Human dose-excretion studies with pyrethroid insecticides cypermethrin and alphacypermethrin: Relevance for biological monitoring

1. Dose-excretion studies with cypermethrin (as a 1:1 cis/trans mixture) and alphacypermethrin (one of the two disastereoisomer pairs which constitute cis cypermethrin) were carried out with, in each case, two volunteers per dose level. The studies included (a) single oral alphacypermethrin doses of 0˙25 mg, 0˙50 mg and 0˙75 mg followed by repeated alphacypermethrin doses at the same levels, daily for five days, (b) repeated oral cypermethrin doses of 0˙25 mg, 0˙75 mg and 1˙5mg daily for five days, and (c) a single dermal application of 25 mg cypermethrin to the forearm. Urine was monitored for the free and conjugated 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid before and after dosing.

2. Metabolism and rate of excretion of a single oral dose of alphacypermethrin was similar to that of cis cypermethrin, on average, 43% of the dose was excreted as the cyclopropanecarboxylic acid in the first 24 h urine. There was no increase in urinary metabolite excretion when alphacypermethrin was administered as a repeated oral dose. Subjects excreted, on average, 49% of the dose as the cyclopropanecarboxylic acid in the subsequent 24 h periods after dosing.

3. There was no increase in the urinary cyclopropanecarboxylic acid excretion when cypermethrin was administered as a repeated oral dose. Subjects excreted, on average, 72% of the trans isomer dose and 45% of the cis isomer dose respectively in the subsequent 24 h periods after dosing.

4. Approximately 0˙1% of the applied dermal dos>e of 25 mg cypermethrin was excreted within 72 h as the urinary cyclopropanecarboxylic acid. No conclusions can be drawn from such urinary excretion data as to the concentration of cypermethrin and its metabolites in the skin or other organs, or the possibility of other routes of metabolism or excretion.     

Human dose-excretion studies with the pyrethroid insecticide, cypermethrin

1. An analytical method for monitoring human exposure to cypermethrin has been developed, based on the detection of the free and conjugated forms of the urinary metabolite, the cyclopropanecarboxylic acid. 2. Four male subjects were given a single oral dose, ranging from 0.25 mg to 1.5 mg, of a 1:1 cis/trans mixture of cypermethrin, and urine was monitored for the free and conjugated cyclopropanecarboxylic acid. Urinary excretion of the individual metabolites (cis and trans isomers) was similar for the different dosages. Subjects excreted, on average, 78% of the trans isomer dose, and 49% of the cis isomer dose respectively in 24 h. 3. Thus, as in other mammals, ester cleavage and elimination of the cis and trans cyclopropanecarboxylic acid moieties in the free and conjugated form is a major route of metabolism of cypermethrin in man.     

Human dose-excretion studies with the pyrethroid insecticide,cypermethrin

1. An analytical method for monitoring human exposure to cypermethrin has been developed, based on the detection of the free and conjugated forms of the urinary metabolite, the cyclopropanecarboxylie acid.

2. Four male subjects were given a single oral dose, ranging from 0.25?mg to 1.5mg, of a 1:1 cis/trans mixture of cypermethrin, and urine was monitored for the free and conjugated cyclopropanecarboxylic acid. Urinary excretion of the individual metabolites (cis and trans isomers) was similar for the different dosages. Subjects excreted, on average, 78% of the trans isomer dose, and 49% of the cis isomer dose respectively in 24h.

3. Thus, as in other mammals, ester cleavage and elimination of the cis and trans cyclopropanecarboxylic acid moieties in the free and conjugated form is a major route of metabolism of cypermethrin in man.     

The metabolism of cypermethrin in man: differences in urinary metabolite profiles following oral and dermal administration.

