Species differences in the metabolic conjugation of clofibric acid and clofibrate in laboratory animals and man

The urinary metabolites of single doses of clofibric acid (p-chlorophenoxyisobutyric acid), and its ethyl ester, clofibrate, have been investigated in rat, guinea pig, rabbit, dog, cat, ferret, and human volunteers. Human volunteers, rodents, and rabbits given clofibric acid excreted 60-90% of the 14C dose in the urine in 24 hr, and the only metabolite found was the ester glucuronide of clofibric acid, together with small amounts of the unchanged acid. In the dog, cat, and ferret, however, urinary excretion of 14C was much slower (23-39% of dose in 24 hr) and these species all formed the taurine conjugate of clofibric acid, excreted together with the unchanged acid. The ester glucuronide was found in the urine of dog and ferret but not cat. The fate of clofibrate, the ethyl ester of clofibric acid, in rat, guinea pig, rabbit, and man was similar to that of the parent acid. The characterization of the glucuronic acid and taurine conjugates of clofibric acid is described.     

Excretion and metabolism of recainam, a new anti-arrhythmic drug, in laboratory animals and humans

The metabolic disposition of recainam, an antiarrhythmic drug, was compared in mice, rats, dogs, rhesus monkeys, and humans. Following oral administration of [14C]recainam-HCl, radioactivity was excreted predominantly in the urine of all species except the rat. Metabolite profiles were determined in excreta by HPLC comparisons with synthetic standards. In rodents and rhesus monkeys, urinary excretion of unchanged recainam accounted for 23-36% of the iv dose and 3-7% of the oral dose. Aside from quantitative differences attributable to presystemic biotransformation, metabolite profiles were qualitatively similar following oral or iv administration to rodents and rhesus monkeys. Recainam was extensively metabolized in all species except humans. In human subjects, 84% of the urinary radioactivity corresponded to parent drug. The major metabolites in mouse and rat urine and rat feces were m- and p-hydroxyrecainam. Desisopropylrecainam and dimethylphenylaminocarboxylamino propionic acid were the predominant metabolites in dog and rhesus monkey urine. Small amounts of desisopropylrecainam and p-hydroxyrecainam were excreted in human urine. Selective enzymatic hydrolysis revealed that the hydroxylated metabolites were conjugated to varying degrees among species. Conjugated metabolites were not present in rat urine or feces, while conjugates were detected in mouse, dog, and monkey urine. Structural confirmation of the dog urinary metabolites was accomplished by mass spectral analysis. The low extent of metabolism of recainam in humans suggests that there will not be wide variations between dose and plasma concentrations.     

The fate of lysergic acid DI[14C]ethylamide ([14C]LSD) in the rat, guinea pig and rhesus monkey and of [14C]iso-LSD in rat.

The qualitative and quantitative aspects of the metabolism and elimination of [¹⁴C]LSD in the rat, guinea pig and rhesus monkey have been investigated. Rats given an i.p. dose (1 mg/kg) excreted 73% of the ¹⁴C in the faeces, 16% in the urine and 3.4% in the expired air as ¹⁴CO₂ in 96 hr. Guinea pigs similarly dosed, excreted 40% in the faeces, 28% (urine) and 18% (expired ¹⁴CO₂) in 96 hr. Rhesus monkeys (0.15 mg/kg i.m.) eliminated 39% of the ¹⁴C in the urine and 23% in the faeces in 96 hr.Extensive biliary excretion of [¹⁴C]LSD occurred in both the rat and guinea pig. Bile duct-cannulated rats excreted 68% of an i.v. dose (1.33 mg/kg) in the bile in 5 hr and the guinea pig 52% in 6 hr.[¹⁴C]LSD is almost completely metabolised by all three species and little unchanged drug is excreted. The metabolites identified were 13- and 14-hydroxy-LSD and their glucuronic acid conjugates. 2-oxo-LSD. de-ethyl LSD and a naphthostyril derivative. There occur, however, important species differences in the nature and amounts of the various metabolites. In the rat and guinea pig the major metabolites were the glucuronic acid conjugates of 13- and 14-hydroxy-LSD which were found in both urine and bile. The guinea pig excreted significant amounts of 2-oxo-LSD in urine and bile. De-ethyl LSD was a minor urinary metabolite in both species.The metabolism of LSD appeared to be more complicated in the rhesus monkey. The urine contained at least nine metabolites of which four were identified as follows: 13- and 14-hydroxy-LSD (as glucuronic acid conjugates) de-ethyl LSD and a naphthostyril derivative. Unlike the rat and guinea pig the glucuronic acid conjugates of 13- and 14-hydroxy-LSD were only present in small amounts. Of the remaining five unidentified metabolites, three were major.The biliary metabolites of [¹⁴C]iso-LSD in the rat have been studied and been shown to be similar to those produced from [¹⁴C]LSD, namely 13- and 14-hydroxy-iso-LSD and their glucuronic acid conjugates and 2-oxo-iso-LSD.     

