Mass spectrometric and NMR characterization of metabolites of roxifiban,a potent and selective antagonist of the platelet glycoprotein IIb/IIIa receptor

1. The methylester prodrug roxifiban is an orally active, potent and selective antagonist of the platelet glycoprotein GPIIb/IIIa receptor and is being developed for the prevention and treatment of arterial thrombosis. 2. Roxifiban was rapidly hydrolyzed to the zwitterion XV459 in vivo and by liver slices from the rat, mouse and human and by intestinal cores from dog. XV459 was metabolized to only a small extent in vitro and in vivo. 3. Studies with rat and dog givenradiolabelled roxifibanshowedlimited oralabsorption with the majority of the radiolabel being excreted in faeces. After i.v. doses of ¹⁴C-roxifiban, most of the radioactivity was recovered in the urine of rat whereas the dog excreted significant amounts of radioactivity in bile and urine. 4. XV459 could be metabolized extrahepatically by dog gut flora to produce an isoxazoline ring-opened metabolite. In vitro hepatic metabolism of XV459 was mainly by hydroxylation at the prochiraland chiralcentres of the isoxazolinering. These hydroxylated metabolites were not detected in the urine and plasma of human volunteers administered roxifiban. 5. Initial LC/MS identification of metabolites was achieved by dosing the rat with an equimolar mixture of d₀:d₄ roxifiban and detecting isotopic clusters of pseudomolecular ions. Unequivocal characterization of these metabolites was achieved by LC/MS, LC/NMR and high-field NMR techniques using synthetic standards of the metabolites. 6. The synthesis of one hydroxylated metabolite enabled the assignment of the correct stereochemistry of the substituted hydroxyl group on the isoxazoline ring.     

Simultaneous quantification of seven active metabolites of roxifiban in human plasma by LC/MS/MS in the presence of an interfering displacer at millimolar concentrations

Roxifiban (DMP 754) is a glycoprotein (GP) IIb/IIIa antagonist. Following oral administration to humans, roxifiban is metabolized to its primary active zwitterionic form, XV459, and several minor, active, hydrolyzed and hydroxylated metabolites, namely, M1a (DPC-AD3508), M1b (DPC-AD6128), M2 (SW156), M3 (DPC-AG2185), M8a (DPC-AF5814), and M8b (DPC-AF5818). Quantification of these metabolites in humans was not workable with a previous analytical method due to ion suppression of at least four of the analytes by a competitive displacer, DMP 728. This compound, which is another GP IIb/IIIa antagonist with very high affinity for the platelet receptor, was added to harvested blood samples in millimolar quantity to liberate XV459 from the GP IIb/IIIa receptor. An automated ion exchange solid phase extraction (IX-SPE) procedure was developed to selectively extract the seven metabolites of roxifiban and its deuterated internal standard while specifically excluding DMP 728. Among the six hydroxylation metabolites, there were two pairs of epimeric diastereomers (M1a/M1b and M8a/M8b) and one pair of geometric isomers (M2/M3), corresponding to three critical chromatographic pairs that needed to be base-line resolved because of the lack of specificity of MS/MS detection for these isomers. A new LC/MS/MS assay was developed to simultaneously quantify the seven metabolites in human plasma. The assay method was validated under GLP conditions over the concentration range of 0.5 to 80 nM for each of the analytes and successfully applied to assaying approximately 500 plasma samples from clinical trials.     

Biotransformation of nevirapine, a non-nucleoside HIV-1 reverse transcriptase inhibitor, in mice, rats, rabbits, dogs, monkeys, and chimpanzees.

The study objectives were to characterize the metabolism of nevirapine (NVP) in mouse, rat, rabbit, dog, monkey, and chimpanzee after oral administration of carbon-14-labeled or -unlabeled NVP. Liquid scintillation counting quantitated radioactivity and bile, plasma, urine, and feces were profiled by HPLC/UV diode array and radioactivity detection. Metabolite structures were confirmed by UV spectral and chromatographic retention time comparisons with synthetic metabolite standards, by beta-glucuronidase incubations, and in one case, by direct probe electron impact ionization/mass spectroscopy, chemical ionization/mass spectroscopy, and NMR. NVP was completely absorbed in both sexes of all species except male and female dogs. Parent compound accounted for <6% of total urinary radioactivity and <5.1% of total fecal radioactivity, except in dogs where 41 to 46% of the radioactivity was excreted as parent compound. The drug was extensively metabolized in both sexes of all animal species studied. Oxidation to hydroxylated metabolites occurred before glucuronide conjugation and excretion in urine and feces. Hydroxylated metabolites were 2-, 3-, 8-, and 12-hydroxynevirapine (2-, 3-, 8-, and 12-OHNVP). 4-carboxynevirapine, formed by secondary oxidation of 12-OHNVP, was a major urinary metabolite in all species except the female rat. Glucuronides of the hydroxylated metabolites were major or minor metabolites, depending on the species. Rat plasma profiles differed from urinary profiles with NVP and 12-OHNVP accounting for the majority of the total radioactivity. Dog plasma profiles, however, were similar to the urinary profiles with 12-OHNVP, its glucuronide conjugate, 4-carboxynevirapine, and 3-OHNVP glucuronide being the major metabolites. Overall, the same metabolites are formed in animals as are formed in humans.     

