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.     

Disposition of clofibrate in the rat: Acute and chronic administration

The disposition of 1-[¹⁴C]clofibrate (0.4 $\text{mmole}\text{kg}$) was studied in rats after acute (single dose) and chronic (b.i.d., for 14 days) administration. With a single dose (orally or by intraperitoneal injection) of clofibrate, most (~90 per cent) of the ¹⁴C-dose appeared in the urine within 24 hr and the recovery of ¹⁴C from the urine and feces was nearly quantitative within 72 hr. Little fecal excretion of ¹⁴C (< 5 per cent) occurred after a single or chronic clofibrate administration. Clofibrate was readily absorbed and eliminated, as evidenced by a rapid increase in plasma ¹⁴C level within 90 min and a calculated biological half-life of 4.1 hr. The pharmacokinetic profile of ¹⁴C-elimination in rats was unaffected by pretreatment with cholestyramine. Clofibric acid [2-(4-chlorophenoxy)-2-methylpropionic acid] was identified as the major metabolite in plasma (~97 per cent) whereas the glucuronide of clofibric acid was the main urinary and biliary metabolite (~96 per cent). Clofibric acid, as the free acid and glucuronide form, accounted for 99 per cent of the total ¹⁴C-dose in rats, and unchanged clofibrate was not detected in any of the biological samples. Two unidentified, minor urinary metabolites were also detected. In cannulated bile duct studies, it was found that [¹⁴C]clofibrate, as clofibric acid, was rapidly and efficiently excreted in the bile. The biliary excretion rates of ¹⁴C and of the glucuronide of clofibric acid were also not altered by phenobarbital pretreatment. Chronic treatment with [¹⁴C]clofibrate did not alter the qualitative or quantitative nature of biotransformation in vivo. An increased rate of urinary ¹⁴C-elimination was observed following chronic 1-[¹⁴C]clofibrate treatment, with concomitant reductions in blood and heart ¹⁴C-content and an elevation in ¹⁴C-content of epididymal fat tissue. Subcellular fractionation of liver, from rats given [¹⁴C]clofibrate chronically, indicated an increased distribution of ¹⁴C into mitochondria and peroxisomes. Tissue ¹⁴C-levels, achieved in these in vivo studies, were an order of magnitude lower than those required for the pharmacological activities of clofibrate and clofibric acid in vitro.     

In vivo metabolites of S-(2-benzothiazolyl)-L-cysteine as markers of in vivo cysteine conjugate beta-lyase and thiol glucuronosyl transferase activities

Cysteine conjugate beta-lyases (beta-lyase), enzymes that are present in mammalian liver, kidneys, and intestinal microflora, were exploited recently for site-selective delivery of 6-mercaptopurine to the kidneys. In this study, in vivo beta-lyase activity was assessed using S-(2-benzothiazolyl)-L-cysteine (BTC). 2-Mercaptobenzothiazole and 2-mercaptobenzothiazole S-glucuronic acid were major metabolites of BTC in rat liver, kidney, plasma, and urine. Total metabolite concentrations in liver, kidney, or plasma at 30 min were similar and were higher than that detected at 3 hr; metabolites were mostly in the glucuronide form. The portions of metabolites excreted in urine at 8 and 24 hr were nearly 93 and 99% of that excreted at 40 hr, respectively. Pretreatment of rats with aminooxyacetic acid did not alter kidney, liver, plasma, or urinary metabolite concentrations. The portion of the BTC dose excreted as metabolites at 24 hr was independent of the BTC dose (100-400 mumol/kg), age (5-12 weeks), or sex of the rats. The rates of in vitro BTC metabolism by guinea pig hepatic and renal beta-lyases were slower than those of rats, but the portion of the BTC dose recovered as metabolites in guinea pig urine at 24 hr was nearly 60%, which was nearly 2-fold higher than that recovered in urine of rats, mice, or hamsters. The amounts of total metabolites excreted into urine by mice or hamsters were similar, but the portion of metabolites that was in the glucuronide form in hamster urine was higher than that in mouse urine.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Biotransformation of sultopride in man and several animal species

The biotransformation of sultopride has been investigated in rat, rabbit, dog and man. In man sultopride was metabolically stable, and about 90% of an oral dose was excreted in urine unchanged and 4% as oxo-sultopride. Rat, rabbit and dog metabolized sultopride more extensively and excreted less than 40% of an oral dose of 14C-sultopride in urine. Four similar metabolites were excreted by the three animal species but the relative portions differed. The major radioactive component in rat urine was O-desmethyl sultopride, whereas oxo-sultopride and O-desmethyl sultopride were the major urinary metabolites in rabbit. Dog formed N-desethyl sultopride and oxo-sultopride as major urinary metabolites. The male rat excreted smaller amounts of unchanged sultopride in urine than did the female rat. The unchanged sultopride excreted in rat urine was increased slightly by repeated administration.     