1. The pyrethroid insecticide cypermethrin was administered orally to six male volunteers as a single dose of 3.3 mg (cis: trans 1:1) and dermally to six volunteers at a dose of 31 mg/800 cm2 (cis:trans 56:44) as a soya oil-based formulation. Urine samples were collected for up to 5 days and analysed for the metabolites cis and trans 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (DCVA), 3-phenoxybenzoic acid (3PBA) and 3-(4'-hydroxyphenoxy) benzoic acid (4OH3PBA) following an acid hydrolysis procedure. 2. Following oral dosing approx. equal amounts of (cis+trans DCVA) and (3PBA+4OH3PBA) were excreted with peak excretion rates occurring between 8 and 24 h after dosing. The ratio of trans:cis DCVA was on average 2:1. Based on DCVA measurements the amount of cypermethrin absorbed was estimated to be between 27% and 57% (mean 36%) of the administered dose. 3. Peak urinary excretion rates of metabolites occurred between 12 and 36 h after dermal dosing. The amount of metabolites derived from the phenoxybenzyl moiety (3PBA+4OH3PBA) was on average 4 times greater than the amount of (cis+trans DCVA) recovered in urine. The ratio of trans:cis DCVA was, on average 1:1.2. Based on the recovery of the phenoxybenzyl metabolites it is estimated that 0.85-1.8% (mean 1.2%) of the administered cypermethrin was absorbed. 4. These studies demonstrate marked differences in the urinary metabolite profile by the two routes, and provide an improved basis for determining the extent and main route of absorption of cypermethrin under occupational exposure conditions.     

Comparative urinary excretion of ethoxyacetic acid in man and rat after single low doses of ethylene glycol monoethyl ether

Male rats were given a single oral dose of ethylene glycol monoethyl ether (EGEE), the dose ranging from plausible human exposures (0.5-1 mg/kg) to doses reported in the literature (100 mg/kg). Urinary excretion of ethoxyacetic acid (EAA) and its glycine conjugate was followed up to 60 h after dosing and compared to data of experimentally exposed human volunteers. In rats, the mean elimination half-life of free as well as conjugated EAA was 7.2 h for all doses. EAA was excreted partly as a glycine conjugate (on average 27%), the extent of conjugation being independent of the dose. The conjugation with glycine showed a clearly diurnal variation, the lowest extent being found during the night. The relative amount of EGEE recovered in urine as EAA was only 13.4% for the lowest dose, but increased as the administered dose of EGEE was higher, indicating that EGEE was metabolised at least in two parallel pathways of which one pathway becomes saturated at relatively low doses. In man, urinary excretion of EAA for equivalent low doses of EGEE differed from that in the rat by a longer elimination half-life (mean 42 h), by the absence of EAA conjugates and by a higher recovery.     

Metabolism and disposition of hydroquinone in Fischer 344 rats after oral or dermal administration.

Studies were conducted to determine the absorption, tissue distribution, excretion, and metabolism of 14C-hydroquinone (HQ) in male and female rats following single oral, repeated oral, or 24-h dermal administration. The concentration of parent compound in blood was also determined following a single 50-mg/kg gavage administration. Absorption into the blood was rapid after oral dosing; the maximum concentration of parent compound was attained within 20 min after dosing, and the maximum concentration of total 14C was attained within 30 min. Parent compound represented 1% of total 14C in blood, indicative of extensive first-pass metabolism. Excretion was primarily via the urine within the first 8h of gavage. Typically, 87-94% of the 14C was excreted in urine. Dermal application of 14C-HQ (20 microCi) as a 5.4% aqueous solution resulted in near background levels of 14C in blood; the maximum mean blood concentration was 0.65 microg HQ equivalents/g in females and not quantifiable in males. The majority (61-71%) of the 14C was recovered from the skin surface by washing at 24 h. HQ was extensively metabolized following oral dosing with typically <3% of the dose excreted as parent compound. The major urinary metabolites of HQ were glucuronide and O-sulfate conjugates, which represented 45-53% and 19-33%, respectively, of an oral dose. A <5% metabolite was identified as a mercapturic acid conjugate of HQ.     