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.     

Pharmacokinetics,metabolism and excretion of the glycine antagonist GV150526A in rat and dog

1. The pharmacokinetics, metabolic fate and excretion of 3-[-2(phenylcarbamoyl) ethenyl-4,6-dichloroindole-2-carboxylic acid (GV150526), a novel glycine antagonist for stroke, in rat and dog following intravenous administration of [C14]-GV150526A were investigated. 2. Studies were also performed in bile duct-cannulated animals to confirm the route of elimination and to obtain more information on metabolite identity. 3. Metabolites in plasma, urine and bile were identified by HPLC-MS/MS and NMR spectroscopy. 4. GV150526A was predominantly excreted in the faeces via the bile, with only trace metabolites of radioactivity in urine (< 5%). Radioactivity in rat bile was predominantly due to metabolites, whereas approximately 50% of the radioactivity in dog bile was due to parent GV150526. 5. The principal metabolites in bile were identified as glucuronide conjugates of the carboxylic acid, whereas in rat urine the main metabolite was a sulphate conjugate of an aromatic oxidation metabolite. Multiple glucuronide peaks were observed and identified as isomeric glucuronides and their anomers arising from acyl migration and muta-rotation.     

Pharmacokinetics,metabolism and excretion of the glycine antagonist GV150526A in rat and dog

1. The pharmacokinetics, metabolic fate and excretion of 3-[-2(phenylcarbamoyl) ethenyl-4,6-dichloroindole-2-carboxylic acid (GV150526), a novel glycine antagonist for stroke, in rat and dog following intravenous administration of [C14]-GV150526A were investigated. 2. Studies were also performed in bile duct-cannulated animals to confirm the route of elimination and to obtain more information on metabolite identity. 3. Metabolites in plasma, urine and bile were identified by HPLC-MS/MS and NMR spectroscopy. 4. GV150526A was predominantly excreted in the faeces via the bile, with only trace metabolites of radioactivity in urine (< 5%). Radioactivity in rat bile was predominantly due to metabolites, whereas approximately 50% of the radioactivity in dog bile was due to parent GV150526. 5. The principal metabolites in bile were identified as glucuronide conjugates of the carboxylic acid, whereas in rat urine the main metabolite was a sulphate conjugate of an aromatic oxidation metabolite. Multiple glucuronide peaks were observed and identified as isomeric glucuronides and their anomers arising from acyl migration and muta-rotation.     

Biotransformation of diclofenac sodium (Voltaren) in animals and in man. I. Isolation and identification of principal metabolites.

1. The anti-inflammatory agent diclofenac sodium (o-[(2,6-dichlorophenyl)amino]phenylacetic acid sodium salt) is extensively metabolized by rat, dog, baboon and man. The main metabolites were isolated from the urine of all species and from the bile of rat and dog and identified by spectroscopy. 2. Metabolism involves direct conjugation of the unchanged drug, or oxidation of the aromatic rings usually followed by conjugation. Sites of oxidation are either position 3' or 4' of the dichlorophenyl ring or, alternatively, position 5 of the phenyl ring attached to the acetic acid moiety. 3. In the urine of rat, baboon and man conjugates of the hydroxylated metabolites predominate, but the major metabolite in dog urine is the taurine conjugate of unchanged diclofenac. 4. In the bile of rat and dog, the main metabolite is the ester glucuroniade of unchanged diclofenac.     

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 metabolism of tolamolol in the mouse, rat, guinea-pig, rabbit and dog.