Urinary glucuronide excretion of fenofibric and clofibric acid glucuronides in man. Is it polymorphic?

Summary The possible polymorphism of the glucuronidation reaction in man has been investigated using two hypolipidaemic compounds, fenofibrate and clofibrate, as the test probes.The formation of fenofibryl and clofibryl glucuronides was identified by their susceptibility to hydrolyses by -glucuronidase. The urinary excretion of the glucuronides was measured in 72 healthy volunteers after a single dose of fenofibrate, and in 104 subjects given a single dose of clofibric acid.Fenofibrate was excreted at a lower rate than clofibrate, since 13.94% and 26.55% of the doses of fenofibrate and clofibrate respectively, were recovered in urine in 8 h. Correlation analysis indicated that sex and body mass index significantly influenced the formation of fenofibryl glucuronide, whereas age and oral contraceptives affected the excretion of clofibryl acid glucuronide. The 8-hour urinary excretion patterns of clofibryl glucuronide and of clofibric acid presented a Gaussian distribution, whereas those of fenofibryl glucuronide and fenofibric acid showed 2 populations. When the metabolic ratio free fenofibric acid/glucuronide was considered, 84.7% of subjects presented the ratio 0.147, and 15.3% had the 3-fold higher ratio of 0.421.The study has shown, in the human population studied, that the glucuronidation of fenofibric acid but not that of clofibric acid may present a polymorphism.     

Fenofibrate: Metabolism and Species Differences for Peroxisome Proliferation in Cultured Hepatocytes

The hypolipidemic agent fenofibrate, which is a peroxisome proliferatorin some rodents in vivo, was studied in cultured hepatocytesfor its metabolism and effects on enzymatic induction relatedto peroxisome proliferation so as to lead to a better understandingof the mechanisms involved in peroxisome proliferation. [¹⁴C]Fenofibratewas completely metabolized within 24 hr by primary culturesof rat hepatocytes and the metabolic pattern corresponded tothat found in vivo. The main products were fenofibric acid andits glucuronidated form. Carbonyl reduction of fenofibric acidalso occurred. The metabolic pattern of [¹⁴C]Fenofibric acidwas nearly the same as that of fenofibrate. Fenofibrate, fenofibricacid, and its reduced metabolite all induced peroxisomal (cyanide-insensitive)palmitoyl-CoA oxidation activity (PCOA) in rat hepatocytes,whereas derivatives lacking the carboxyl group were nearly inactive.The known species differences with respect to sensitivity toperoxisome proliferators in vivo was mirrored in cultured cellsbecause fenofibric acid did not induce peroxisomal PCOA in primaryculture of guinea pig hepatocytes nor in the human hepatomacell line HepG2. The mechanistic association between the inductionof CYP4A1-catalyzed lauric acid -hydroxylase (LAH) activityand peroxisomal PCOA induction was investigated. Fenofibricacid concomitantly Induced LAH activity and peroxisomal PCOAin rat hepatocytes. Specific inhibition of LAH activity (–52%)by 10-undecynoic acid partially prevented induction of peroxisomalPCOA (–32%). The putative role of dicarboxylic acids,the oxidation product of -hydroxymonocarboxylic acids, in PCOAinduction was further substantiated by the observed inductionof peroxisomal PCOA by 1-12-dodecanedioic acid. We concludethat (1) fenofibric acid is the possible proximate peroxisomeproliferator of fenofibrate in rat hepatocytes, (2) culturedhepatocytes reflect in vivo sensitivity to fenofibrate withrespect to peroxisome proliferation, and (3) there is some evidencethat the catalytic activity of the CYP4A1 enzyme mediates, atleast in part, peroxisomal PCOA induction.     

