromomethane, bromoform, chlorine, or chloramine was administered to both sexes of F344/N rats and (C57BL/6 x C3H)F1 mice (hereafter called B6C3F1 mice). Chloroform was given to both sexes of Osborne-Mendel rats and B6C3F1 mice. Chlorine or chloramine was administered daily in the drinking water for 2 years at doses ranging from 0.05 to 0.3 mmol/kg per day. The trihalomethanes were administered by gavage in corn oil at doses ranging from 0.15 to 4.0 mmol/kg per day for 2 years, with the exception of chloroform, which was given for 78 weeks. RESULTS: The trihalomethanes were carcinogenic in the liver, kidney, and/or intestine of rodents. There was equivocal evidence for carcinogenicity in female rats that received chlorinated or chloraminated drinking water; this evidence was based on a marginal increase in the incidence of mononuclear cell leukemia. Rodents were generally exposed to lower doses of chlorine and chloramine than to the trihalomethanes, but the doses in these studies were the maximum that the animals would consume in the drinking water. The highest doses used in the chlorine and chloramine studies were equivalent to a daily gavage dose of bromodichloromethane that induced neoplasms of the large intestine in rats. In contrast to the results with the trihalomethanes, administration of chlorine or chloramine did not cause a clear carcinogenic response in rats or mice after long-term exposure. CONCLUSION: These results suggest that organic byproducts of chlorination are the chemicals of greatest concern in assessment of the carcinogenic potential of chlorinated drinking water.     

The venous antithrombotic profile of naroparcil in the rabbit

The venous antithrombotic profile of naroparcil or (4-[4-cyanobenzoyl]-phenyl)-1.5-dithio-beta-D-xylopyranoside was investigated in the rabbit following single i.v. and oral administration. Naroparcil attenuated thrombus development in a Wessler stasis model of venous thrombosis (jugular vein) employing bovine factor Xa as a thrombogenic stimulus giving ED50 values of 21.9 mg/kg and 36.0 mg/kg after respectively i.v. and oral administration. Venous antithrombotic activity was maximal 2-3 h after i.v. administration and 4-8 h after oral administration. Four hours after the oral administration of maximal antithrombotic (Wessler model, factor Xa) doses (100 and 400 mg/kg), naroparcil had no significant effect on bleeding time. In platelet poor plasma obtained from animals treated 4 h previously with various doses (25 to 400 mg/kg) of naroparcil, there was no detectable anti-factor Xa nor antithrombin activity. Similarly, naroparcil had no effect on APTT nor on thrombin time. A sensitized thrombin time (to about 35 s) was modestly but significantly increased following oral administration of the compound at 400 mg/kg. However, thrombin generation by the intrinsic pathway was reduced in a dose-related manner, maximal reduction being 65% at 400 mg/kg. The same dose of naroparcil enhanced the formation of thrombin/heparin cofactor II complexes at the expense of thrombin/antithrombin III complexes in plasma incubated with (125I)-human alpha-thrombin and induced the appearance of dermatan sulfate-like material in the plasma of treated rabbits, as measured by a heparin cofactor II-mediated thrombin inhibition assay.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neurosteroids, GABA receptors and neuronal protection

The anti-inflammatory activity of the methanol extract of Nelumbo nucifera rhizome as well as of betulinic acid, a steroidal triterpenoid isolated from it, were evaluated on carrageenin and serotonin induced rat paw edema. Methanol extract at doses of 200 and 400 mg/kg and betulinic acid at doses of 50 mg/kg and 100 mg/kg p.o., showed significant anti-inflammatory activity in both the models of inflammation in rats. The effects produced were comparable to that of phenylbutazone and dexamethasone, two prototype anti-inflammatory drugs.     

Murine cerberus homologue mCer-1: a candidate anterior patterning molecule

The fungal toxin fumonisin B1 (FB1) is a contaminant of corn-based foods and feeds produced by members of the genus Fusarium. Fumonisin B1 toxicity was examined using gavage administration of purified toxin to female Sprague-Dawley rats. For 11 consecutive days each rat received a single dose of FB1 at the following concentrations: control (saline), 1, 5, 15, 35, or 75 mg FB1/kg body weight/d. Significantly depressed body weight and food consumption occurred at 35 and 75 mg FB1/kg/d. By the end of the dosing period there were no significant changes in food consumption. Kidneys and bone marrow were most sensitive to FB1 exposure. Changes in renal morphology were observed from 5 to 75 mg FB1/kg/d, accompanied by transient changes in urine osmolality and urine enzyme levels. Increased cellular vacuolation was the primary change associated with bone-marrow toxicity, starting at doses of 5 mg FB1/kg/d. Hepatotoxicity was indicated by reduced liver weight, elevated serum alanine amonitransferase (ALT), and mild histopathological changes occurring at doses of 15 mg FB1/kg/d and higher. Increased cytoplasmic vacuolation of adrenal cortex cells occurred in rats treated with 15 mg FB1/kg/d and higher, indicating that the adrenals are also potential targets of FB1. Elevated serum cholesterol, which is a consistent response to FB1 was observed at 5 mg FB1/kg/d and higher. Based on responses in this study, gavage is an appropriate substitute for longer feeding studies. Compared to previous work with male rats, gender-related difference in FB1 responses lacked consistency but indicated that males may be marginally more sensitive than female Sprague-Dawley rats.     