1. [3H, 14C]Tolamolol was well absorbed after oral administration to mice, rats, guinea-pigs, rabbits and dogs. 2. The major route for excretion of radioactivity by mice, rats and guinea-pigs was the faeces; in rabbits the major route was the urine. Dogs excreted similar amounts of radioactivity by both routes. Biliary excretion of radioactivity by the rat and guinea-pig was demonstrated. 3. Tolamolol was extensively metabolized by all five species. The major metabolite in mice, rats, guinea-pigs and rabbits was the product of hydroxylation of the tolyl ring, which was excreted as such as the glucuronide and sulphate conjugates. 4. In the dog the major metabolite was the acid resulting from hydrolysis of the carbamoyl group. This acid was also excreted by the rabbit, but was only a minor metabolite in the other species studied.     

The metabolism of [14C]N-ethoxycarbonyl-3-morpholinosydnonimine (molsidomine) in laboratory animals

[14C]N-Ethoxycarbonyl-3-morpholinosydnonimine (molsidomine, Corvaton) was found to be extensively metabolized following oral dosing to rat and dog and intravenous dosing to rabbit. The majority of the radiolabel was rapidly excreted in the urine with the main radiolabelled components being characterized as acidic metabolites resulting from oxidative metabolism of the morpholine ring. A new metabolite, (N-cyanomethylenamino-2-aminoethoxy)-acetic acid, was identified and shown to be a major component of the 14C-labelled urinary metabolites in all three species. However, the previously identified metabolite, N-cyanomethylenaminomorpholine-2-one (compound D) was not detected and may therefore have been formed artefactually in the earlier studies. The long terminal half-life for plasma radioactivity observed in previous studies was shown to be the result of the production of small amounts of 14C-thiocyanate from the nitrile-containing metabolites of molsidomine.     

Metabolism of the thiocarbamate herbicide SUTAN in rats.

1. The metabolism of the thiocarbamate herbicide SUTAN (butylate) was studied after administration of single oral doses of [isobutyl-1-14C]SUTAN to male and female rats. 2. The radiolabelled dose was rapidly absorbed and excreted, with 79% of the dose excreted in the urine in 72 h. The small percentages of radioactivity excreted in the faeces and as 14CO2 were significantly higher (P less than or equal to 0.05) in males than in females. 3. SUTAN was extensively metabolized, and no unmetabolized SUTAN was found in the urine. A total of 18 of the 29 urinary metabolites were identified, and identified metabolites represented 83-88% of the urinary radioactivity. 4. Diisobutylamine was the major urinary metabolite in both males and females, averaging 51% of the urinary radioactivity. 5. Other significant urinary metabolites included primary hydroxylated and tertiary hydroxylated diisobutylamines and a series of mercapturic acid pathway metabolites, including an S-glucuronide and several hydroxylated and unhydroxylated mercapturates. 6. Oxidations at the three alkyl groups produced a variety of minor urinary metabolites, and hydroxylation of the primary or tertiary carbon on the isobutyl groups, followed by an intramolecular reaction, generated a series of minor cyclized metabolites.     

Metabolism and disposition of 14C-granisetron in rat,dog and man after intravenous and oral dosing

1. The disposition and metabolic fate of ¹⁴C-granisetron, a novel 5-HT₃ antagonist, was studied in rat, dog, and male human volunteers after intravenous and oral administration.

2. Complete absorption occurred from the gastrointestinal tract following oral dosing, but bioavailability was reduced by first-pass metabolism in all three species.

3. There were no sex-specific differences observed in radiometabolite patterns in rat or dog and there was no appreciable change in disposition with dose between 0·25 and 5 mg/kg in rat and 0·25 and 10mg/kg in dog. Additionally, there were no large differences in disposition associated with route of administration in rat, dog and man.

4. In rat and dog, 35–41% of the dose was excreted in urine and 52–62% in faeces, via the bile. Metabolites were largely present as glucuronide and sulphate conjugates, together with numerous minor polar metabolites. In man, about 60% of dosed radioactivity was excreted in urine and 36% in faeces after both intravenous and oral dosing. Unchanged granisetron was only excreted in urine (5–25% of dose).

5. The major metabolites were isolated and identified by MS spectroscopy and nmr. In rat, the dominant routes of biotransformation after both intravenous and oral dosing were 5-hydroxylation and N1-demethylation, followed by the formation of conjugates which were the major metabolites in urine, bile and plasma. In dog and man the major metabolite was 7-hydroxy-granisetron, with lesser quantities of the 6,7-dihydrodiol and/or their conjugates.     

The Metabolism of Tolamolol* in the Mouse,Rat, Guinea-pig,Rabbit and Dog

1. [³H, ¹⁴C]Tolamolol was well absorbed after oral administration to mice, rats, guinea-pigs, rabbits and dogs.

2. The major route for excretion of. radioactivity by mice, rats and guineapigs was the faeces; in rabbits the major route was the urine. Dogs excreted similar amounts of radioactivity by both routes. Biliary excretion of radioactivity by the rat and guineapig was demonstrated.

