Contribution of metabolites to the route- and time-dependent hepatic effects of di-(2-ethylhexyl)phthalate in the rat

The effects of exposure to the plasticizer di-(2-ethyl-hexyl)phthalate (DEHP) and its two primary products of presystemic de-esterification, mono-(2-ethylhexyl)phthalate and 2-ethyl-hexanol, on hepatic microsomal oxidation were investigated in rats. The metabolic clearance of antipyrine was utilized as an in vivo measure of the activity of the hepatic microsomal oxidative enzyme system. Subchronic (7 days) p.o. treatment of rats with DEHP, mono-(2-ethylhexyl)phthalate or 2-ethylhexanol produced a substantial increase in both wet liver weight and antipyrine clearance relative to corn oil-treated controls. In contrast, i.p. administration of DEHP resulted in a minor but statistically significant stimulation of liver growth and antipyrine metabolism. Whereas chronic administration of the plasticizer or its metabolites produced apparent induction of hepatic microsomal oxidative enzymes, administration of a single dose of each compound was associated with immediate inhibition of the metabolism of antipyrine. The present data suggest that the products of deesterification of DEHP are primarily responsible for the stimulation of hepatic metabolism observed after long-term exposure to the plasticizer, whereas the parent compound and both metabolites have the potential to produce acute inhibition of hepatic microsomal oxidation in vivo.     

Diltiazem treatment impairs hepatic drug oxidation: studies of antipyrine

To evaluate the effect of diltiazem on antipyrine disposition and metabolism, 10 healthy subjects received 1.2 gm antipyrine on two occasions, once while taking no other medications and once during long-term oral diltiazem, 120 mg three times daily. Antipyrine oral clearance was markedly reduced from (mean +/- SEM) 41.7 +/- 4.1 to 29.9 +/- 2.8 ml/min (P less than 0.01) during diltiazem treatment, resulting in prolongation of antipyrine elimination t1/2 from 12.2 +/- 1.0 to 16.7 +/- 1.3 hours (P less than 0.01), with no change in apparent volume of distribution (42.1 +/- 4.0 vs. 41.3 +/- 3.1 L; not significant). Measurement of urinary antipyrine and metabolites excreted in the urine during 24 hours after the antipyrine dose (percent of total 24-hour excretion) showed increased antipyrine (4.4% +/- 1.0% vs. 7.8% +/- 1.6%; P less than 0.01) during diltiazem treatment with no significant change in proportion of 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine excretion between trials. Chronic oral diltiazem in therapeutic doses markedly impairs antipyrine oxidation. Diltiazem may therefore impair the clearance of other coadministered drugs that undergo hepatic oxidation.     

The Effects of Lansoprazole on the Disposition of Antipyrine and Indocyanine Green in Normal Human Subjects

This study was designed to evaluate the potential effects of acute and chronic daily oral doses of lansoprazole (60 mg) on the disposition of antipyrine, an almost completely metabolized low hepatic extraction compound, and indocyanine green, a hepatically secreted compound with high extraction ratio. The study utilized a randomized, placebo-controlled, double-blind, two-period crossover design. Sixteen of 18 subjects completed all phases of the study. Both antipyrine (10 mg kg(minus sign1)) and indocyanine green (0.5 mg kg(minus sign1)) were administered as single intravenous bolus doses on Days 1 and 7 of lansoprazole or placebo dosing. Acute exposure to lansoprazole had no statistically significant effects on the plasma pharmacokinetics of indocyanine green or antipyrine. After the seventh dose, there was a small but statistically significant reductions in indocyanine green total body clearance (CL), and elimination rate constant of 10.6% and 8%, respectively. Additionally, a small statistically significant reduction (8.6%) in antipyrine volume of distribution was detected. No other plasma antipyrine pharmacokinetic parameters were changed with concomitant lansoprazole administration. About a 12% increase in the recovery of one of the major antipyrine urine metabolites (NORA) was detected. Overall, this study demonstrates little or no effect of lansoprazole on the pharmacokinetics of antipyrine and indocyanine green.     