cis-Amminedichloro(2-methylpyridine) platinum(II) (AMD473), a novel sterically hindered platinum complex: in vivo activity, toxicology, and pharmacokinetics in mice

A novel sterically hindered platinum complex, AMD473 [cis-amminedichloro(2-methylpyridine) platinum(II)], designed primarily to be less susceptible to inactivation by thiols, has shown in vitro activity against several ovarian carcinoma cell lines. Notably, AMD473 has shown activity in vitro in human carcinoma cells that have acquired cisplatin resistance due to reduced drug transport (41M/41McisR) or enhanced DNA repair/increased tolerance of platinum-DNA adducts (CH1/CH1cisR). In this study, we show that AMD473, at its maximum tolerated dose of 35-40 mg/kg i.p. administration, produced marked in vivo antitumor activity against a variety of murine (ADJ/PC6 plasmacytoma, L1210 leukemia) and human ovarian carcinoma xenograft models, including several possessing acquired resistance to cisplatin [ADJ/PC6cisR, L1210cisR, CH1cisR, and HX110 (carboplatin-resistant)]. In the ADJ/PC6 model, an increased therapeutic index was noted following oral as opposed to i. p. administration. In a head-to-head comparison using CH1cisR xenografts and equitoxic doses (q7dx4 schedule), comparative growth delays were as follows: AMD473, 34 days; cisplatin, 10.4 days; carboplatin, 6.4 days; and JM216 (p.o. administration), 3.5 days (in a previous experiment, the trans-platinum complex JM335 induced a growth delay of 5.4 days against this model). In this model, oral activity was also noted with a growth delay of 34 days at 400 mg/kg every 7 days (total of four doses). In addition, AMD473 showed promising activity against CH1 xenografts that had regrown following initial treatment with cisplatin (additional growth delay of 30 days over that observed for retreatment with cisplatin). Across the whole panel of cisplatin-sensitive to cisplatin-resistant human ovarian carcinoma xenografts, AMD473 showed improved or at least comparable activity to that observed for an equitoxic dose (4 mg/kg) and schedule of cisplatin. Platinum pharmacokinetics showed that following i.v. administration of 20 mg/kg AMD473 in saline to Balb/c- mice bearing murine plasmacytoma (ADJ/PC6), a biexponential decay was observed in the plasma with a rapid distribution t1/2alpha of 24 min followed by a slow elimination t1/2beta of 44 h. Platinum accumulated in various organs with platinum tissue to plasma area under the curve ratios of 8.6 for liver and kidney, 5.7 for spleen, 3.7 for heart, 5.2 for lung, and 5 for tumor. The plasma and tissue concentration time curve following i.p. administration was similar to that observed following i.v. administration, with a bioavailability of 89%. When AMD473 was given p.o., the platinum absorption was rapid (K01 of 30 min) and the bioavailability was 40%. A less than proportional increase in area under the curve and Cmax was noted in tissue, plasma, and plasma ultrafiltrate following increasing oral doses of AMD473. In vitro, with AMD473, the rate of binding to different plasma proteins was approximately half of that of cisplatin. Following administration of 45 mg/kg i.p. in oil, 33% of the administered platinum was eliminated in the urine after 24 h, and 40% was eliminated after 72 h. Fecal recovery represented 13% of the administered dose after 3 days. Similar results were observed following oral and i.v. administration of 20 mg/kg, but significantly more was excreted in the feces (over 50% of the administered dose) following oral administration of 400 mg/kg, showing that absorption might be a limiting factor by this route of administration. The dose-limiting toxicity for AMD473 in mice was myelosuppression, and no renal toxicity was observed. The promising antitumor activity of AMD473, together with its lack of nephrotoxicity and favorable pharmacokinetic profile, suggests that AMD473 is a good candidate for clinical development. AMD473 is entering Phase I clinical trials under the auspices of the United Kingdom Cancer Research Campaign in 1997.     