Lack of pharmacokinetic interaction of colestipol and fenofibrate in volunteers

Summary The possibility of a pharmacokinetic interaction between two hypolipidemic drugs, colestipol, an ion exchange resin, and fenofibrate, a phenoxyacid derivative, was studied in 6 male volunteers. The investigation followed a four-step protocol during 18 days, and relied on determination of plasma and urinary levels of fenofibric acid, the active metabolite of fenofibrate. The kinetics of a single dose of fenofibrate 300 mg was established over 3 days. Thereafter, from Days 4 to 9 fenofibrate was given daily as 200 mg in the morning and 100 mg in the evening; the plasma fenofibric acid level reached about 10 µg/ml. From Days 9 to 15 the same dose of fenofibrate was administered together with colestipol 10 g in the morning and 5 g in the evening. Plasma fenofibric acid concentrations remained unchanged and the 24 h urinary excretion of fenofibric acid did not fall. On Day 15, a last single dose of fenofibrate 300 mg was given with colestipol 15 g. The pharmacokinetic pattern of fenofibric acid on Days 15 to 18 did not differ significantly from that found previously (Days 1 to 3). From these results, it is likely that there is no pharmacokinetic interaction between the two hypolipidemic drugs.     

Studies on the metabolism of arylacetic acids. 6. Comparative metabolic conjugation of 1- and 2-naphthylacetic acids in the guinea pig, mouse, hamster and gerbil

The patterns of metabolic conjugation of the isomeric 1- and 2-naphthylacetic acids have been compared in guinea pig, mouse, hamster and gerbil. Equimolar doses of [carboxy-14C]1- and 2-naphthylacetic acids were given to these species by i.p. injection, their urine collected and urinary metabolites examined by t.l.c. before and after treatment with beta-glucuronidase or mild alkali. 2. Urinary excretion of 14C following administration of 14C-1-naphthylacetic acid was 76-93% of dose in 72 h, the bulk being eliminated in 24 h. Urinary metabolites comprised 1-naphthylacetic-glycine and -glucuronide together with the unchanged acid. 3. Following administration of 14C-2-naphthylacetic acid, some 68-94% of the 14C dose was recovered in the urine in 72 h, with the majority in the 0-24 h urine. All four species excreted 2-naphthylacetyl-glucuronide and -glycine: additionally, 2-naphthylacetyl-taurine was excreted by mouse, gerbil and hamster and the glutamine conjugate was also present in hamster urine.     