Evidence of significant absorption of antipyrine from urinary bladder of rats.

We examined the in vivo absorption and pharmacokinetics of antipyrine, a base that is unionized at physiologic pH, from the urinary bladder of adult female Fischer rats. The clearance of an i.v. dose of antipyrine (25 mg/kg) was found to vary considerably between animals, which is consistent with the literature data. Therefore, it was necessary to simultaneously determine drug clearance and bladder absorption in the same animal. This was accomplished by giving concomitantly an i.v. dose of [14C]antipyrine (2.5 muCi, about 90 micrograms/kg) via a jugular vein catheter and an intravesical dose of unlabeled antipyrine (33 mg/kg) via a urethral catheter. Unlabeled antipyrine was detected in plasma, indicating the absorption of antipyrine into systemic circulation. The bioavailability of the intravesical dose was calculated using the clearance of [14C]antipyrine and the plasma concentrations of unlabeled antipyrine. The intravesical dose was withdrawn through the urethral catheter after 90 min. To minimize mechanical manipulation and damage, the bladder was not rinsed. This may have caused the incomplete recovery of the unabsorbed dose; about 65 +/- 18% (mean +/- S.D.) of the dose was recovered at 90 min. Maximal plasma concentrations were achieved at 10 to 48 min after removal of the intravesical dose, which is consistent with a continued absorption of the residual dose. The intravesical bioavailability was variable between animals, with an average of 11.6 +/- 6.4% (mean +/- S.D.; range, 4.1-19.2%). In conclusion, these data demonstrate that neutral drugs such as antipyrine are absorbed from the bladder, that the extent of absorption is variable and that the urinary bladder may be a site of significant re-entry of drugs into the systemic circulation.     

Studies on the disposition of antipyrine, aminopyrine, and phenacetin using plasma, saliva, and urine.

In normal male subjects, the half-lives of antipyrine, aminopyrine, or phenacetin were not significantly different from the half-lives of each drug in saliva. Apparent volumes of distribution (aVd) in plasma and saliva differed by the extent to which each drug has been reported to bind to plasma proteins. Thus, the aVd of antipyrine in plasma and saliva was similar; there were significant differences in aVd for aminopyrine; even greater differences were observed for penacetin. The expression (see article) equals the fraction of the drug bound to plasma proteins. Rates of appearance in the urine of metabolites of antipyrine and aminopyrine were measured. General equations were used to show the relationship between half-life for elimination of the parent drug from the body and rate of excretion of metabolites. There were significant correlations between the half-life for elimination of antipyrine from the body and the half-life for production of 4-OH antipyrine (r equal 0.90), as well as between the plasma half-life of aminopyrine and the half-life of 4-aminoantipyrine (r equal 0.95). No significant correlation was observed in the same individual between the plasma half-lives of antipyrine and phenacetin (r equal 0.05, p greater than 0.05), of aminopyrine and phenacetin (r equal 0.11, p greater than 0.05), or of antipyrine and aminopyrine (r equal 0.50, p greater than 0.05).     

Enterohepatic physiology of 1,25-dihydroxyvitamin D3.

After intravenous administration of radiolabeled 1,25-dihydroxyvitamin D3 to rats, approximately 25% of the administered radioactivity appeared in the bile within 24 h. Instillation of the biliary radioactivity into the duodena of other rats was followed by recovery of 15% of the radioactivity in newly secreted bile within 24 h. The process by which products of 1,25-dihydroxyvitamin D3 were excreted in bile was not saturable in the dose range tested (0.275-650 ng). The metabolites of 1,25-dihydroxyvitamin D3 present in bile were found to be much more polar than 1,25-dihydroxyvitamin D3 and were resolved into three fractions on high performance liquid chromatography. 60% of the radioactivity present in bile was retained selectively by DEAE-cellulose; the radioactive material could be eluted from the gel at a low pH or at high salt concentrations. When bile containing the radiolabeled metabolites was incubated at 37 degrees C and pH 5 with beta-glucuronidase, there was an increase in the amount of radioactivity comigrating with 1,25-dihydroxyvitamin D3. Treatment of the products of radiolabeled 1,25-dihydroxyvitamin D3 in bile with diazomethane, an agent which converts acids into methyl esters, transformed one of the metabolites into a less polar compound. These results demonstrate that there is a quantitatively important enterophepatic circulation of the products of 1,25-dihydroxyvitamin D3 in the rat.     