Exposure to the organophosphate diazinon: data from a human volunteer study with oral and dermal doses

Biological monitoring of occupational exposure to diazinon is possible by the determination of blood cholinesterase activity and by the measurement of metabolites in urine. However, there is little data to aid in the interpretation of results. This study gave oral (11 microg kg(-1) (36 nmol kg(-1)) body weight) and occluded dermal (100 mg (329 micromol)) doses of diazinon to five volunteers and analysed blood and urine samples for plasma and erythrocyte cholinesterase and urinary dialkyl phosphate (DAP) metabolites of diazinon: diethyl phosphate (DEP) and diethyl thiophosphate (DETP). Following oral and dermal exposure, peak urinary DAP levels occurred at 2 and 12 h, respectively. The apparent urinary elimination half-lives of DAP metabolites following oral and dermal exposure were approximately 2 and 9 h, respectively. Approximately 60% of the oral dose and 1% of the dermal dose was excreted as urinary DAP metabolites, with 90% of the dermal dose being recovered from the skin surface. On a group basis, there was no statistically significant mean depression in plasma or erythrocyte cholinesterase when compared with pre-exposure levels for either dosing experiment. The observed elimination kinetics of diazinon metabolites suggest a biological monitoring strategy for occupational exposure to diazinon based on urine samples collected at the end of shift.     

Oral and dermal application of 2,4-dichlorophenoxyacetic acid sodium and dimethylamine salts to male rats: Investigations on absorption and excretion as well as induction of hepatic mixed-function oxidase activities

Absorption and urinary excretion of 2,4-dichlorophenoxyacetic acid sodium (sodium 2,4-D) and 2,4-dichlorophenoxyacetic acid dimethylammonium (2,4-DMA) salts were examined after single oral and middorsal skin applications of the herbicides to male rats. Doses of 2.6 mg 2,4-D/kg body wt (sodium 2,4-D) and 1.9 mg 2,4-D/kg body wt (2,4-DMA) were applied. Quantitatively, with both salts, most of the orally administered herbicide (over 90%) was excreted in urine within 28 h. However, 2,4-D urinary peak concentrations were measured 4.5 and 20.5 h after dosing with 2,4-DMA and sodium 2,4-D, respectively. Additionally, the volume of urine in the oral study was significantly increased with both salts when compared with the controls or the dermal exposure. After topical application, 2,4-D absorption was much lower than in the oral study. Urinary excretion only reached about 10 and 15% of the applied dose for sodium 2,4-D and 2,4-DMA, respectively, by 5 days post-treatment. Further, we found some elevations in hepatic cytochrome P-450 activities. Ethylmorphine N-demethylase was only slightly induced by the herbicides while ethoxyresorufin O-deethylase activity was increased nearly 2-fold by sodium 2,4-D.     

Metabolism and disposition of [14C]5-amino-o-cresol in female F344 rats and B6C3F1 mice

The metabolism and disposition of [(14)C]5-amino-o-cresol (AOC) in female F344 rats following oral, intravenous, and dermal administration and in female B6C3F1 mice following oral administration were studied. Greater than 80% of a single oral dose (4.0-357 mg kg(-1)) or intravenous dose (2.7 mg kg(-1)) was excreted in urine within 24 h. When the dosing site was protected from grooming, less than 10% of the dermal dose (2.5 and 26 mg kg(-1), rinsed off after 6 h) was absorbed within 24 h, and most of the absorbed radioactivity was excreted in urine. For the unprotected dermal dose, grooming played a major role in the absorption of AOC. Very little AOC-derived radioactivity was present in the surveyed tissues after 24 or 72 h regardless of route, dose level, or species. Five urinary metabolites were identified: 5-acetamido-1,4-dihydroxy-2-methylbenzene glucuronide, AOC O-glucuronide, AOC O-sulfate, N-acetyl-AOC O-glucuronide, and N-acetyl-AOC O-sulfate.     