Metabolic disposition of isoxicam in man, monkey, dog, and rat

Isoxicam a new nonsteroidal antiinflammatory agent was radiolabeled with 14C at the 3-position of the benzothiazine nucleus. It was well absorbed following peroral administration to man, monkey, dog, and rat, reaching peak plasma concentrations in 4-8 hr. Over 90% of the plasma radioactivity was due to unchanged drug. Plasma elimination half-lives were 22-45 hr in man and 49-53 hr in dogs and 20-35 hr in rats and monkeys. Isoxicam was distributed to most tissues in rats, but the tissue-plasma ratio did not exceed unity, indicating a small volume of distribution. It was extensively metabolized with only a few per cent of the dose appearing as unchanged drug in the urine. The principal urinary metabolite in man was formed by hydroxylation of the methyl group on the isoxozole ring and accounted for 30-35% of an isoxicam dose. In the rat, oxoacetic acid, the major urinary metabolite, was formed by opening of the benzothiazine ring followed by hydrolytic cleavage of the C-3 to N-2 bond. In addition to the hydroxymethyl and oxoacetic acid, two unknown metabolites, accounting for only a small percentage of dose, were detected in the urine of all four species. Urinary excretion of 14C activity accounted for about 60% of a dose in man and rats, 31% in monkeys, and 17% in dogs. These results indicate that there is only a quantitative rather than a qualitative species difference in the metabolic disposition of isoxicam.     

Bromobenzene metabolism in the rat and guinea pig

The metabolism of bromobenzene was studied in the rat and guinea pig with respect to three considerations: the dose and species dependence of 3-bromophenol excretion; the formation of methylthio analogs of dihydrodiols and catechols; and the identification of acidic bivalent sulfur metabolites. In the guinea pig, 3-bromophenol was the major monohydric phenolic metabolite under conditions of both relatively low and relatively high dosage. In the rat, 3-bromophenol and 4-bromophenol were formed in approximately equal amounts. 2-Bromophenol was a minor metabolite in both species. Methylthio analogs of dihydrodiols were found as guinea pig, but not rat, metabolites. Two di(methylthio)dihydroxytetrahydrobromobenzene metabolites were excreted by the rat but not by the guinea pig. These methylthio compounds have not been reported in earlier studies of bromobenzene metabolism. In the guinea pig, the acidic urinary metabolites were a mercaptoacetate, a mercaptolactate, and a mercapturate. In the rat, the acidic metabolites were a mercapturic acid and premercapturic acids. This species difference in urinary acids indicates a difference in acetylation/deacetylation processes for cysteine conjugates.     

Formation and metabolism of [14C]dopamine 3-O-sulfate in dog,rat and guinea pig

Oral administration of [¹⁴C]dopamine to dogs resulted in urinary excretion of predominantly [¹⁴C]dopamine 3-O-sulfate, while after intravenous administration the labeled drug was metabolized largely by O-methylation and deamination pathways. Experiments in vitro pinpointed the small intestinal wall of the dog as the site of dopamine sulfate conjugate formation. The small intestines of rat and guinea pig lack this sulfating ability. When trace amounts of [¹⁴C]dopamine 3-O-sulfate were administered to dog, rat and guinea pig, the compound turned out not to be metabolically inert. In the guinea pig, [¹⁴C]dopamine 3-O-sulfate was almost completely desulfated and metabolized according to the pattern characteristic to orally administered dopamine in this animal species. In rat, about 40 per cent of the administered [¹⁴C]dopamine 3-O-sulfate (19.1 μg/kg) was excreted in urine unchanged, whereas a smaller dose (7.4 μg/kg) was totally metabolized according to the pattern characteristic to rat. In dog urine, more than 80 per cent of the radioactive dose (2.5 μg/kg) emerged in urine as unchanged [¹⁴C]dopamine 3-O-sulfate, the normal metabolism end product of dopamine in dog.     

The metabolic disposition of (S)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-cyanopyridine in rats, dogs, and humans