Studies on digitalis. XII. Kinetic pattern of digitoxin metabolism in patients with biliary fistulas.

The metabolic pattern of cardioactive and inactive, conjugated metabolites (a maximum of 24 substances) was studied after a single intravenous dose of 0.6 mg digitoxin in two female patients (aged 72 and 62 yr) with biliary fistulas. Bile and urine were collected every twenty-fourth hour and the 1-, 2-, 4-, 6-, and 8-day samples were analyzed. With the methods used, enzymatic cleavage of conjugation bonds, TLC (thin-layer chromatography), and a modified 86Rb method, the products of hydroxylation, hydrolysis, and conjugation could be separated. All cardioactive metabolites were present in bile and all were conjugated. Unchanged digitoxin was the main substance excreted. Hydrolyzed and conjugated metabolites formed a greater part of the substances excreted in bile than hydroxylated metabolites. The metabolic pattern in bile did not change much with time. The metabolic pattern in urine showed no close resemblance to that in bile. Hydroxylated, hydrolyzed, and conjugated metabolites were equally predominant in urine. Interruption of the enterohepatic circulation by T tube drainage not only changed the elimination kinetics of digitoxin but also changed the pattern of digitoxin metabolites in urine.     

The fate of diastereomeric glutathione conjugates of alpha-bromoisovalerylurea in blood in the rat in vivo and in the perfused liver. Stereoselectivity in biliary and urinary excretion

The mixture of the two diastereomeric glutathione (GSH) conjugates of alpha-bromoisovalerylurea, (RS)-IU-G, was administered i.v. to anesthetized rats. Bile and urine were collected for 6 hr. Some 70 to 75% was recovered in urine as mercapturates. The half-lives of the urinary excretion were the same for the two mercapturates: 18 min and approximately 130 min, respectively, for the rapid and the slow phase. In bile only 1.5% of the dose of (R) and (S)-IU-G was found; two unidentified metabolites were also found. In rats with ligated kidneys, 4% of the dose of each glutathione conjugate was excreted in bile. Again, the two unidentified metabolites were found. In the isolated recirculating liver perfusion experiments, 1.4% of the administered GSH conjugates was found in bile. The concentration of the GSH conjugates in the perfusion medium remained constant and no other metabolites were formed. When (RS)-alpha-bromoisovalerylurea itself was added to the perfusate, the GSH conjugates in bile increased rapidly. The results show that the GSH conjugate in blood is little excreted in bile due to a slow uptake of the conjugate by the liver. The diastereomeric GSH conjugates show no stereoselectivity in their pharmacokinetics, indicating that the rate limiting step in this process is not stereoselective.     

Quinine-induced alterations in drug disposition.

In normal volunteers, chronic quinine administration shortened plasma antipyrine half-life and significantly increased the intraindividual correlation between the disposition of quinine and antipyrine. Decreased plasma antipyrine half-life appears to be due to a quinine-induced enhancement of antipyrine metabolism. A dose-dependent prolongation of plasma quinine half-life was observed and attributed primarily to an increased apparent volume of distribution of quinine, although our data did not permit separation of an effect on quinine metabolism from an effect on quinine distribution between the peripheral and central compartments. Plasma protein binding of quinine was similar at both the low and high doses of quinine. Studies in dogs given quinine intravenously revealed a biphasic plasma decay curve compatible with a 2-compartment open model for quinine disposition. Dose dependence of plasma quinine half-life in the dog after intravenous quinine eliminated altered gastrointestinal absorption of quinine as a cause for the dose dependence of plasma quinine half-life. These studies illustrate the importance of such conditions as dose and time of administration in determining the type and magnitude of interaction observed between drugs.     

