Comparative neurotoxicity and metabolism of ethyl n-butyl ketone and methyl n-butyl ketone in rats

The six-carbon compounds methyl n-butyl ketone (MnBK) and n-hexane are metabolized by oxidation of their subterminal carbons through a series of steps leading to the production of 2,5-hexanedione (2,5Hxdn). Each oxidative step increases the neurotoxic potential so that 2,5Hxdn is the most active compound in the metabolic series. The most likely seven-carbon compound commercially available that would produce a metabolic analog to 2,5Hxdn is ethyl n-butyl ketone (EBK). A study was conducted to determine the neurotoxicity of EBK and to identify its major metabolites. Rats were exposed to 700 ppm MnBK by inhalation for 11 weeks or EBK for 24 weeks, twice the exposure period needed to produce a severe, clinically evident neuropathy with MnBK. No clinical or neuropathological evidence of neurotoxicity was evident after EBK exposure. These findings appear to be due to the low serum concentrations of 2,5-heptanedione (6.8 ± 4.0 μg/ml) formed from EBK in comparison to the much higher concentrations of 2,5Hxdn (133.2 ± 36.7 μg/ml) formed from MnBK. This argument is strengthened by the fact that in a companion study, 2,5-heptanedione administered to rats 5 days per week by gavage in 1000 and 2000 mg/kg/day doses was found to produce the same type of neurotoxicity as seen with 2,5-Hxdn.     

Taurolithocholate-induced intrahepatic cholestasis: potentiation by methyl isobutyl ketone and methyl n-butyl ketone in rats

Haloalkane-induced hepatonecrogenesis can be potentiated by the prior administration of methyl isobutyl ketone (MIBK) and methyl n-butyl ketone (MBK). We investigated the possibility that these ketones could potentiate the cholestasis induced by taurolithocholate (TLC) in rats. Daily ketone pretreatment for 3 or 7 days resulted in an enhancement of the diminution in bile flow observed after TLC challenge. When the ketones were administered without TLC challenge, cholestasis was not observed; in fact, slight increases in bile flow did occur. The data suggest that MIBK may be more effective than MBK as a potentiator. Preliminary experiments with 2,5-hexanedione (HD), a metabolite of MBK and a potent potentiator of haloalkane hepatonecrosis, were included in the study. HD appeared to be a less potent potentiator of TLC-induced cholestasis. Although some ketones can potentiate cholestatic as well as hepatonecrogenic reactions, different mechanisms of action appear to be involved in these two phenomena.     

Effects of acetone and methyl n-butyl ketone on hepatic mixed-function oxidase

The administration of ketones potentiates CCl4 hepatotoxicity; however, the potencies of the ketones differ. The aim of the present study was to assess potential differences between acetone and methyl n-butyl ketone (MnBK) on cytochrome P-450. The effects of single and repetitive doses of acetone and MnBK were determined in male rats by estimating the rate of metabolite formation of three substrates and the hepatic content of cytochrome P-450. A single treatment with acetone (13.5 mmol/kg or greater) enhanced the oxidation of aniline and 7-ethoxycoumarin, whereas repetitive treatments also increased aminopyrine demethylation and cytochrome P-450 content. Single and repetitive treatments of MnBK (15 mmol/kg) augmented the oxidation of all three substrates and increased cytochrome P-450 content. The effects of the ketones on cytochrome P-450 isozymes were characterized using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Acetone and MnBK increased the 52.1 and 54.1 kD forms and, in addition, MnBK tended to increase the 50.6 kD species. The data indicate that ketones differ in the type of isozymes induced and in the degree of induction. The higher potency of MnBK, compared to acetone, is probably associated with the fact that MnBK affects a greater number of isozymes than acetone.     

