The disposition of [14C]iprindole in man, dog, miniature swine, rhesus monkey and rat.

1. Absorption of a single oral dose of [14C]iprindole was rapid in rats, rhesus monkeys, miniature swine, dogs and human volunteers. In all species except the rat, most of the radioactivity in the blood resided in the plasma. Small amounts of unchanged iprindole were detected in the plasma of rats and rhesus monkeys but not in man and miniature swine. 2. Radioactivity was excreted mainly in the urine of man, miniature swine and rhesus monkey, but in the faeces of rat and dog. 3. Urinary radioactivity was associated with basic (free and conjugated), acidic and highly polar, water soluble metabolites. At least 20 metabolites as well as small amounts of unchanged drug were detected in the basic fractions of each species' urine. 4. Many of these metabolites were common to all species; however, qualitative as well as quantitative differences were apparent. Mass-spectrometric analysis of several metabolites indicated N-demethylation and oxidation of the alicylic ring or a combination of both pathways.     

Direct high pressure liquid chromatographic analysis and preliminary pharmacokinetics of enantiomers of oxazepam and temazepam with their corresponding glucuronide conjugates

Three high pressure liquid chromatographic systems for the separation of oxazepam, temazepam and their glucuronides (system A), the separation of theirR,S glucuronide diastereomers (system B) and the chiral separation of the parent drugs (system C) are described. Preliminary pharmacokinetics ofR,S-oxazepam andR,S-temazepam in a human volunteer reveal that the protein binding of the glucuronides is lower than that of the parent drugs, but that there is no difference in protein binding between theR-oxazepam/temazepam andS-oxazepam/temazepam and their corresponding glucuronides. TheS-glucuronide is the main metabolite formed and excreted by man. The plasma ratioR/S-glucuronide is 11 for both oxazepam and temazepam. The renal clearances ofR-temazepam, andS-temazepam are similar, and those ofR-oxazepam andS-oxazepam tend to be different.     

Species-dependent glucuronidation of drugs by immobilized rabbit, rhesus monkey, and human UDP-glucuronyltransferases

The utility of immobilized microsomal enzymes from rabbit liver for the synthesis of a variety of conjugated drug metabolites has been demonstrated in our laboratory. Here, this capability is extended to microsomal preparations from monkey and human liver. A comparative study of glucuronidation of various substrates was carried out using immobilized uridine-5'-diphosphoglucuronyltransferase from rabbit, rhesus monkey, and human liver. The three drugs used for the study (sulfadimethoxine, oxazepam, and cyproheptadine) were chosen on the basis of their previously reported in vivo species differences in glucuronidation. Aglycons were incubated with UDP-glucuronic acid in the presence of immobilized UDP-glucuronyl-transferase at pH 7.4 for 16 hr at 37 degrees C. Glucuronide products were purified by high performance liquid chromatography and further characterized by thin layer chromatography and mass spectometry. Species-dependent glucuronidation was observed in all three cases. Differences in the in vitro product formation paralleled in vivo species differences for the three drugs studied. The same glucuronides were produced by immobilized human liver microsomes as have been found to be formed in vivo from the three drugs studied.     

Disposition and metabolism of benoxaprofen in laboratory animals and man.

1. The absorption, distribution, metabolism and excretion of benoxaprofen, a novel anti-inflammatory compound, has been studied in the dog, mouse, rat, rabbit, rhesus monkey and man. 2. Benoxaprofen was well absorbed after oral administration of doses of 1 to 10 mg/kg in all six species. Only unchanged drug was detected in plasma. It was extensively bound to plasma proteins, the highest binding occurring in man (99.8%) and rhesus monkey (99.6%). 3. Species differences were observed in the plasma elimination half-life, the longest being in man (33 h). The rat and mouse also had high values (28 and 24 h respectively) whereas in the other species, values were less than 13 h. 4. After an oral dose of [14C]benoxaprofen (20 mg/kg) to female rats, tissue concn. was highest in liver, kidney, lungs, adrenals and ovaries. Tissue distribution in the pregnant rat was identical to the normal female. The compound was found in the foetus but at a concn. lower than in all maternal organs. 5. There was a marked species difference in the route of excretion. In man, rhesus monkey and rabbit, excretion in the urine was a major route, whilst biliary--faecal excretion was the only effective route in the rat and dog. 6. No major metabolic transformation of benoxaprofen was observed. Man and dog excreted the compound predominantly as the ester glucuronide whereas the rat, mouse, rabbit and rhesus monkey excreted a large proportion of the dose unchanged.     