Studies of the metabolic disposition of (S)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-[14C]cyanopyridine (I) have been performed in humans, dogs, and spontaneously hypertensive rats. After an iv injection of I (5 mg/kg), a substantial fraction of the radioactivity was excreted in the feces of rats (32%) and dogs (31%). After oral administration of I (5 mg/kg) the urinary recoveries of radioactivity for rat and dog were 19% and 53%, respectively, and represented a minimum value for absorption because of biliary excretion of radioactivity. In man, bililary excretion of I appeared to be of minor significance because four male subjects, after receiving 6 mg of I p.o., excreted 76% and 9% of the dose of radioactivity in the urine and feces, respectively. Unchanged I represented 58% of the radioactivity excreted in human urine. The half-life for renal elimination of I was determined to be 4.0 +/- 0.9 /hr. In contrast, unchanged I represented 7% and 1% of excreted radioactivity in rat and dog urine, respectively. A metabolite of I common to man, dog, and rat was identified as 5-hydroxy-I, which represented approximately 5% of the excreted radioactivity in all species. Minor metabolites of I in which the pyridine nucleus had undergone additional hydroxylation were present in dog urine along with an oxyacetic acid metabolite, also bearing a hydroxylated pyridine nucleus.     

The metabolic disposition of aprepitant, a substance P receptor antagonist, in rats and dogs.

The absorption, metabolism, and excretion of [14C]aprepitant, a potent and selective human substance P receptor antagonist for the treatment of chemotherapy-induced nausea and vomiting, was evaluated in rats and dogs. Aprepitant was metabolized extensively and no parent drug was detected in the urine of either species. The elimination of drug-related radioactivity, after i.v. or p.o. administration of [14C]aprepitant, was mainly via biliary excretion in rats and by way of both biliary and urinary excretion in dogs. Aprepitant was the major component in the plasma at the early time points (up to 8 h), and plasma metabolite profiles of aprepitant were qualitatively similar in rats and dogs. Several oxidative metabolites of aprepitant, derived from N-dealkylation, oxidation, and opening of the morpholine ring, were detected in the plasma. Glucuronidation represented an important pathway in the metabolism and excretion of aprepitant in rats and dogs. An acid-labile glucuronide of [14C]aprepitant accounted for approximately 18% of the oral dose in rat bile. The instability of this glucuronide, coupled with its presence in bile but absence in feces, suggested the potential for enterohepatic circulation of aprepitant via this conjugate. In dogs, the glucuronide of [14C]aprepitant, together with four glucuronides derived from phase I metabolites, were present as major metabolites in the bile, accounting collectively for approximately 14% of the radioactive dose over a 4- to 24-h period after i.v. dosing. Two very polar carboxylic acids, namely, 4-fluoro-alpha-hydroxybenzeneacetic acid and 4-fluoro-alpha-oxobenzeneacetic acid, were the predominant drug-related entities in rat and dog urine.     

The metabolism and disposition of 14C-fenofibrate in human volunteers

The metabolic fate of a single dose of 14C-fenofibrate has been studied in a panel of eight healthy volunteers (four males and four females). In 7 days, a total of 84% of the administered dose was recovered, with 59% in the urine and 25% in the feces. The majority of the urinary 14C was excreted within 24 hr, whereas the bulk of the fecal 14C was recovered over the first 3 days after dosing. The major urinary metabolite was the ester glucuronide of fenofibric acid, accompanied by much smaller amounts of fenofibric acid and the benzhydrol and its glucuronide. The principal compound in feces was unchanged fenofibrate, together with smaller quantities of fenofibric acid and polar unknown metabolite(s). Experiments on the stability of fenofibryl glucuronide showed it to be less reactive than most ester glucuronides.     

Metabolism and disposition of morpholine in the rat,hamster, and guinea pig

The blood plasma levels and urinary metabolites of morpholine were examined in three rodent species: the Sprague-Dawley rat, the Syrian golden hamster, and the strain II guinea pig. Marked differences were found between the guinea pig and the other two species with respect to plasma levels as well as the metabolism of morpholine. After ip administration of 125 mg/kg [¹⁴C]morpholine (50 μCi) per animal, the blood plasma half-lives in the rat, hamster, and guinea pig were: 115, 120, and 300 min, respectively. In all three species, approximately 80% of the radioactivity was excreted in the urine in 24 hr. However, while nonmetabolized [¹⁴C]morpholine constituted up to 99% of the urinary radioactivity in the rat and hamster, a significant portion of the dose (approximately 20%) appeared in guinea pig urine as N-methylmorpholine-N-oxide. This new metabolite of morpholine was isolated by Sephadex LH-20 chromatography and confirmed by thin-layer chromatography, gas chromatography, and mass spectrometry.     