3. Tolamolol was extensively metabolized by all five species. The major metabolite in mice, rats, guinea-pigs and rabbits was the product of hydroxylation of the tolyl ring, which was excreted as such and as the glucuronide and sulphate conjugates.

4. In the dog the major metabolite was the acid resulting from hydrolysis of the carbamoyl group. This acid was also excreted by the rabbit, but was only a minor metabolite in the other species studied.     

Metabolism and excretion of imrecoxib in rat

The metabolism and excretion of imrecoxib, a novel and moderately selective cyclooxygenase-II inhibitor, were investigated in rat. The structures of metabolites were identified by mass spectrometry (MSn) and nuclear magnetic resonance. Metabolic profiles of imrecoxib in urine, bile and faeces were obtained by HPLC and LC/MSn, and cumulative excretion was determined by LC/MSn. Imrecoxib was extensively metabolized in rat after intravenous administration, with less than 2% of the dose excreted as parent drug in either urine or faeces. The major metabolic pathway was that the 4'-methyl group of imrecoxib was first oxidized to the 4'-hydroxymethyl metabolite (M4), followed by additional oxidation to 4'-carboxylic acid metabolite (M2). The dihydroxylated metabolite, 4'-hydroxymethyl-5-hydroxyl imrecoxib (M3), was further oxidized to 4'-hydroxymethyl-5-carbonyl metabolite (M5), and glucuronide conjugates of M2-4 were formed. After intravenous (5 mg kg-1) administration, the majority of the dose was recovered in the faeces. The dose was primarily excreted as the carboxylic acid metabolite in addition to the 4'-hydroxymethyl metabolite. The carboxylic acid metabolite was mainly excreted in faeces, while the 4'-hydroxymethyl metabolite was mainly excreted in urine.     

Disposition and metabolism of triprolidine in mice.

The disposition of the antihistamine, triprolidine, was studied in male and female CD-1 mice after a single oral 50 mg/kg dose of [14C]triprolidine HCl. Urine and feces collected over 72 hr postdosing were analyzed for total radiocarbon, and for parent drug and metabolites by radiochromatography. Structures of metabolites were determined by GC/MS, direct probe MS, FAB/MS, LC/MS, NMR, and IR techniques. More than 80% of the dose was recovered in the urine, with the remainder recovered in the feces. The carboxylic acid analog of triprolidine (219C69) was found to be the major metabolite in urine and feces, accounting for an average of 57.6% of the administered dose. Three minor metabolites were identified as a gamma-aminobutyric acid analog of triprolidine, a pyrrolidinone analog of 219C69, and a pyridine-ring hydroxylated derivative of triprolidine. Parent drug could only be detected in urine and accounted for 0.3% (females) to 1.1% (males) of the dose. The results of this study showed that triprolidine was absorbed well but extensively metabolized when administered orally to mice.     

Metabolism of pamaqueside, a cholesterol absorption inhibitor, in Long-Evans rat: effect of bile duct cannulation on absorption

The metabolism of pamaqueside, a cholesterol absorption inhibitor, was studied in the bile duct cannulated and non-cannulated rat after an oral dose (100 mg/kg) and an i.v. dose (6 mg/kg) of [14C]pamaqueside. Faeces was the major route of excretion in all rat. Only 0.1% of the radioactivity was recovered in the urine of the non-cannulated rat. In contrast, approximately 17% of the total dose was recovered in the bile and urine in the bile duct cannulated rat. Following an i.v. dose, an almost equal percentage of radioactivity was excreted in the bile and urine of the bile duct cannulated rat. 3. The aglycone (M1) was the major metabolite in rat and was present in greater amounts in the faeces of the bile duct cannulated rat. The structural elucidation of metabolites in the bile and urine indicated that M1 was metabolized oxidatively via a novel ring opening, and the oxidative metabolites further underwent sulphate conjugation. The oxidative ring opening of pamaqueside (the cellobioside ring intact) was also observed following an i.v. dose to rat suggesting that oxidative ring opening was the major route of metabolism of saponins, at least in rat. The study demonstrated that the absorption and metabolism of pamaqueside was altered by surgical cannulation of rat.     