Metabolism and disposition of a potent group II metabotropic glutamate receptor agonist, in rats, dogs, and monkeys.

Metabolism and disposition of MGS0028 [(1R,2S,5S,6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid monohydrate], a potent group II metabotropic glutamate receptor agonist, were examined in three preclinical species (Sprague-Dawley rats, beagle dogs, and rhesus monkeys). In rats, MGS0028 was widely distributed and primarily excreted in urine as parent and as a single reductive metabolite, identified as the 4R-isomer MGS0034 [(1R,2S,4R,5S,6S)-2-amino-6-fluoro-4-hydroxybicyclo[3.1.0]-hexane-2,6-dicarboxylic acid]. MGS0028 had a low brain to plasma ratio at efficacious doses in rats and was eliminated more slowly in rat brain than in plasma. Exposure increased proportionally (1--10 mg/kg p.o.) in rats, with bioavailability>60% at all doses. However, bioavailability was only approximately 20% in monkeys, and MGS0034 was found in relatively high abundance in plasma. In dogs, oral bioavailability was >60%, and the metabolite was not detected. In vitro metabolism was examined in liver subcellular fractions (microsomes and cytosol) from rat, dog, monkey, and human. Reductive metabolism was observed in rat, monkey, and human liver cytosol incubations, but not in dog liver cytosol incubations. No metabolism of MGS0028 was detected in incubations with liver microsomes from any species. Similar to in vivo results, MGS0028 was reduced in cytosol stereospecifically to MGS0034. The rank order of in vitro metabolite formation (monkey > rat approximately human > dog) was in agreement with in vivo observations in rats, dogs, and monkeys. Based on the observation of species difference in reductive metabolism, rat and monkey were recommended to be the preclinical species for further characterization prior to testing in humans. Finally, allometric scaling predicts that human pharmacokinetic parameters would be acceptable for further development.     

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.     

Biotransformation of zeranol: disposition and metabolism in the female rat, rabbit, dog, monkey and man

The disposition of [3H]zeranol has been studied in the female Wistar rat, New Zealand rabbit, beagle dog, rhesus monkey and man. The blood elimination half-life of total radioactivity in rabbit was 26 h, monkey 18 h and man 22 h. In all species studied the drug was absorbed, oxidized and/or conjugated, and was extensively excreted via the bile in all species except rabbit and man, in which urinary excretion predominated. Blood total radioactivity in man probably consisted entirely of conjugates of zeranol and/or its metabolites. Urinary metabolites in all species included conjugates (beta-glucuronides and/or sulphates) of zeranol and the major metabolite zearalanone. A more polar minor metabolite was isolated from human urine and was shown to be hydroxy-zeranol. Taleranol (7 beta-zearalanol, the lower-melting diastereoisomer), a probable metabolite of zeranol (7 alpha-zearalanol, the higher-melting diastereoisomer) in animals and in man, was shown to be a urinary metabolite in a female New Zealand white rabbit which had received [3H]zeranol (8 mg/kg per day) for seven days. A reverse isotope dilution method was developed for the quantification of both diastereoisomers of zearalanol, and also zearalanone, in urine.     