Pharmacokinetics of the angiotensin converting enzyme inhibitor benazepril.HCl (CGS 14 824 A) in healthy volunteers after single and repeated administration

The pharmacokinetics of the new angiotensin converting enzyme (ACE) inhibitor benazepril.HCl were evaluated in healthy male volunteers. The single dose kinetics were established from data of 62 subjects receiving an oral 10 mg dose of the drug. The steady state kinetics were investigated in 15 subjects after once-daily oral doses of 5, 10 or 20 mg. The compound is a prodrug which, on absorption, is hydrolysed to the pharmacologically active metabolite benazeprilat. Thus, plasma concentrations and urinary excretion of parent compound and active metabolite were determined. Benazepril.HCl was rapidly absorbed (tmax = 0.5 h) and rapidly eliminated from plasma (t1/2 = 0.6 h). Only trace amounts were excreted unchanged in urine. The drug was rapidly metabolized to benazeprilat (tmax = 1.5 h). The elimination of the metabolite from plasma was biphasic. About 80 per cent of benazeprilat formed was eliminated within 24 h (t 1/2 = 2.7 h), whereas the terminal phase (t1/2 = 22.3 h) controlled a minor amount of elimination. About 17 per cent of dose was excreted in the 24-h urine as benazeprilat. The drug disposition did not change during repeated oral dosing and only small accumulation of the metabolite occurred. The accumulation ratio was 1.20 for AUC and 1.24 for urinary excretion. The effective half-life for accumulation was estimated at about 10-11 h. The comparison with other ACE inhibitors showed similarities but also marked differences with respect to the drug kinetics and excretion.     

Relative bioavailability of sodium cromoglycate to the lung following inhalation, using urinary excretion

AIMS: To determine if a urinary excretion method, previously described for salbutamol, could also indicate the relative bioavailability of sodium cromoglycate to the lung following inhalation from a metered dose inhaler. Method Inhaled (INH), inhaled+oral charcoal (INHC), oral (ORAL) and oral+oral charcoal (ORALC) 20 mg doses of sodium cromoglycate were given via a randomised cross-over design to 11 healthy volunteers trained on how to use a metered dose inhaler. Urine samples were collected at 0.0, 0.5, 1.0 and up to 24 h post dosing and the sodium cromoglycate urinary concentration was measured using a high performance liquid chromatographic method. RESULTS: No sodium cromoglycate was detected in the urine up to 24 h following ORALC dosing. A mean (s.d.) of 3.6 (4.3) microg, 10.4 (10.9) microg and 83.7 (71.1) microg of the ORAL dose was excreted, in the urine, during the 0.5, 1.0 and 24 h post dose collection periods, respectively. Following INH dosing, the renal excretion was significantly higher (P<0.01) with 32.9 (14.5) microg, 61.2 (28.3) microg and 305.6 (82.3) microg excreted, respectively. The SCG excreted at 0.5, 1.0 and 24 h collection periods following INHC dosing were 26.3 (8.4) microg, 49.3 (18.1) microg and 184.9 (98.4) microg, respectively. There was no significant difference between the excretion rate of sodium cromoglycate following INHC when compared with INH dosing in the first 0.5 and 1.0 h. CONCLUSIONS: The urinary excretion of sodium cromoglycate in the first 0.5 h post inhalation can be used to compare the relative lung deposition of two inhaled products or of the same product using different inhalation techniques. This represents the relative bioavailability of sodium cromoglycate to the lung following inhalation. Similar 24 h urinary excretion of sodium cromoglycate can be use to compare the total dose delivered to the body from two different inhalation products/inhalation methods. This represents the relative bioavailability of sodium cromoglycate to the body following inhalation. Because of the lack of difference between the INH and INHC in the first 0.5 h, the use of activated charcoal is not necessary when this method is used to compare the relative lung bioavailability of different products or techniques.     