Metabolism of styrene oxide in the rat and guinea pig

The metabolism of styrene oxide has been studied in the rat and guinea pig, with emphasis upon bivalent sulfur metabolites. Methylthio analogs of phenylethylene glycol, with the methylthio group in both possible positions, were found as urinary metabolites in both species. These compounds were present in more than trace amounts. The excretion of 2-hydroxy-1-methylthio-1-phenylethane amounted to about 7% of the administered dose in the guinea pig, and about 2% in the rat, in o-24 hr urine samples. The positional isomer 1-hydroxy-2-methylthio-1-phenylethane was excreted in lesser amounts in both species. Acidic urinary metabolites derived from glutathione conjugates are species dependent. In this study, the only products observed in the rat were the mercapturic acids expected as a result of reaction of the oxide with glutathione. In the guinea pig, the major bivalent sulfur acids were the corresponding mercaptoacetic acids. Other related metabolites included a mercaptolactic and a mercaptopyruvic acid, together with one of the mercapturic acids. These metabolites result from partial acetylation or acetylation/deacetylation of cysteine or cysteinylglycine adducts. The hitherto unobserved dihydrodiol formed via an arene oxide was found as a minor metabolite for both styrene and styrene oxide.     

The Metabolism of Isopropyl Oxitol in Rat and Dog

1. An intraperitoneal dose of [¹⁴C]isopropyl Oxitol is rapidly metabolized in the rat.

2. The major routes of excretion of radioactivity are the urine (73% dose) and in the expired air as [¹⁴C]carbon dioxide (14%).

3. The major urinary metabolites were characterized as isopropoxyacetic acid (30% of the urinary radioactivity), N-isopropoxyacetyl glycine (46%) and ethanediol (13%).

4. The metabolism of the compound in the dog is similar to that in the rat.     

Metabolism of [14C]phenol by sheep, pig and rat.

1. Following an oral dose of [14C]phenol (12.5 or 25 mg/kg) to sheep, pig and rat, urinary elimination of radioactivity was rapid, 80-90% dose being excreted in the first 8 h. 2. In anaesthetized, ureter-cannulated rats, 70-80% of an intraduodenal dose was eliminated in 2 h; 2% dose was excreted as phenol conjugates in the urine within 10 min. 3. The major urinary metabolites from phenol (25 mg/kg) were phenylglucuronide and phenylsulphate. In the sheep, pig and rat, the glucuronide accounted for 49%, 83% and 42% respectively, of the total urinary metabolites and sulphate accounted for 32%, 1% and 55%. Conjugates of quinol were minor urinary metabolites (less than 7%) in all three species. 4. In sheep some 12% of the urinary metabolites was conjugated with phosphate; this metabolite was not found in rat or pig.     

The metabolic disposition of acifran, a new antihyperlipidemic agent, in rats and dogs

The metabolic disposition of the antihyperlipidemic agent acifran (AY-25, 712) was determined in rats and dogs. The synthesis of 14C-labelled acifran is described. Serum levels of 14C and acifran were measured in rats and dogs after p.o. and i.v. administration of 14C-acifran at a dose of 10 mg/kg. Over 80% of the 14C in serum was due to acifran. The drug was rapidly absorbed and the pharmacokinetics, unaffected by increasing the dose or by daily multiple doses, were characterized by a two-compartment open model. Food reduced the bioavailability of acifran by 27% in the dog. About 65% of the dose was absorbed in rats, and at least 88% in dogs. The elimination t 1/2 of acifran from serum was 1.5 h in the rat and 3 h in the dog. Acifran was partially bound to serum proteins, man greater than rat greater than dog; the drug was found to displace protein-bound warfarin in rat and dog, but not in human serum. Radioactivity did not tend to accumulate in tissues, except for the kidney, where the 14C concentration was five times higher than in the serum; elimination of 14C from all the tissues was similar to that from serum. Most of the absorbed dose was excreted in the urine. Acifran did not undergo enterohepatic circulation in the rat. Virtually all the urinary 14C in both species was due to the unchanged compound. In conclusion, the disposition of acifran was similar in rats and dogs. The drug was rapidly absorbed and eliminated, and underwent no detectable biotransformation. There was no tissue retention and excretion was mainly in the urine.     