Comparison of celecoxib metabolism and excretion in mouse,rabbit, dog,cynomolgus monkey and rhesus monkey

1. The metabolism and excretion of celecoxib, a specific cyclooxygenase 2 (COX-2) inhibitor, was investigated in mouse, rabbit,the EM(extensive) and PM(poor metabolizer) dog, and rhesus and cynomolgus monkey. 2. Some sex and species differences were evident in the disposition of celecoxib. After intravenous (i.v.) administration of [¹⁴C]celecoxib, the major route of excretion of radioactivity in all species studied was via the faeces: EM dog (80.0%), PM dog (83.4%), cynomolgus monkey (63.5%), rhesus monkey (83.1%). After oral administration, faeces were the primary route of excretion in rabbit (72.2%) and the male mouse (71.1%), with the remainder of the dose excreted in the urine. After oral administration of [¹⁴C]celecoxib to the female mouse, radioactivity was eliminated equally in urine (45.7%) and faeces (46.7%). 3. Biotransformation of celecoxib occurs primarily by oxidation of the aromatic methyl group to form a hydroxymethyl metabolite, which is further oxidized to the carboxylic acid analogue. 4. An additional phase I metabolite (phenyl ring hydroxylation) and a glucuronide conjugate of the carboxylic acid metabolite was produced by rabbit. 5. The major excretion product in urine and faeces of mouse, rabbit, dog and monkey was the carboxylic acid metabolite of celecoxib.     

Comparison of celecoxib metabolism and excretion in mouse, rabbit, dog, cynomolgus monkey and rhesus monkey

1. The metabolism and excretion of celecoxib, a specific cyclooxygenase 2 (COX-2) inhibitor, was investigated in mouse, rabbit, the EM (extensive) and PM (poor metabolizer) dog, and rhesus and cynomolgus monkey. 2. Some sex and species differences were evident in the disposition of celecoxib. After intravenous (i.v.) administration of [14C]celecoxib, the major route of excretion of radioactivity in all species studied was via the faeces: EM dog (80.0%), PM dog (83.4%), cynomolgus monkey (63.5%), rhesus monkey (83.1%). After oral administration, faeces were the primary route of excretion in rabbit (72.2%) and the male mouse (71.1%), with the remainder of the dose excreted in the urine. After oral administration of [14C]celecoxib to the female mouse, radioactivity was eliminated equally in urine (45.7%) and faeces (46.7%). 3. Biotransformation of celecoxib occurs primarily by oxidation of the aromatic methyl group to form a hydroxymethyl metabolite, which is further oxidized to the carboxylic acid analogue. 4. An additional phase I metabolite (phenyl ring hydroxylation) and a glucuronide conjugate of the carboxylic acid metabolite was produced by rabbit. 5. The major excretion product in urine and faeces of mouse, rabbit, dog and monkey was the carboxylic acid metabolite of celecoxib.     

Characterization of the rhesus monkey CYP3A64 enzyme: species comparisons of CYP3A substrate specificity and kinetics using baculovirus-expressed recombinant enzymes.

The rhesus monkey (Macaca mulatta) is a primate species used extensively as a preclinical safety species in drug development. In this report, we describe the cloning, expression, and characterization of CYP3A64 (AY334551), a CYP3A4 homolog expressed in rhesus liver. The deduced amino acid sequence was found to be 93% similar to human CYP3A4, 83% similar to human CYP3A5, and identical to the previously reported cynomolgus monkey CYP3A8 (Komori et al., 1992). The substrate specificity of CYP3A64 for testosterone (0-250 microM), midazolam (0-200 microM), nifedipine (0-200 microM), and 7-benzoxy-4-trifluoromethylcoumarin (0-200 microM) were compared with recombinant enzymes from rat (CYP3A1, CYP3A2), dog (CYP3A12, CYP3A26), rabbit (CYP3A6), and human (CYP3A4, CYP3A5). Immunoinhibition and chemical inhibition of CYP3A64 was demonstrated using the inhibitory monoclonal antibody (MAb) 10-1-1 (anti-3A4) and ketoconazole (0-10 microM). The utility of CYP3A64 to be used as a standard in monkey induction assays was shown and the concentration of CYP3A64 protein in rhesus liver microsomes was estimated to be 72 pmol/mg protein. In summary, these results support the utilization of rhesus monkey CYP3A64 for in vitro drug metabolism studies and provide a more complete understanding of CYP3A substrate specificities and species differences in metabolic capabilities.     