Studies on the absorption and excretion of rokitamycin in infant beagle dogs. Comparison with adult beagle dogs

Absorption and excretion of rokitamycin (RKM) were studied after oral administration of 50 mg/kg to fasted infant and adult Beagle dogs. In infant Beagle dogs, the mean plasma level of RKM reached its peak of 6.53 micrograms/ml in 15 minutes after administration. The area under the curve (AUC) value was 11.04 micrograms.hr/ml. In adult Beagle dogs, the mean plasma level of RKM reached its peak of 8.62 micrograms/ml in 30 minutes after administration. The AUC value was 18.25 micrograms.hr/ml. Ratios of Cmax and AUC value in infant Beagle dogs to those in adults were about 75% and 60%, respectively. In infant Beagle dogs, urinary excretion of RKM was 2.55% of the dose within 24 hours. In adult Beagle dogs, urinary excretion of RKM was 3.03% of the dose within the same period. The excretion ratio of RKM in infant Beagle dogs was about 85% of the adults' value.     

Investigation of the mechanism of the potentiation of chloroform-induced hepatotoxicity and nephrotoxicity by methyl n-butyl ketone

Twenty-four hours after administration of CHCl₃ (0.5 ml/kg) to methyl n-butyl ketone (MBK)-pretreated rats, both the plasma glutamic pyruvic transaminase (GPT) and the blood urea nitrogen (BUN) levels were significantly elevated above those of sesame oil-pretreated animals. In contrast, deuterium-labeled chloroform (CDCl₃) (0.5 ml/kg) caused insignificant alterations in either plasma GPT or BUN levels of MBK-pretreated rats. Treatment with MBK caused a decrease in hepatic GSH levels to 61% of control values after 20 hr. When administered 18 hr after MBK pretreatment, CHCl₃ caused a further decrease in hepatic GSH levels to 20% of control values within 2 hr, whereas CDCl₃ treatment decreased them to 34% of control values. Renal GSH levels were unchanged by these treatments. Eighteen hours after administration of MBK, hepatic cytochrome P-450 levels were up by 70% but no change was detected in the amount of renal cytochrome P-450. Pretreatment of rats with MBK increased the metabolism of CHCl₃ to diglutathionyl dithiocarbonate both in vivo and in hepatic microsomal incubation mixtures containing GSH. These results suggest that MBK potentiates the hepatic toxicity produced by CHCl₃ in part by decreasing GSH levels and in part by increasing the metabolism of CHCl₃ to phosgene. Although the mechanism of potentiation of renal toxicity by MBK pretreatment remains unclear, the deuterium isotope effect on BUN levels indicates that metabolism of the CH bond of CHCl₃ may be involved in the renal toxicity.     

Metabolites and ketone body production following methyl n-butyl ketone exposure as possible indices of MnBK potentiation of carbon tetrachloride hepatotoxicity

While the biotransformation of methyl n-butyl ketone (MnBK) in animals is well characterized, little is known about the quantitative relationship between hepatic and plasma MnBK concentrations. This study provides such information and emphasizes the usefulness of MnBK metabolite quantification, as well as MnBK-induced metabolic ketosis for the biological monitoring of MnBK exposure in rats. Elimination of MnBK was followed 24 hr after oral administration (0.95, 1.90, and 5.70 mmol/kg in corn oil) to male Sprague-Dawley rats. Two metabolites [2-hexanol (2HOL), and 2,5-hexanedione (2,5HD)] were also monitored and their kinetics determined. These data were compared to ketone body (KB) concentrations found in plasma and liver during the same period. Plasma concentrations of MnBK and 2,5HD correlated well with those in the liver. This was not the case for 2HOL. MnBK, 2HOL, and 2,5HD were no longer detected in plasma and liver 18 hr after dosing. Meanwhile, a marked ketosis was observed from 12 to 24 hr. This ketotic state was due to an increase in beta-hydroxybutyrate (BOHB), while acetoacetate remained at its basal levels. These data indicate that MnBK can induce ketosis in rats and suggest that the resulting BOHB might be used as an alternative biological monitor of MnBK exposures at high concentrations.     

The absorption and excretion of fluoride and arsenic in humans

The absorption and excretion of fluoride and arsenic were measured in a group of healthy volunteers given drinking water with naturally high concentration of fluoride (F 2.3 mg/l)(,) or high concentration of arsenic (As 0.15 mg/l), or high concentrations of both fluoride and arsenic (F 2.25 mg/l, As 0.23 mg/l and F 4.05 mg/l, As 0.58 mg/l), respectively. The results indicated that, for arsenic, the absorption rate, the proportion of urinary excretion and the biological-half-life did not show statistically significant differences between drinking water containing high arsenic alone and drinking water containing different levels of high arsenic and fluoride. Excretion and retention of arsenic were positively correlated to the total arsenic intake. Similar results were observed for fluoride. This suggests that there are different metabolic processes for arsenic and fluoride in respect to absorption and excretion; and no joint action can be attributed by these two elements.     