Metabolism of Femoxetine

Abstract: The metabolism of femoxetine, a serotonin uptake inhibitor, has been investigated in rats, dogs, monkeys, and human subjects using two ¹⁴C-femoxetine compounds with labelling in different positions. The metabolic pathways were oxidation (and glucuronidation) and demethylation, both reactions most probably taking place in the liver. Nearly all femoxetine was metabolised, and the same metabolites were found in urine from all four species. Only a small percentage of the radioactivity excreted in the urine was not identified. Rat and dog excreted more N-oxide than monkey and man, while most of the radioactivity (60–100%) in these two species was excreted as two hydroxy metabolites. The metabolic pattern in monkey and man was very similar. About 50% was excreted in these two species as one metabolite, formed by demethylation of a methoxy group. A demethylation of a N-CH₃ group formed an active metabolite, norfemoxetine. The excretion of this metabolite in urine from man varied from 0 to 18% of the dose between individuals. Most of the radioactivity was excreted with the faeces in rat and dog, while monkey and man excreted most of the radioactivity in urine. This difference in excretion route might be explained by the difference in the metabolic pattern. No dose dependency was observed in any of the three animal species investigated.     

A double antibody radioimmunoassay for the determination of XV459, the active hydrolysis metabolite of roxifiban,in human plasma

A radioimmunoassay (RIA) was developed for the determination of XV459, the active hydrolysis metabolite of the oral prodrug roxifiban (DMP 754), in human plasma. XV459 is a potent antagonist of the glycoprotein IIb/IIIa receptor. The method utilizes a competitive double antibody format employing an 125I-labeled XV459 analogue tracer which competes with XV459 for antibody binding sites and a second antibody precipitation step to separate antibody bound analyte from free analyte. The method has a validated lower quantification limit of 0.35 ng/ml (0.81 nM) using 12.5 microl of plasma and with dilution can accommodate clinical plasma samples ranging up to 48.0 ng/ml (110.7 nM). Cross-validation to an existing quantitative liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method showed good correlation (r(2)=0.98). The RIA has been successfully used to assay over 10000 clinical samples with sensitivity and specificity comparable to the LC-MS/MS method, but with faster turn around time and at greatly reduced costs.     

Metabolism of the thiocarbamate herbicide SUTAN® in rats

1. The metabolism of the thiocarbamate herbicide SUTAN° (butylate) was studied after administration of single oral doses of [isobutyl-1-¹⁴C]SUTAN to male and female rats.

2. The radiolabelled dose was rapidly absorbed and excreted, with 79% of the dose excreted in the urine in 72?h. The small percentages of radioactivity excreted in the faeces and as ¹⁴CO₂ were significantly higher (P≤0.05) in males than in females.

3. SUTAN was extensively metabolized, and no unmetabolized SUTAN was found in the urine. A total of 18 of the 29 urinary metabolites were identified, and identified metabolites represented 83–88% of the urinary radioactivity.

4. Diisobutylamine was the major urinary metabolite in both males and females, averaging 51% of the urinary radioactivity.

5. Other significant urinary metabolites included primary hydroxylated and tertiary hydroxylated diisobutylamines and a series of mercapturic acid pathway metabolites, including an S-glucuronide and several hydroxylated and unhydroxylated mercapturates.

6. Oxidations at the three alkyl groups produced a variety of minor urinary metabolites, and hydroxylation of the primary or tertiary carbon on the isobutyl groups, followed by an intramolecular reaction, generated a series of minor cyclized metabolites.     

Species differences in the metabolism of suprofen in laboratory animals and man

The metabolism of the oral anti-inflammatory agent suprofen (S), 2-4-(2-thienylcarbonyl)phenyl)propionic acid, has been studied in mice, rats, guinea pigs, dogs, monkeys, and human volunteers. The major metabolites of S in the serum, urine, and feces of these species were determined by GC/MS and HPLC techniques. The metabolic pathways of S in these species involved reduction of the ketone group to an alcohol (S-OH), hydroxylation of the thiophene ring (T-OH), elimination of the thiophene ring to a dicarboxylic acid (S-COOH), and conjugation with glucuronic acid or taurine. In 72-hr urine and feces of these species after po dosing of 1.6 to 2 mg/kg of S, S and these metabolites accounted for 46 to 92% of the dose and were mainly excreted in the urine. S was present as a major product (excreted mainly in conjugated form) in all species. S-OH was a major component in guinea pig and dog but a minor one in other species. T-OH was identified as a major metabolite in monkey, rat, mouse, and man, but a minor one in guinea pig, and it was absent in the dog. S-COOH was present as the minor metabolite in mouse and rat, and present at trace levels in dog, monkey, and man. Conjugation of the propionic acid functionality with taurine was observed only in the dog; in the other species, conjugation with glucuronic acid was extensive. Absorption parameters of S in the rat and monkey were similar to those in man; however, other species were very different from man.