Tyrosinemia produced by 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC) in experimental animals and its relationship to corneal injury

2-(2-Nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC) is a potent inhibitor of rat liver 4-hydroxyphenylpyruvate dioxygenase (HPPD) leading to tyrosinemia and corneal opacity. We examined the effect of NTBC on the extent of tyrosinemia and production of corneal lesions in the beagle dog, rabbit and rhesus monkey, as part of safety evaluation on this drug. A single oral dose of 10 mg NTBC/kg to beagle dogs or rabbits increased the concentration of tyrosine in plasma and aqueous humour of the eye, the tyrosinemia being both time- and dose-dependent. Hepatic HPPD was markedly inhibited with little effect on the activity of tyrosine aminotransferase (TAT) and homogentisic acid oxidase at the time of peak plasma tyrosine. Daily oral administration of NTBC to beagle dogs at 0.1, 0.5, 1.5 and 5 mg/kg/day produced corneal opacities with an incidence of 34% following 11 weeks of dosing, which reversed upon withdrawal of the drug. Tyrosine in plasma and aqueous humour was increased at all dose levels, 18 weeks after dosing. In contrast, daily oral administration of NTBC to rabbits for 6 weeks and rhesus monkeys for 12 weeks at 10 mg/kg/day produced no evidence of corneal opacities although tyrosine values were markedly increased. Our studies have shown that NTBC is a potent inhibitor of rabbit, beagle dog and by inference rhesus monkey liver HPPD producing a marked tyrosinemia in all species studied, while only beagle dogs show corneal lesions. The production of corneal lesions in experimental animals exposed to NTBC does not appear to be simply related to the concentration of tyrosine in ocular fluid, other as yet unidentified factors appear to be necessary to trigger tissue injury.     

Effect of Pentobarbital on the Formation of Diastereomeric Oxazepam Glucuronides in Man: Analysis by High Performance Liquid Chromatography

Abstract: Barbiturate treatment can enhance drug oxidation in man, but its effects on glucuronidation of clinically used drugs are unknown. We have studied the effect of 10 days treatment with pentobarbital on oxazepam glucuronidation in six volunteers. The diastereomeric (+ and minus;) glucuronides in urine were analyzed separately by high performance liquid chromatography and oxazepam in plasma by gas liquid chromatography. The area under the plasma concentration time curve for oxazepam (15 mg sod) decreased after pentobarbital treatment in all subjects, mean 10.4 before and 6.9 hXμmol/l after treatment (P<0.05) and oxazepam's plasma clearance increased by about 50 per cent. The glucuronides appeared more rapidly in the initial urinary fractions. The ratio between the glucuronides (+/minus;) appearing in urine decreased on pentobarbital treatment. Our data indicate that pentobarbital treatment increases the clearance of oxazepam by increased glucuronide conjugation, probably reflecting barbiturate induced changes of UDP glucuronyltransferase.     

The absorption, metabolism and excretion of disodium cromoglycate in nine animal species

The plasma concentrations and excretion of disodium cromoglycate after iv administration were studied in 9 animal species: mouse, rat, rabbit, dog, silky marmoset, squirrel monkey, Java (cynomolgus) monkey, stump-tailed macaque and baboon. In each species the decline of plasma concentration was rapid and the compound was quickly excreted in the bile and urine. Bile: urine ratios of excreted compound varied, the squirrel monkey excreted most of the dose in the bile (78–88%) whereas the rabbit excreted most of the dose in the urine (74–84%). Other species were intermediate between these two extremes. Tissue residues were low. Poor absorption (1–5%) after oral administration was found. No metabolites were detected in any species.     