西红花苷-1大鼠吸收及排泄的研究

目的:研究经口服给药西红花苷-1的吸收及排泄情况.方法:采用大鼠在体小肠回流实验、西红花苷-1溶液2和4h恒温孵育实验以及灌胃给药吸收及排泄实验.HPLC法测定西红花苷-1的含量.结果:西红花苷-1经大鼠在体小肠回流4h后药量消失率分别为:十二指肠10.1%,空肠9.55%,回肠9.15%,结肠12.24%.在不同肠段的空白回流液中孵育4h,降解率分别为:十二指肠9.85%,空肠10.85%,回肠11.49%,结肠12.64%.大鼠灌胃给药24h后粪及肠内容物药量占给药量的79.9%.在蒸馏水及空白肠回流液中经24h孵育,降解率为15.64%和17.62%.大鼠血和尿中均未检测出西红花苷-1.结论:西红花苷-1口服给药后不能以原形经肠道吸收,有少部分转化为苷元(西红花酸)吸收,但浓度很低.     

The absorption and excretion of butylated hydroxyanisole in beagle dogs

Recent studies have indicated that administration of [14C]butylated hydroxyanisole (BHA) to rats, either orally or by intraperitoneal (i.p.) injection, resulted in high retention of radioactivity in the forestomach. The present study was undertaken to investigate the fate of [14C]BHA in non-rodents. 2 Groups of 5-mth-old male beagle dogs were fed a diet containing either 3% or 0.03% BHA for 7 days, and were injected i.p. with 3-tert-[methyl-14C]butyl-4-hydroxyanisole (Amersham International) at a dose of 30 muCi/kg. On the 7th day after [14C]BHA injection, all dogs were killed after fasting overnight, and the liver, kidney, heart, fat tissue and stomach were collected for radioanalysis. An additional 3 beagles served as control group. The fate of BHA after the single i.p. injection of [14C]BHA was examined by the determination of 14C-radioactivity in whole body, blood, urine, feces and several tissues. Blood, urine and feces samples were collected daily for 7 days. Blood samples were collected at intervals for 24 h. BHA was rapidly taken up in the bloodstream, and 50-80% of the total radioactivity was recovered in the urine within 2 days. 15-30% Appeared in the feces within 2 days. The tissue distribution of radioactivity 7 days after [14C]BHA injection showed only a small portion remaining in the stomach (0.16-0.19% of dose/g), liver (0.3-1.7%) and other tissues (0.02%). The radio-activity was almost evenly distributed in the three parts of the stomach (cardia, corpus and pylorus). These findings are in contrast with the previous data in rats that BHA can accumulate in high concentrations in the forestomach.     

Percutaneous uptake and kinetics of methyl isobutyl ketone (MIBK) in the guinea-pig

Continuous intravenous infusion of 0.478 mumol/min methyl isobutyl ketone (MIBK) was performed for 30 min in pentobarbital-anesthetized guinea-pigs. Epicutaneous exposure for 150 min was carried out 2.5 h later after administration of MIBK to a sealed glass ring on the clipped back of the animals. Arterial blood was analyzed for MIBK by gas chromatography. Blood clearance averaged 201 ml.min-1.kg-1 body wt. A maximum percutaneous uptake of 1.1 mumol.min-1.cm-2 was reached 10-45 min after the onset of exposure and decreased to 0.56 mumol.min-1.cm-2 during the latter part of exposure.     