Age-related changes in the disposition of benzyl acetate. A model compound for glycine conjugation

The in vivo metabolism and excretion of benzyl acetate (BA), a model compound for glycine conjugation, was examined in male Fischer 344 rats and C57BL/6N mice. Rats aged 3-4, 9, and 25 months received a single oral dose of either 5 or 500 mg/kg 14C-BA, while male mice aged 2, 13, and 25 months received a single oral dose of 10 mg/kg 14C-BA. Urine and feces were collected for 96 hr. Biliary excretion and plasma elimination were also examined in male Fischer rats after iv administration of 5 mg/kg 14C-BA. In both young and old rats and mice, hippuric acid (HA) was the major urinary metabolite after oral dosing of BA. No significant age-related difference was observed in rats in the urinary elimination of BA-derived radioactivity or in the percentage of the total dose excreted as hippuric acid (approximately 95%). Twenty-five-month old rats excreted a significantly higher percentage of the total dose as benzyl mercapturic acid (approximately 2%) than did 3- to 4-month-old rats (approximately 1%) at the 5 mg dose. Benzyl mercapturic acid excretion in 3- to 4-month-old rats was also increased significantly at 500 mg/kg BA vs. 5 mg/kg BA. Fecal excretion of BA-derived radioactivity declined significantly in 25-month-old rats at both the 5 and 500 mg dose. This decrease was reflected by an age-related decline in biliary excretion and higher plasma levels of BA-derived radioactivity. Examination of plasma metabolites revealed a significantly higher level of HA and benzoyl glucuronide in 25-month rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Absorption,distribution and excretion of nilvadipine,a new dihydropyridine calcium antagonist,in rats and dogs

1. The absorption, distribution and excretion of nilvadipine have been studied in male rats and dogs after an i.v. (1 mg/kg for rats, 0.1 mg/kg for dogs) and oral dose (10 mg/kg for rats, 1 mg/kg for dogs) of ¹⁴C-nilvadipine.

2. Nilvadipine was rapidly and almost completely absorbed after oral dosing in both species; oral bioavailability was 4.3% in rats and 37.0% in dogs due to extensive first-pass metabolism. The ratios of unchanged drug to radioactivity in plasma after oral dosing were 0.4–3.5% in rats and 10.4–22.6% in dogs. The half-lives of radioactivity in plasma after i.v. and oral dosing were similar, i.e. 8–10h in rats, estimated from 2 to 24 h after dosing and 1.5 d in dogs, estimated from 1 to 3 d. In contrast, plasma concentrations of unchanged drug after i.v. dosing declined biexponentially with terminal phase half-lives of 1.2 h in rats and 4.4 h in dogs.

3. After i.v. dosing to rats, radioactivity was rapidly distributed to various tissues, and maintained in high concentrations in the liver and kidneys. In contrast, after oral dosing to rats, radioactivity was distributed mainly in liver and kidneys.

4. With both routes of dosing, urinary excretion of radioactivity was 21–24% dose in rats and 56–61% in dogs, mainly in 24 h. After i.v. dosing to bile duct-cannulated rats, 75% of the radioactive dose was excreted in the bile. Only traces of unchanged drug were excreted in urine and bile.     