Pharmacokinetics of rolipram in the rhesus and cynomolgus monkeys, the rat and the rabbit. Studies on species differences

1. The pharmacokinetics of rolipram were studied in rat, rabbit, rhesus monkey and cynomolgus monkey using 14C- or 3H-labelled rolipram and a radioimmunoassay for measurement of unchanged drug. 2. Rolipram was rapidly and completely absorbed after oral doses of up to 50 mg/kg. Bioavailability was 0.1% in rhesus monkey, 3.7% in cynomolgus monkey, 3.6% in rabbit, 35% in rat, and 75% in man. 3. Rolipram was able to pass the blood-brain barrier achieving concentrations in brain twice those in plasma. 4. Plasma levels of the unchanged drug declined with a similar half-life of 1-3 h in all species investigated. In the rat, there were indications for a different clearance of the two rolipram enantiomers. 5. Labelled rolipram was excreted rapidly and completely. The main route of elimination was via the urine.     

The metabolism of 5,5'-methylenedisalicylic acid in various species

Commercial methylenedisalicylic acid has been shown to be grossly impure. Pure 5,5′-methylendisalicylic acid (4,4′-dihydroxydiphenylmethane-3,3′-dicarboxylic acid) has been prepared and labelled with ¹⁴C. The fate of the pure compound in the rat, mouse, hamster, rhesus monkey, rabbit, guinea-pig and chicken has been investigated. The compound is excreted entirely unchanged in the urine and faeces in all the above species and no metabolites have been found. The biliary excretion of the injected compound is high (50–60%) in the rat and dog and low (5%) in the guinea-pig and rabbit. In the monkey, rabbit and guinea-pig, the compound is excreted almost exclusively in the urine. In the rat about 50% of the dose is excreted in the faeces. In the mouse and hamster, the main route of excretion is the urine, about 10% appearing in the faeces.     

Metabolism and clearance of proxicromil--studies in rat, hamster, rabbit, dog, squirrel monkey, cynomolgus monkey, baboon and man

Proxicromil was extensively metabolized and eliminated as metabolites in urine and faeces by the rat, hamster, rabbit, squirrel monkey, cynomolgus monkey, baboon and man after oral administration. The pathway of metabolism in these species was by hydroxylation of the alicyclic ring principally to yield monohydroxylated metabolites with trace amounts of a dihydroxylated product. Elimination of proxicromil by the dog, however, was essentially as the unchanged drug. The lack of metabolism of the drug by the dog resulted in the dog having a dependence on biliary excretion of the unchanged drug for clearance. These differences in clearance routes between species were reflected in the plasma clearance of the drug. The value for rat, a species capable of metabolism, was approximately 20 fold (4.1 ml min-1 kg-1) greater than the corresponding value for dog (0.2 ml min-1 kg-1). Inhibiting the metabolism of proxicromil in the rat with SKF-525A lowered plasma clearance of proxicromil (0.6 ml min-1 kg-1) and elevated the proportion of unchanged drug cleared by biliary excretion.     

Metabolism of bepridil in laboratory animals and humans

The metabolism of bepridil was studied in the Swiss mouse, Sprague-Dawley rat, New Zealand rabbit, rhesus monkey, and healthy human. After oral administration of bepridil-14C-hydrochloride, recoveries of total radioactivity in urine and feces (7 days) were greater than or equal to 80% of the administered dose in all five species. Bepridil and 25 metabolites have been isolated by HPLC and TLC from representative plasma, urine, and fecal extract pools from all species and identified on the basis of TLC, HPLC, and mass spectrometry. The identified metabolites explained 60-99% of the total radioactivity in each sample for rabbit plasma, in which only 17% of the total radioactivity was characterized. Metabolic pathways involving oxidative reactions at seven sites on the bepridil molecule are proposed for each species. Metabolite formation in the five species is described by four interrelated pathways. The metabolic pathway involving aromatic hydroxylation followed by N-dealkylation, N-debenzylation, and N-acetylation was important in all species. Major metabolites produced by this pathway included 4-hydroxy(at N-phenyl)-bepridil (Ia), N-benzyl-4-amino-phenol (IV), and N-acetyl-4-aminophenol (Vy). Metabolite Ia was isolated in significant amounts (greater than or equal to 5% of sample) in all fecal and urine samples except rat urine. Metabolite IV was a major circulating metabolite in all species and a major urinary metabolite in humans. Metabolite Vy was present in significant quantities in urine in all species except rabbit. Other important pathways involved primary reactions such as iso-butyl hydroxylation, pyrrolidine ring oxidation, and N-debenzylation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dydrogesterone: metabolism in animals