Acute alteration of chloroform-induced hepato- and nephrotoxicity by n-hexane,methyl n-butyl ketone,and 2,5-hexanedione

Previous studies have suggested that administration of ketones or agents which are metabolized to ketones potentiates haloalkane toxicity in animals. To test this hypothesis, CHCl₃-induced hepato- and nephrotoxicity was evaluated in male Sprague-Dawley rats pretreated with 15 mmol/kg (po) n-hexane (H), its ketonic metabolites methyl n-butyl ketone (MBK), and 2,5-hexanedione (2,5-HD) or acetone (A). Eighteen hours after pretreatment a challenging dose of CHCl₃ (0.5 ml/kg, ip) was given. Liver and kidney damage were determined 24 hr later. Neither H, MBK, 2,5-HD, A, or the CHCl₃ challenge dose produced marked liver or kidney injury when given alone. However, H, MBK, 2,5-HD, and A pretreatment potentiated CHCl₃-induced liver and kidney injury. The ability to potentiate CHCl₃-induced liver injury increased in the order of H < A < 2,5-HD ? MBK. The relative ranking of these chemicals in order of increasing ability to potentiate CHCl₃-induced nephrotoxicity was H ? A < 2,5-HD ? MBK. These results support the concept that ketones increase the susceptibility of animals to the toxic effects of haloalkanes.     

The urinary excretion of dextromethorphan and three metabolites in dogs and humans

Quantitative data were obtained for the urinary excretion of dextromethorphan (I) and its metabolites in dogs and humans using recently developed gas chromatographic methods. The recovery of I was 2.8% after iv administration in dogs and only 0.7 and 0.1% after ip and po administration, respectively, confirming previous reports of first-pass metabolism. Of the three known metabolites, only (+)-17-methylmorphinan-3-ol and (+)-morphinan-3-ol were present in significant quantities. In four of five human subjects, less than 0.5% of the dose was excreted unchanged after a single oral dose. The same two metabolites accounted for the bulk of excreted material, and they were largely conjugated, probably as the glucuronide.     

Characterization of the metabolites of methyl n-butyl ketone,methyl iso-butyl ketone,and methyl ethyl ketone in guinea pig serum and their clearance

Methyl n-butyl ketone (MnBK) has been reported to produce peripheral neuropathy in experimental animals and in man. The metabolism of MnBK and related ketones was studies as part of a program to elucidate the molecular events in MnBK-induced neuropathy. Guinea pigs were given single 450 mg/kg ip doses of MnBK, methyl iso-butyl ketone (MiBK) or methyl ethyl ketone (MEK). Metabolites in serum were identified and quantitated by gas chromatography and gas chromatography-mass spectrometry. MnBK metabolites were 5-hydroxy-2-hexanone, 2,5-hexanedione, and 2-hexanol. MiBK was converted to 4-hydroxy-2-methyl-2-pentanone and 4-methyl-2-pentanol. MEK produced 2-butanol, 3-hydroxy-2-butanone, and 2,3-butanediol. The fate of several of the above metabolites was also investigated. Our results show that aliphatic ketones are metabolized both by reduction of the carbonyl group to form a secondary alcohol and by oxidation at the ω-1 carbon atom to form an hydroxylated ketone. Guinea pigs and other mammalian species receiving MnBK by various routes of administration showed qualitatively similar metabolic patterns in serum. Serum half-lives and clearance times for MnBK, MiBK, and MEK in the guinea pig were 78 min, 6 hr; 66 min, 6 hr; and 270 min, 12 hr; respectively. Our studies have shown that 2-hexanol, 5-hydroxy-2-hexanone, and 2,5-hexanediol may be neurotoxic by virtue of their conversion to the neurotoxin 2,5-hexanedione. n-Hexane, a reputed neurotoxin, was also investigated and was found to produce 5-hydroxy-2-hexanone and 2,5-hexanedione in guinea pig serum. The neurological effects of MnBK, n-hexane, and 2,5-hexanedione, therefore, may have a common metabolic origin.     