Metabolism in vivo of the tropane alkaloid, scopolamine, in several mammalian species.

1. In vivo metabolism of scopolamine was studied in rats, mice, guinea pigs and rabbits. The structures of eight urinary metabolites including unchanged drug were elucidated by mass and nuclear magnetic resonance spectrometry. Determination of these metabolites was achieved by a g.l.c. method using a semi-capillary column. 2. The major metabolites in rats were the three phenolic metabolites, p-hydroxy-, m-hydroxy- and p-hydroxy-m-methoxy-scopolamine. 3. Significant intra-species difference of the metabolism was observed in rabbits. Tropic acid was the major metabolite in two rabbits out of three, while the other rabbit excreted mainly unchanged scopolamine, accompanied by five metabolites. Tropic acid was also the major metabolite in guinea pigs, but was of minor importance in mice. 4. The dehydrated metabolites, aposcopolamine and aponorscopolamine, were abundantly excreted in guinea pigs, moderately in mice, and least in rabbits and rats. 5. Excretion of glucuronide conjugates of scopolamine and norscopolamine were high in mice compared with other species. On the other hand, phenolic metabolites in rat urine; and tropic acid in rabbit and guinea pig urine, were excreted as the free forms. 6. These results indicate that scopolamine metabolism is highly species-specific.     

Metabolism of arylacetic acids. 2. The fate of [14C]hydratropic acid and its variation with species.

1. (+/-)-[methyl-14C]-Hydratropic acid was administered to man, rhesus monkey, cat, rabbit and fruit bat. 2. All species excreted 60-100% of administered 14C in the urine in 24 h, and unchanged hydratropic acid accounted for 0-17% of the dose. 3. In man, the urinary 14C consisted of a very small quantity (1%) of unchanged hydratropic acid with the remainder as hydratropylglucuronide. 4. Hydratropylglucuronide was the major urinary excretion product in the 4 animal species, while the glycine conjugate was present in the urine of cat and rat. Additionally, cats excreted the taurine conjugate of hydratropic acid. 5. Bile-duct cannulated rats excreted 20-30% of an injected dose of [14C] hydratropic acid in the bile in 3 h mainly as hydratropylglucuronide.     

Oxymorphone metabolism and urinary excretion in human, rat, guinea pig, rabbit, and dog

Oxymorphone was extensively metabolized by human, rat, dog, and guinea pig and to a lesser extent by rabbit. The most abundant metabolite in urine for all species was conjugated oxymorphone (12.7-81.7% administered dose) followed by 6 beta- and 6 alpha-carbinols produced by 6-keto reduction of oxymorphone. 6 beta-Oxymorphol (0.2-3.1%) was found in the urine of all species, whereas 6 alpha-oxymorphol (0.1-2.8%) was found only in human, rabbit, and guinea pig. Small amounts of free oxymorphone (less than or equal to 10%) were excreted by all species except rabbit, which excreted 31.7%. Overall recoveries of oxymorphone and metabolites from urine ranged from 15-96%, of which greater than 80% was excreted in the first 24 hr by all species except dog. Only 35% was excreted by dog during the first day. Stereoselectivity of 6-keto- reduction was observed for all species with the 6 beta-carbinol metabolite being most abundant in the urine of all but guinea pig. Considerable individual variability occurred in the excretion of free and conjugated oxymorphone by six human subjects following oral dosing. Species trends in the metabolism of 6-keto-opioids are discussed.     

Metabolic studies of salbutamol-H: A new bronchodilator,in rat,rabbit, dog and man

Salbutamol-³H, labelled on the β-carbon atom, was rapidly absorbed from the gastro-intestinal tract of rat, rabbit, dog and man. 60–90%, depending upon the species studied, of the administered radioactivity was recovered in the 24 hr urine. 70–90% of the radioactivity present in the dog urine was due to unchanged salbutamol-³H, whereas 90% in the rabbit and 40% in the rat urine was due to salbutamol-³H o-phenylglucuronide. The latter has been isolated and shown to be neither a β-stimulant nor a β-blocker. The rat conjugated salbutamol-³H in the liver, and excreted the glucuronide via the bile. 0–48 hr rat faeces contained 25–40% of the label. Analysis of the tissues from the rat and dog indicated that the drug was completely cleared from the body. Salbutamol-³H inhaled by dogs and humans as an aerosol was slowly adsorbed from the lung, and excreted via the urine.     

Biotransformation of sultopride in man and several animal species

1. The biotransformation of sultopride has been investigated in rat, rabbit, dog and man.

2. In man sultopride was metabolically stable, and about 90% of an oral dose was excreted in urine unchanged and 4% as oxo-sultopride.