The metabolic pattern of dydrogesterone was investigated in the rat, dog, mouse, rabbit and rhesus monkey. The drug was administered orally in 3H-labelled form. Following enzymatic hydrolysis of conjugates the radioactive metabolites were extracted from the urine, and in rat and dog also from bile. The separation method used for the development of the metabolite patterns was reversed-phase high performance liquid chromatography. Dydrogesterone and 4 derivatives, known or suspected to be metabolites, were used as marker substances. In all the species a substantial portion of the urinary or biliary radioactivity was too polar to be extracted, or it was not resolved in the chromatographic system used. The radioactivity which did develop into a pattern coincided with two or more of the marker substances. Only in the monkey, the pattern contained a peak of some substance which did not coincide with any marker. The urinary patterns of rat, dog, and mouse differed substantially, from each other as well as from those of rabbit and monkey. The patterns for the latter two animals showed certain similarities, both to each other and to the human urinary pattern as reconstructed from previous studies. It is concluded that with regard to the metabolic fate of dydrogesterone, the rabbit resembles man more than does any other species.     

Metabolism of MK-0524, a prostaglandin D2 receptor 1 antagonist, in microsomes and hepatocytes from preclinical species and humans.

(3R)-4-(4-Chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl acetic acid (MK-0524) is a potent orally active human prostaglandin D(2) receptor 1 antagonist that is currently under development for the prevention of niacin-induced flushing. The major in vitro and in vivo metabolite of MK-0524 is the acyl glucuronic acid conjugate of the parent compound, M2. To compare metabolism of MK-0524 across preclinical species and humans, studies were undertaken to determine the in vitro kinetic parameters (K(m) and V(max)) for the glucuronidation of MK-0524 in Sprague-Dawley rat, beagle dog, cynomolgus monkey, and human liver microsomes, human intestinal microsomes, and in recombinant human UDP glucuronosyltransferases (UGT). A comparison of K(m) values indicated that UGT1A9 has the potential to catalyze the glucuronidation of MK-0524 in the liver, whereas UGT1A3 and UGT2B7 have the potential to catalyze the glucuronidation in the intestine. MK-0524 also was subject to phase I oxidative metabolism; however, the rate was significantly lower than that of glucuronidation. The rate of phase I metabolism was ranked as follows: rat approximately monkey > human intestine > dog > human liver with qualitatively similar metabolite profiles across species. In all the cases, the major metabolites were the monohydroxylated epimers (M1 and M4) and the keto-metabolite, M3. Use of inhibitory monoclonal antibodies and recombinant human cytochromes P450 suggested that CYP3A4 was the major isozyme involved in the oxidative metabolism of MK-0524, with a minor contribution from CYP2C9. The major metabolite in hepatocyte preparations was the acyl glucuronide, M2, with minor amounts of M1, M3, M4, and their corresponding glucuronides. Overall, the in vivo metabolism of MK-0524 is expected to proceed via glucuronidation, with minor contributions from oxidative pathways.     

Studies on the disposition of a 5-nitroimidazole in laboratory animals

The disposition and metabolism of a 5-nitroimidazole compound (SC 28538) was investigated in the rat, beagle dog and rhesus monkey. The absorption of [14C]-SC 28538 was rapid and essentially complete after oral dosage in male animals, and also after intravaginal dosage in the female rat. Peak plasma levels of radioactivity occurred within 2 h of dosage. In the rat and dog the radioactivity was excreted predominantly in the faeces (greater than 60%) but in the monkey more than 60% was excreted in the urine. In both the male and pregnant female rat radioactivity was concentrated in the gastro-intestinal tract, liver and harderian gland and the concentrations of radioactivity in other tissues was generally lower than in plasma. Radioactivity was cleared more rapidly from plasma than from the majority of tissues. SC 28538 was extensively metabolised to form glucuronide and amino acid conjugates. The half-life of SC 28538 was of the order of 1 h in the dog and 3.7 h in the monkey.