Urinary excretion of cocaine, benzoylecgonine, and ecgonine methyl ester in humans

The excretion kinetics of cocaine (C) and its two major metabolites, benzoylecgonine (BZ) and ecgonine methyl ester (EME), were determined by collecting all urine for 30 h from 5 cocaine users (subjects C, D, E, F, and G) given bolus doses followed by exponential cocaine infusions that delivered doses of 253 (subject C), 444 (subjects D, E, and F), and 700 mg (subject G). Plasma cocaine, urine cocaine, BZ, and EME were measured by gas chromatography, with a nitrogen detector. Elimination half-times for EME and BZ, estimated from semilog plots of excretion rates vs. time, averaged 3.1 and 4.5 h respectively, in agreement with our previous report. Urinary recovery in D, E, and F was 27-41% of the dose, with 14-17% as BZ, 12-21% as EME, and 2% as cocaine. Subject C excreted very little EME--5-6-fold less than the mean for the other subjects and amounting to only 3% of the dose. Cocaine disposition in subject G, who received the largest dose and attained plasma levels of 3000 ng/mL, showed some characteristics of a nonlinear process.     

Effects of acetone, methyl ethyl ketone and methyl isobutyl ketone on a match-to-sample task in the baboon.

Acetone, methyl ethyl ketone (MEK) and methyl isobutyl ketone (MIBK) were evaluated for effects on a delayed match-to-sample discrimination task in the juvenile baboon. The animals were exposed to 1/2 the threshold limit value (TLV) of each gas for 24 hr per day during a 7-day period. They were also exposed to a combination of MEK and MIBK at the same exposure concentrations. Each exposure condition affected accuracy of performance minimally but resulted in increased and decreased extra responses during the delay intervals. Response times were slowed under acetone, MEK or MIBK. In contrast to the effects of the individual gases, exposure to a combination of the same doses of MEK and MIBK produced a consistent increase in extra responses during delay and a concomitant decrease in response times. Changes in tissue uptake and metabolism are suggested as possible mechanisms to explain this observation.     

Studies on absorption and excretion of rokitamycin dry syrup in healthy volunteers

The absorption and excretion of rokitamycin (RKM) in dry syrup form for children were studied following oral administration to fasted healthy volunteers with high gastric acidity as a suitable model to estimate bioavailability of RKM in children. In a comparative study on tablet and dry syrup forms, peak plasma concentrations of RKM and areas under plasma concentration-time curve (AUC) values were calculated using the trapezoidal rule. RKM dry syrup gave about 84 and 86% of these values for RKM tablet. Urinary recovery of RKM in 8 hours with the administration of dry syrup was also about 80% of the value obtained with tablet. Judging from these results, the bioavailability of RKM administered as dry syrup, was fairly close to that obtained with RKM tablet. The AUC values were dose dependent when examined with dose levels of 300, 500 and 800 mg administered as RKM dry syrup. The AUC value and urinary recovery of RKM administered as dry syrup were 3-4 times higher than these values for midecamycin acetate administered also as dry syrup.     

Dermal absorption of camphor, menthol, and methyl salicylate in humans

Camphor, menthol, and methyl salicylate occur in numerous over-the-counter products. Although extensively used, there have been no estimates of human exposure following administration via dermal application. Furthermore, there is little information about the pharmacokinetics of those compounds. The authors report the plasma concentrations of the intact compounds as a function of dose following dermal patch application. Three groups of 8 subjects (4 male, 4 female) applied a different number of commercial patches (2, 4, or 8) to the skin for 8 hours. Plasma samples were assayed using sensitive and selective gas-chromatographic methods. For the 8-patch group, the average maximum plasma concentrations (Cmax +/- SD) were 41.0 +/- 5.8 ng/mL, 31.9 +/- 8.8 ng/mL, and 29.5 +/- 10.5 ng/mL for camphor, menthol, and methyl salicylate, respectively. The corresponding values for the 4-patch group were 26.8 +/- 7.2 ng/mL, 19.0 +/- 5.4 ng/mL, and 16.8 +/- 6.8 ng/mL. The harmonic mean terminal half-lives were 5.6 +/- 1.3 hours, 4.7 +/- 1.6 hours, and 3.0 +/- 1.2 hours for camphor, menthol, and methyl salicylate, respectively. The 2-patch group had measurable but low plasma concentrations of each compound. Low-dose dermal application for an extended time results in low plasma concentrations of all 3 compounds. Four and 8 patches, when applied for 8 hours, gave measurable and nearly proportional plasma concentrations. Although unable to determine the absolute dermal bioavailability of these compounds, there appears to be relatively low systemic exposure to these potentially toxic compounds, even when an unrealistically large number of patches are applied for an unusually long time.