Comparative metabolic disposition of [1-Me14C]caffeine in rats, mice, and Chinese hamsters

The metabolic disposition of [1-Me14C]caffeine has been studied and compared in three male rodent species: the rat, the mouse, and the Chinese hamster. No interspecies differences appeared in urinary and fecal excretion of radioactivity. However, 1-methyldemethylation was significantly more important in the rat with 20.6 +/- 0.8% of the dose recovered as 14CO2 compared with the Chinese hamster, 16.1 +/- 2%, and the mouse, 13.9 +/- 0.9%. HPLC and TLC analysis of 1-methyl-labeled metabolites showed that the rat exhibits a significantly higher urinary excretion of the four trimethyl derivatives: caffeine, 1,3,7-trimethyluric acid, trimethylallantoin, and 6-amino-5-[N-formylmethylamino]-1,3-dimethyluracil [40.8% of total urine radioactivity) when compared with the Chinese hamster (21.1%) and the mouse (19.7%). Compared with man (6%), these rodents have a greater ability to excrete caffeine without any demethylation. The rat was also characterized by a higher excretion of theophylline while the Chinese hamster excreted more paraxanthine, 1-methylxanthine, and the uracil derivative of paraxanthine. In the mouse, in addition to 1-methylxanthine and 1-methyluric acid, higher amounts of 1,3- and 1,7-dimethyluric acid were found. The mouse was particularly characterized by the presence of an unknown polar metabolite amounting to 22 +/- 3% of urine radioactivity. This metabolite must be produced from paraxanthine because its quantitative formation was inversely related to the excretion of paraxanthine and its metabolites. The observations that this metabolite is neither 5-acetylamino-6-amino-3-methyluracil nor 5-acetylamino-6-formylamino-3-methyluracil reported in humans demonstrate that both quantitative and qualitative interspecies differences occur for caffeine metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Polychlorinated biphenyls (PCBs): dermal absorption, systemic elimination, and dermal wash efficiency

The objectives of this study were to determine the dermal absorption, systemic elimination, and dermal wash efficiency for polychlorinated biphenyls (PCBs). 14C-Labeled 42% PCB and 14C-labeled 54% PCB were topically and parenterally administered to rhesus monkeys and guinea pigs. Dermal absorption, determined by 14C urinary excretion, was extensive. In guinea pigs, 33% of the applied 14C-labeled 42% PCB dose and 56% of the 14C-labeled 54% PCB dose were absorbed. In rhesus monkeys, 15-34% of the labeled 42% PCB was dermally absorbed, depending on the magnitude of the applied dose. 14C-labeled 42% PCB applied to guinea pig skin was immediately washed with water and acetone. Only 59% of the applied dose was removed from the skin. A post-24-h washing removed only 1% of applied labeled 42% PCB and 20% of applied labeled 54% PCB. Postcontamination washing cannot be assumed to remove all contaminated PCB from skin. The body elimination of 14C was continuous and slow, with elimination half-lives on the order of 2-3 d in the guinea pig and 4-7 d in the monkey. Only 50-65% of an intramuscular dose could be accounted for in urine and feces for up to 28 d excretion. The elimination half-lives following topical administration were not much greater than that following intramuscular administration. This suggests that PCBs are rapidly and extensively absorbed through the skin, and that they are then probably generally distributed throughout the body, and then slowly eliminated.