3. Rat, rabbit and dog metabolized sultopride more extensively and excreted less than 40% of an oral dose of ¹⁴C-sultopride in urine.

4. Four similar metabolites were excreted by the three animal species but the relative portions differed. The major radioactive component in rat urine was O-desmethyl sultopride, whereas oxo-sultopride and O-desmethyl sultopride were the major urinary metabolites in rabbit. Dog formed N-desethyl sultopride and oxo-sultopride as major urinary metabolites.

5. The male rat excreted smaller amounts of unchanged sultopride in urine than did the female rat.

6. The unchanged sultopride excreted in rat urine was increased slightly by repeated administration.     

Metabolism of Arylacetic Acids: 2. The Fate of [14C]Hydratropic Acid and its Variation with Species

1. (±)-[methyl-¹⁴C]-Hydratropic acid was administered to man, rhesus monkey, cat, rabbit and fruit bat.

2. All species excreted 60-100% oi administered ¹⁴C in the urine in 24?h, and unchanged hydratropic acid accounted for 0-17% of the dose.

3. In man, the urinary ¹⁴C consisted of a very small quantity (1%) of unchanged hydratropic acid with the remainder as hydratropylglucuronide.

4. Hydratropylglucuronide was the major urinary excretion product in the 4 animal species, while the glycine conjugate was present in the urine of cat and rat. Additionally, cats excreted the taurine conjugate of hydratropic acid.

5. Bile-duct cannulated rats excreted 20-30% of an injected dose of [¹⁴C] hydratropic acid in the bile in 3?h mainly as hydratropylglucuronide.     

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.     

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.     

Biotransformation of diclofenac sodium (Voltaren) in animals and in man. II. Quantitative determination of the unchanged drug and principal phenolic metabolites, in urine and bile.

1. Quantitative determinations of unchanged diclofenac and two of its major phenolic metabolites were made by reverse isotope dilution analysis on urine of rat, dog, rhesus monkey, baboon and man and on bile of rat, dog and man. Isotope dilution analysis was performed before and after various methods of enzymic and chemical hydrolysis. 2. The same samples were also analysed by two-dimensional t.l.c. and subsequent autoradiography, to estimate the remaining phenolic metabolites. 3. In contrast to rat, rhesus monkey, baboon and man, which excrete mainly hydroxylated metabolites, the dog does not oxidize diclofenac. Dog urine contained a relatively stable taurine conjugate of diclofenac, and in the bile an ester glucuronide was excreted, which decomposed even in weakly alkaline soln. 4. The unstable ester glucuronide found in dog bile was also demonstrable in rat bile. It presumably hydrolyses in the duodenum, releasing diclofenac which undergoes enterohepatic circulation.     

Taurine conjugates as metabolites of arylacetic acids in the ferret.

1. The pattern of conjugation in the ferret of 8 arylacetic acids and, for comparison, benzoic acid and 4-nitrobenzoic acid was examined. 2. The arylacetic acids, phenylacetic, 4-chloro- and 4-nitro phenylacetic, alpha-methylphenylacetic (hydratropic), 1- and 2-naphthylacetic and indol-3-ylacetic acids, were excreted in the urine as taurine and glycine conjugates. Diphenylacetic acid did not form an amino acid conjugate and was excreted as a glucuronide. 3. The taurine conjugate was the major metabolite of 4-nitrophenylacetic, alpha-methylphenylacetic, 1- and 2-naphthylacetic and indol-3-ylacetic acids, whereas the glycine conjugate was the major metabolite of phenylacetic and 4-chlorophenylacetic acids. Taurine conjugation did not occur with benzoic and 4-nitrobenzoic acids which were excreted as glycine and glucuronic acid conjugates. 4. Phenacetylglutamine and 4-hydroxyphenylacetic acid were minor urinary metabolites of phenylacetic in the ferret. 5. A number of taurine conjugates of aliphatic and aromatic acids were synthesized and their characterization and properties were studied. The role of taurine as an alternative to glycine in the metabolic conjugation of arylacetic acids is discussed.     

The metabolism of bifluranol by rat, dog and ferret

The synthesis of monohydroxy- and dihydroxy-bifluranol, and of glucuronide and sulphate conjugates of bifluranol are described. Bifluranol administered orally to rats, ferrets and dogs at a dosage of 50 to 200 microgram kg-1 is mostly excreted in the faeces as unchanged bifluranol and bifluranol monosulphate, disulphate and monoglucuronide. The bifluranol is well absorbed and is mostly excreted in the bile, as six different conjugates, including a glucuronide sulphate found in all 3 species, and a glucuronide phosphate found only in ferret and dog bile. Hydroxylation of the aromatic rings occurs in the rat, to an extent of about 8% of the dose, but was not detected in ferret or dog.     