Interactions of itraconazole with amphotericin B in the treatment of murine invasive candidiasis

The interactions of amphotericin B and itraconazole were studied in murine invasive candidiasis. Candida albicans-infected mice were treated for 10 consecutive days, 24 h after infection. Survival was monitored over 30 days and kidney cultures were done. Mice treated with amphotericin B (0.2 mg/kg/day intraperitoneally) or itraconazole (100 mg/kg/day by oral gavage in two divided doses/ day) had a 30-day survival of 20% or 40%. Concomitant administration of both drugs resulted in 100% mortality; 90% of mice treated with amphotericin B (1 mg/kg/day) survived. With the combination, 100% were dead by day 28 (P < or = .001 vs. amphotericin B). With sequential therapy (i.e., 5 days with one drug and then 5 days with the other), survival was inferior to that with amphotericin B alone but similar to that with itraconazole alone. Kidney culture results confirmed the antagonism of the combination compared with amphotericin B alone. In treatment of murine invasive candidiasis, the concomitant or sequential use of amphotericin B and itraconazole results in a negative interaction.     

Toxicity of fumonisin B1 to B6C3F1 mice: a 14-day gavage study

Fumonisin B1 (FB1) is a fungal toxin produced by members of the genus Fusarium. Ingestion of FB1 causes species-specific neurotoxic, nephrotoxic, hepatotoxic and pulmonary effects. The clinical, haematological and pathological responses of adult male and female B6C3F1 mice to FB1 were assessed following 14 daily gavage doses ranging from 1 to 75 mg FB1/kg body weight/day. There were no consistent sex-related changes. Although all responses were modest, the most notable effects of FB1 were on the liver, bone marrow, adrenals and kidneys. In the liver, hepatocellular single cell necrosis, mitosis and anisokaryosis were observed, accompanied by elevated serum ALT. In the kidneys, minor histopathological changes were confined to female mice, while mild decreases in ion transport and increases in blood urea nitrogen were seen only in males. Small changes in glutathione levels were observed in the kidneys and livers of male mice. Adrenal cortical cell vacuolation was observed at 15 mg FB1/kg and higher in females and from 35 mg FB1/kg in males. Serum cholesterol was elevated in both male and female mice, possibly due to FB1-induced changes in lipid metabolism in the liver and adrenals. Although bone marrow cell numbers were unchanged, increases in vacuolated myeloid cells and lymphocytes were observed in female mice. In general, the degree of changes observed indicate that mice are not as sensitive a model of FB1 toxicity as rats.     

The renal effects of the water-soluble, non-folylpolyglutamate synthetase-dependent thymidylate synthase inhibitor ZD9331 in mice

ZD9331 is a novel, potent thymidylate synthase (TS) inhibitor which does not require polyglutamation by folylpolyglutamate synthetase (FPGS) for its activity. In contrast to Tomudex (ZD1694), ZD9331 may therefore be active against tumours with low FPGS activity. ZD9331 shows anti-tumour activity by both 24-h infusion and bolus administration in the murine thymidine kinase-deficient (TK -/-) lymphoma L5178Y. In view of the history of renal toxicity with some earlier TS inhibitors and the possible therapeutic use of bolus ZD9331, we have examined the effects of bolus ZD9331 dose and route of administration on plasma and kidney pharmacokinetics and renal function in mice. Renal function was assessed by measuring [14C]inulin clearance, and drug concentrations were assayed by reverse-phase high-performance liquid chromatography (HPLC). Renal function was unaffected by ZD9331 up to 150 mg kg(-1) either i.v. or i.p. However, at 200 mg kg(-1), glomerular filtration rate was significantly inhibited following i.v. but not i.p. administration. Pharmacokinetic studies showed that these effects were consistent with the markedly higher plasma drug concentrations occurring during early times following i.v. dosing, although the plasma drug profiles were otherwise similar for both routes. Kidney drug concentrations were slightly elevated in i.v.- versus i.p.-treated animals at the low dose (50 mg kg(-1)), with a correspondingly larger area under the curve. However, at the highest dose (200 mg kg(-1)), peak kidney drug concentrations were 20-fold higher following i.v. administration than after i.p., with marked kidney retention, resulting in a 50-fold greater kidney drug exposure for the i.v. versus the i.p. route. These data show that ZD9331 is non-nephrotoxic at active anti-tumour doses (50 mg kg(-1) i.p.) in mice, and only at very high bolus i.v. doses is there impaired renal function as a result of very high peak plasma concentrations. These adverse effects can be readily overcome by i.p. administration, indicating the likely need for short infusions in clinical settings.