Oral absorption, metabolism and excretion of 1-phenoxy-2-propanol in rats

1. This study was designed to determine the absorption, metabolism and excretion of 1-phenoxy-2-propanol in Fischer 344 rats following oral administration in an effort to bridge data with other propylene glycol ethers. 2. Rats were administered a single oral dose of 10 or 100 mg kg(-1) 14C-1-phenoxy-2-propanol as a suspension in 0.5% methyl cellulose ether in water (w/w). Urine was collected at 0-12, 12-24 and 24-48 h and faeces at 0-24 and 24-48 h post-dosing and the radioactivity was determined. Urine samples were pooled by time point and dose level and analysed for metabolites using LC/ESI/MS and LC/ESI/MS/MS. 3. The administered doses were rapidly absorbed from the gastrointestinal tract and excreted. The major route of excretion was via the urine, accounting for 93 +/- 5% of the low and 96 +/- 3% of the high dose. Most of the urinary excretion of radioactivity occurred within 12 h after dosing; 85 +/- 2% of the low and 90 +/- 1% of the high dose. Total faecal excretion remained < 10%. Rats eliminated the entire administered dose within 48 h after dosing; recovery of the administered dose ranged from 100 to 106%. Metabolites tentatively identified in urine were conjugates of phenol (sulphate, glutathione) with very low levels (< 2%) of hydroquinone (glucuronide), conjugates of parent compound (glucuronide, sulphate) and a ring-hydroxylated metabolite of parent. There was no free parent compound or phenol in non-acid-hydrolysed urine. In acid-hydrolysed urine, 61% of the dose was identified as phenol and 13% as 1-phenoxy-2-propanol. Although the parent compound was stable to acid hydrolysis, some of the phenol in acid hydrolysed urine may have arisen from degradation of acid-labile metabolite(s) as well as hydrolysis of phenol conjugates. 4. Rapid oral absorption, metabolism and urinary excretion of 1-phenoxy-2-propanol in rats were similar to other propylene glycol ethers.     

Diethanolamine absorption,metabolism and disposition in rat and mouse following oral,intravenous and dermal administration

1. The disposition of [¹⁴C]diethanolamine (DEA) (1) was determined in rat after oral, i.v. and dermal administration, and in mouse after dermal administration. 2. Oral administration of DEA to rat was by gavage of 7?mg/kg doses once and after daily repeat dosing for up to 8 weeks. Oral doses were well absorbed but excreted very slowly. DEA accumulated to high concentrations in certain tissues, particularly liver and kidney. The steady-state of bioaccumulation was approached only after several weeks of repeat oral dosing, and the half-life of elimination was approximately 1 week. 3. DEA was slowly absorbed through the skin of rat (3-16% in 48?h) after application of 2-28?mg/kg doses. Dermal doses ranging from 8 to 80?mg/kg were more readily absorbed throughmouseskin(25-60%) in 48?h of exposure,withthe percent of the applied dose absorbed increasing with dose. 4. Single doses (oral or i.v.) of DEA were excreted slowly in urine (c. 22-25% in 48?h) predominantly as the parent compound. There was minimal conversion to CO₂ or volatile metabolites in breath. The profile of metabolites appearing in urine changed after several weeks of repeat oral administration, with significant amounts of N-methylDEA and more cationic metabolites appearing along with unchanged DEA.     

Oral absorption,metabolism and excretion of 1-phenoxy-2-propanol in rats

1. This study was designed to determine the absorption, metabolism and excretion of 1-phenoxy-2-propanol in Fischer 344 rats following oral administration in an effort to bridge data with other propylene glycol ethers.

2. Rats were administered a single oral dose of 10 or 100?mg?kg^{?1 14}C-1-phenoxy-2-propanol as a suspension in 0.5% methyl cellulose ether in water (w/w). Urine was collected at 0–12, 12–24 and 24–48?h and faeces at 0–24 and 24–48?h post-dosing and the radioactivity was determined. Urine samples were pooled by time point and dose level and analysed for metabolites using LC/ESI/MS and LC/ESI/MS/MS.

3. The administered doses were rapidly absorbed from the gastrointestinal tract and excreted. The major route of excretion was via the urine, accounting for 93 ± 5% of the low and 96 ± 3% of the high dose. Most of the urinary excretion of radioactivity occurred within 12?h after dosing; 85 ± 2% of the low and 90 ± 1% of the high dose. Total faecal excretion remained 4. Rapid oral absorption, metabolism and urinary excretion of 1-phenoxy-2-propanol in rats were similar to other propylene glycol ethers.     