Metabolism of methylphenidate in dog and rat

The urinary metabolites of methylphenidate in the dog and rat were investigated. After oral administration of 14C-labeled methylphenidate, approximately 86% and 63% of the dose was recovered in the urine of the dog and rat, respectively. Less than 1% of the dose was excreted as unchanged drug. Metabolism involved oxidation, hydrolysis, and conjugation processes. The primary hydrolytic product was alpha-phenyl-2-piperidineacetic acid (24%, dog; 35-40%, rat). The primary metabolites of oxidation were methyl 6-oxo-alpha-phenyl-2-piperidineacetate (3%, dog; 1.5%, rat) and the glucuronide of alpha-(p-hydroxyphenyl)-2-piperidineacetic acid (10%, rat). The former also underwent extensive biotransformation, including: 1) hydrolysis to the lactam acid (27%, dog; 7-10%, rat) and subsequent carboxylic acid O-glucuronidation (15%, dog); or 2) hydroxylation at the 5-position (1%, dog; 2%, rat) and subsequent hydrolysis (4%, dog; 15-17%, rat); or 3) 5-O-glucuronidation (12%, dog). Additional minor metabolites from methyl-6-oxo-alpha-phenyl-2-piperidineacetate were the phenolic O-glucuronide of methyl alpha-(p-hydroxyphenyl)-6-oxo-2-piperidineacetate (1%, dog), and the 4-O-glucuronide of methyl 4-hydroxy-6-oxo-alpha-phenyl-2-piperidineacetate (1%, dog), and the taurine amide conjugate of alpha-(p-hydroxyphenyl)-6-oxo-2-piperidineacetic acid (1%, dog). Additional products from methylphenidate conjugation included methyl 1-carbamoyl-alpha-phenyl-2-piperidineacetate (1%, dog or rat) and its carboxylic acid hydrolysis product (1%, rat). The chirality of the major metabolites isolated from dog urine showed that metabolism was partially stereoselective in all investigated cases, except in the formation of alpha-phenyl-2-piperidineacetic acid.     

Study on metabolism of pyridonecarboxylic acid II. Determination of metabolites of (+-)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)- 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid p-toluenesulfonate hydrate (T-3262) in blood, urine, bile, and feces

The fate of (+-)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl-1,4- dihyro-4-oxo-1,8-naphthyridine-3-carboxylic acid p-toluenesulfonate hydrate (T-3262) was studied using T-3262 and 14C-T-3262 in various animals. 1. Metabolites in serum and urine were assayed for mouse, rat, rabbit, dog and monkey following oral administration of T-3262. In serum, besides unchanged T-3262 base, T-3262A (N-acetylated) was detected in rat, rabbit and monkey; T-3262B (deamino-hydroxylated) was detected in monkey. In urine, unchanged T-3262 base was excreted mainly. But a few of metabolites (T-3262A, T-3262B, T-3262 glucuronide, T-3262A glucuronide, T-3262B glucuronide, and unknown compound M-1) were detected, and species difference existed in types of metabolites. 2. Metabolites in bile and feces were assayed for mouse and rat following oral administration of T-3262 and 14C-T-3262. Metabolites in bile were similar to the urine, but the volume of T-3262A and T-3262A glucuronide was larger than in urine. In feces, the excreted compounds mainly consisted of unchanged T-3262 base. 3. p-Toluenesulfonic acid, which is the counter acid for T-3262 base, was absorbed following the oral administration of T-3262, and excreted in urine in the unchanged form.     

Identification of DP-1904 and its ester glucuronide in human urine and determination of their enantiomeric compositions by high-performance liquid chromatography with optical activity and ultraviolet detection

The parent compound and one metabolite have been isolated from urine of five healthy male volunteers who received a single 200 mg oral dose of DP-1904. These compounds were extracted by using a Sep-Pak C18 cartridge and purified by the preparative HPLC method. On the basis of proton magnetic resonance and mass spectral data, unchanged drug and its ester glucuronide have been identified in human urine. DP-1904 has one asymmetric carbon and is used as a racemate in the current clinical trial. The enantiomeric compositions of unchanged DP-1904 and aglycon of DP-1904 glucuronide were determined by HPLC with optical activity and ultraviolet detection. The (R)-(+)-enantiomer percentages in unchanged DP-1904 and aglycon of its ester glucuronide in human urine collected at 0-4 hr after oral dosing were 60 +/- 1.3% and 38 +/- 1.4% (mean +/- SE, n = 5), respectively. The 0-4 hr urine collection represented approximately 80% of the given dose. These studies demonstrate that DP-1904 undergoes stereoselective disposition in humans. However, the difference in urinary excretion between DP-1904 enantiomers was rather small.     

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.