Disposition of valproic acid in the rat: dose-dependent metabolism, distribution, enterohepatic recirculation and choleretic effect.

A specific gas chromatographic assay has been developed for measurement of valproic acid (VPA) and its major conjugated metabolites. In rats given single intravenous doses, the decline in blood concentration of VPA was dose-dependent and followed first-order kinetics only at the lowest dose. The time required for the maximum concentration of VPA, after completion of the brief distribution phase, to decline by 50% was 11.7, 41 and 125 min at doses of 15, 150 and 600 mg of NaVPA per kg, respectively. A secondary increase in drug concentration, abolished by exteriorization of the bile, was observed in all intact rats with all doses. Some 45 to 55% of the dose appeared in the bile in 5 hr as VPA glucuronide. Urinary excretion of VPA glucuronide in intact animals accounted for 23 and 51% of the 15 and 150 mg/kg doses, respectively. Tissue distribution studies in rats sacrificed 20 and 90 min after dosage with [14C] NaVPA (150 mg/kg) showed that the drug concentration was highest in blood, moderate in liver, kidney, heart and lung and low in brain, fat, testis and skeletal muscle. During this interval the drug concentration declined in all tissues, whereas the total conjugated metabolites in the small intestine increased from 7 to 28% of the administered dose. The large intestine contained 30 times as much free drug as conjugate. Reabsorption of free VPA, released by hydrolysis of conjugate in the large bowel, accounted for the secondary rise in concentration of VPA observed in blood after single doses. The major urinary metabolites, VPA-glucuronide and 2-n-propylgutaric acid, were identified by gas chromatography/chemical ionization mass spectrometry. Sodium VPA caused a dose-dependent stimulation of bile flow, the magnitude and duration of which closely followed the blood concentration of VPA.     

Excretion of doxifluridine catabolites in human bile assessed by 19F NMR spectrometry

The biliary excretion of doxifluridine (5'dFUR) catabolites was studied in a patient with external bile derivation using 19F NMR spectrometry, alpha-fluoro-beta-alanine (FBAL) and fluoride ion were detected in patient's bile samples but represented only about 10% of the excreted fluorinated metabolites. The major biliary metabolite (congruent to 90%), whose structure is still unknown, is a conjugate of FBAL. The cumulative biliary excretion of 5'dFUR fluorinated metabolites was low and represented 0.8% of the injected dose.     

The effect of antipyrine and rifampin on the metabolism of diazepam

The elimination of diazepam and antipyrine and the urinary excretion of their metabolites were investigated in 21 healthy volunteers before and after 7 days of administration of antipyrine, 1200 mg, and rifampin, 600 or 1200 mg. After administration of antipyrine and rifampin in two doses, antipyrine total body clearance increased by 53% and 60% or 98%, respectively. The clearance to metabolite showed a preferential induction of the norantipyrine pathway with different proportions after antipyrine and rifampin; rifampin, 1200 mg, also enhanced the 4-hydroxyantipyrine pathway further. After antipyrine, diazepam total body clearance was increased by 102%, affecting all metabolic pathways to a similar extent. After rifampin in both doses, diazepam total body clearance rose equally to 300% and desmethyl- and 3-hydroxydiazepam metabolic clearance to 400%. Therefore rifampin preferentially affects norantipyrine or desmethyl- and 3-hydroxydiazepam metabolic formation, suggesting induction of different (iso)zymes of cytochrome P-450.     