The absorption, distribution, metabolism and elimination of bevirimat in rats

Bevirimat is the first drug in the class of maturation inhibitors, which treat HIV infection by disrupting the activity of HIV protease enzyme with a mechanism of action distinct from that of conventional protease inhibitors. The absorption, distribution, metabolism and elimination characteristics of single intravenous (25 mg/kg) and oral (25 mg/kg and 600 mg/kg) doses of 14C-bevirimat were studied in male Sprague Dawley and Long Evans rats. Pharmacokinetic and mass-balance studies revealed that bevirimat was cleared rapidly (within 12-24 h) after dosing, although plasma radioactivity was quantifiable up to 168 h. Radioactive metabolites of bevirimat were responsible for approximately 60-80% of plasma radioactivity. Systemically available bevirimat was predominantly (97%) excreted via bile in the faeces, with 相似文献   

The pharmacokinetics of pranoprofen in humans

The pharmacokinetics of pranoprofen, 2-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl) propionic acid (I) in humans were examined. 1-O-Acylglucuronide of I (II) and its isomer (III) were isolated from the human urine after oral administration of I. The stability of II was tested in order to establish the suitable conditions for the storage and handling of biological samples. Maximum stability of II was found at pH 3-4. Unchanged drugs, II and III were detected in the human plasma after oral administration of I. Plasma concentrations of these compounds reached the maximum at 1-2 h after the administration and thereafter decreased biphasically. From the urinary sample, 1-O-acylglucoside of I (IV) was detected in addition to unchanged drugs, II and III. Within 24 h after dosing, 1.3, 84.0, 7.0 and 0.6% of the dose were excreted as I, II, III and IV, respectively and the total urinary excretion amounted to 92.9% in term of unchanged drug.     

Urinary cyclophosphamide excretion in rats after intratracheal, dermal, oral and intravenous administration of cyclophosphamide

The urinary excretion of unmetabolized cyclophosphamide was studied in rats after intratracheal, dermal, oral and intravenous administration. Rats were given two doses of 1 mg kg-1 cyclophosphamide 48 h apart and urine was collected for 96 h after the first treatment. With the help of a phosphor-specific filter in a flame photometer attached to a gas chromatograph, low levels of cyclophosphamide were determined after derivatization with trifluoroacetic anhydride. Cumulative excretion as a percentage of dose ranged from 4.0 to 6.9 after the first dose and 2.7 to 5.5 after the second dose. The highest rate of excretion after the second administration was observed in rats treated intratracheally, while cumulative excretion was higher (6.9%) after the first than after the second (2.7%) intravenous treatment. The most prolonged excretion was observed after dermal application.     

Absorption,bioavailability, and metabolism of para-nonylphenol in the rat

To better interpret the responses to para-nonylphenol (NP; CASRN84852-15-3) in in vivo toxicity studies, including estrogen-like activity, the bioavailability of 14C-radiolabelled NP has been determined in male and female CD rats following either single oral doses of 10 and 100 mg/kg, single i.v. doses of 10 mg/kg, or repeated daily oral doses of 10 mg/kg for up to 14 d. Up to 80% of an oral dose of NP was rapidly absorbed, the remainder being excreted unchanged in faeces. Excretion was largely complete within 24 h of dosing. Following absorption, NP was metabolised in the liver, with the majority of the metabolites excreted in bile, mainly as glucuronide conjugates. Unchanged NP was found only in bile and urine from female rats given a 100 mg/kg dose, indicating that metabolic saturation occurred. Following repeated dosing, steady state was reached within 7 d. There was no evidence of significant accumulation into tissue compartments nor of a significant change in clearance or the metabolite profiles in urine. These data suggest that the estrogen-like effects observed in toxicity studies with female rats at oral NP doses of approximately 50 mg/kg/d and greater are a result of the increased bioavailability of NP which occurs following metabolic saturation.