Substrate-selective inhibition by verapamil and diltiazem: differential disposition of antipyrine and theophylline in humans

Antipyrine and theophylline disposition was studied in healthy volunteer subjects in the control state while the subjects were taking verapamil (120 mg) orally four times daily or diltiazem (120 mg) orally three times daily. Both verapamil and diltiazem treatment decreased antipyrine clearance (verapamil, 42.5 to 30.1 ml/min, P less than .01; diltiazem, 41.7 to 29.9 ml/min, P less than .01), resulting in prolonged antipyrine half-life with no change in distribution volume. Fractional clearances of urinary antipyrine metabolites 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, norantipyrine and unchanged antipyrine were differentially changed by verapamil and diltiazem treatment. With verapamil treatment, 4-hydroxyantipyrine and norantipyrine fractional clearances were markedly decreased, with 3-hydroxymethylantipyrine slightly decreased and antipyrine unchanged. With diltiazem treatment, 3-hydroxymethylantipyrine was decreased, with no significant change in 4-hydroxyantipyrine, norantipyrine or antipyrine. Effect on theophylline clearance differed between verapamil treatment (57.7 to 44.7 ml/min; P less than .01) and diltiazem treatment (50.2 to 49.4 ml/min; N.S.), with prolonged theophylline half-life during verapamil treatment, no change in half-life during diltiazem treatment and distribution volume unchanged by either treatment. Fractional clearances of urinary theophylline metabolites 3-methylxanthine, 1-methyluricacid, 1,3-dimethyluricacid and unchanged theophylline reflected the differential plasma theophylline clearance. During verapamil treatment, 3-methylxanthine and 1,3-dimethyluricacid fractional clearances were decreased, with no change in 1-methyluricacid or theophylline. During diltiazem treatment, 1,3-dimethyluricacid fractional clearance was slightly decreased, and 3-methylxanthine, 1-methyluricacid and theophylline were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

alpha-Bromoisovalerylurea as model substrate for studies on pharmacokinetics of glutathione conjugation in the rat. II. Pharmacokinetics and stereoselectivity of metabolism and excretion in vivo and in the perfused liver

The hypnotic drug alpha-bromoisovalerylurea (BIU) has been studied in the rat with respect to its potential use as model substrate to investigate the pharmacokinetics of glutathione conjugation in vivo. The major metabolites of racemic BIU are the diastereomeric glutathione conjugates (bile) and mercapturates (urine). BIU was metabolized mainly by glutathione conjugation: after i.v. administration of [14C]BIU to freely moving rats, 89% of the dose was recovered in urine within 24 hr, mostly as mercapturates. The rate-limiting step in the clearance of BIU from blood most likely is glutathione conjugation as it was shown that rate-limitation is not due to flow-limited clearance in the liver (the initial extraction ratio of BIU in the perfused liver preparation was low: hepatic extraction ratio = 0.23), protein binding (60% was unbound in plasma) or enzyme saturation (linear pharmacokinetics in the dose range studied: 22-270 mumol/kg). Water solubility of BIU was sufficient to allow its i.v. administration, whereas the absence of toxic effects enables animal as well as human studies. Thus, BIU is a promising model substrate for studies of glutathione conjugation in vivo. In pentobarbital-anesthetized rats with a bile duct catheter, equal amounts of metabolites were excreted in bile (almost exclusively as the two diastereomeric BIU glutathione conjugates) and urine (mostly as the two diastereomeric mercapturates). Based on similar experiments with bile duct-ligated rats, it was concluded that the appearance of the mercapturates in urine could also occur without biliary excretion and subsequent gut metabolism of the BIU glutathione conjugates. The ability of the liver to metabolize BIU was studied in a hemoglobin-free, recirculating liver perfusion system. Of the recovered radioactivity 40% was excreted in bile within 2 hr, almost exclusively in the form of the two BIU glutathione conjugates. Also, glutathione conjugates were found in the perfusate (16% of the radioactivity present in the perfusate after 2 hr). A distinct stereoselectivity was observed in the metabolite excretion rates. The excretion half-lives of the two diastereomeric glutathione conjugates in bile differed 2- to 3-fold, both in anesthetized rats and in the perfused liver preparation. A similar difference in excretion half-lives was found for the urinary excretion of the diastereomeric mercapturates. Thus, BIU can be used to investigate in vivo the stereoselectivity of glutathione conjugation.     

Genetic control of the phenobarbital-induced shortening of plasma antipyrine half-lives in man

The mean half-life of antipyrine in the plasma of four sets of identical and four sets of fraternal twins after a single oral dose of 16 mg/kg of antipyrine was 12.7 +/-(SD) 3.3 hr. After 2 wk on sodium phenobarbital (2 mg/kg daily) the half-life of antipyrine in the plasma of these twins was reduced to 8.0 +/-(SD) 1.5 hr. Shortening of the plasma antipyrine half-life occurred in all but one of these 16 normal, adult volunteers, but there was considerable variation in the extent of reduction which ranged from 0 to 69%. Phenobarbital administration decreased individual variations in antipyrine metabolism as indicated by the smaller standard deviation of the plasma antipyrine half-lives after phenobarbital than observed initially and by the narrowed range of variation in plasma antipyrine half-lives from 2.8-fold initially to 1.8-fold after phenobarbital. These results suggest that some inducing agents may be used to minimize individual variations in drug metabolism where such variations create therapeutic problems by exposing patients who slowly metabolize certain drugs to toxicity and other patients who rapidly metabolize some drugs to undertreatment.During the course of phenobarbital administration blood levels were determined. Phenobarbital blood levels correlated neither with the final values for plasma antipyrine half-lives nor with the per cent reduction in plasma antipyrine half-life produced by phenobarbital treatment. There was a direct relationship between initial antipyrine half-lives and the per cent shortening of antipyrine half-life produced by phenobarbital administration: the shorter the initial antipyrine half-life, the less the reduction caused by phenobarbital treatment. Larger intrapair variances in fraternal than in identical twins indicate genetic, rather than environmental, control of phenobarbital-induced alterations in plasma antipyrine half-life.     

Disposition of [14C]aztreonam in rats, dogs, and monkeys

[14C]aztreonam was administered as single 25-mg/kg doses to dogs (intravenously and subcutaneously) and monkeys (intramuscularly and intravenously) and as single 50-mg/kg doses (intramuscularly and intravenously) to rats. In rats and dogs, radioactive moieties were excreted primarily in urine; in monkeys, they were excreted about equally in urine and feces. Unchanged aztreonam accounted for 77 to 86% of the radioactivity excreted in the urine of rats, dogs, and monkeys; SQ 26,992, the metabolite resulting from hydrolysis of the monobactam ring, accounted for 10 to 15%; and minor, unidentified metabolites accounted for the remainder. In rats with cannulated bile ducts, about 15% of an intramuscular dose was excreted in bile in 24 h; the bile contained a greater percentage of metabolites than that found in urine. In dogs, the apparent elimination half-life of aztreonam in serum was 0.7 h after intravenous administration. Aztreonam and SQ 26,992 accounted for most of the radioactivity in the sera of dogs and monkeys. Serum protein binding of aztreonam and its metabolites ranged from 28 to 35% in dogs and from 49 to 59% in monkeys. In the three species studied, aztreonam was most extensively metabolized in monkeys; SQ 26,992 and other minor metabolites from monkey urine were tested and found to be devoid of any significant antimicrobial activity.     

The effect of propylene glycol on antipyrine clearance in humans

To evaluate the potential interaction of propylene glycol on hepatic drug oxidation, antipyrine disposition was measured in 10 healthy subjects who received 1.2 gm antipyrine alone on one occasion and 1.2 gm antipyrine with propylene glycol on a second occasion. Propylene glycol was given as a 5 ml dose every 4 hours during the 48 hours of the study. Propylene glycol had no effect on antipyrine half life (11.7 hours control vs. 12.1 hours treatment), clearance (42.6 vs. 39.2 ml/min), or volume of distribution (42.1 vs 41.9 L). At a dose similar to that used as a vehicle for administration of other drugs, propylene glycol had no significant effect on antipyrine clearance in humans.     

Antipyrine elimination and hepatic microsomal enzyme activity in patients with liver disease

Induction of hepatic monooxygenases reflected by 7-ethoxycoumarin O-deethylase has been proposed to be associated with the initiation of liver damage. This study investigated a possible correlation between 7-ethoxycoumarin O-deethylase, reduced nicotinamide adenine dinucleotide phosphate cytochrome c reductase and benzypyrene hydroxylase activity in liver biopsy specimens of 31 patients with liver disease and antipyrine elimination, an in vivo parameter of hepatic monooxygenase activity. No correlation was found between the enzyme activities and antipyrine clearance or half-life. When microsomal enzyme activities were compared with the formation rate of 4-hydroxyantipyrine, 3-methylhydroxyantipyrine, and norantipyrine, a correlation was found only between benzo[alpha]pyrene hydroxylase and 3-methylhydroxyantipyrine (r = 0.89; p less than 0.0005). There was also a correlation between 7-ethoxycoumarin O-deethylase and reduced nicotinamide adenine dinucleotide phosphate cytochrome c reductase (0.56; p less than 0.05). Our data suggest that antipyrine elimination is not related to 7-ethoxycoumarin O-deethylase activity in liver disease. However, the formation rate of antipyrine metabolites, rather than antipyrine half-life and clearance, may correlate with the activity of certain microsomal enzymes.     

Species variation in toxication and detoxication of acetaminophen in vivo: a comparative study of biliary and urinary excretion of acetaminophen metabolites

Acetaminophen (AA) is converted to a toxic electrophile that may subsequently form a glutathione conjugate (AA-GS). In addition to the toxication pathway metabolites, which consist of AA-GS and its hydrolysis products (AA-cysteinylglycine, AA-cysteine and AA-mercapturate), detoxication pathway metabolites, such as AA-glucuronide and AA-sulfate, are also formed. In order to evaluate the role of these opposing pathways in the reported species variations in susceptibility to AA-induced liver injury, AA was administered to hamsters and mice, species which are susceptible to AA-induced liver injury, and to rats, rabbits and guinea pigs, species which are relatively resistant to AA-induced liver injury, and the biliary and urinary excretion of AA metabolites were measured simultaneously for 2 hr after administration of AA (1 mmol/kg i.v.). The AA-susceptible species excreted 27 to 42% of the dose as toxication pathway metabolites, whereas the resistant species excreted only 5 to 7% of the dose as toxication pathway metabolites. Most of the toxication pathway metabolites appeared in bile, where their composition reflected hepatic gamma-glutamyltranspeptidase activity; hamsters and mice (low gamma-glutamyltranspeptidase activity) excreted mainly AA-GS, whereas bile from rabbits and guinea pigs (high gamma-glutamyltranspeptidase activity) contained significant amounts of AA-GS hydrolysis products. Thus, the biliary excretion of AA-GS and its hydrolysis products may be used as an index of toxic activation of AA. The excretion of the detoxication pathway metabolites (AA-glucuronide and AA-sulfate) was 74, 62, 41, 27 and 12% of the dose in guinea pigs, rats, mice, rabbits and hamsters respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolism of Vitamin D3-3H in Human Subjects: Distribution in Blood, Bile, Feces, and Urine

Vitamin D(3)-(3)H has been administered intravenously to seven normal subjects, three patients with biliary fistulas, and four patients with cirrhosis. Plasma D(3)-(3)H half-times normally ranged from 20 to 30 hours. in vivo evidence that a metabolic transformation of vitamin D occurs was obtained, and a polar biologically active vitamin D metabolite was isolated from plasma.Urinary radioactivity averaged 2.4% of the administered dose for the 48-hour period after infusion, and all the excreted radioactivity represented chemically altered metabolites of vitamin D. The metabolites in urine were mainly water-soluble, with 26% in conjugated form.From 3 to 6% of the injected radioactivity was excreted in the bile of subjects with T-tube drainage and 5% in the feces of patients having no T-tube. The pattern of fecal and biliary radioactivity suggested that the passage of vitamin D and its metabolites from bile into the intestine represents an essential stage for the fecal excretion of vitamin D metabolites in man.Abnormally slow plasma disappearance of vitamin D(3)-(3)H in patients with cirrhosis was associated with a significant decrease in the quantity and rate of glucuronide metabolite excretion in the urine.