Metabolism profiles and excretion of 14C-aminoglutethimide in several animal species and man

1. Following administration of a single oral dose of 14C-aminoglutethimide to rats, guinea-pigs, rabbits and man, greater than 89% of the dose was excreted in urine and faeces within 72 h; dogs eliminated only 51% in this time. 2. Extensive metabolism occurred in all species, with N-acetylaminoglutethimide being the major metabolite except for dog and man. In the latter two species unchanged drug was the main product excreted. 3. A metabolite, 3-(4-acetamidophenyl)-3-(2-carboxamidoethyl)tetrahydrofuran-2-one, not previously found in human urine, was identified. 4. Chronic administration of aminoglutethimide to rats produced no detectable change in the excretory or metabolite patterns of the drug. However chronic administration of phenobarbitone decreased the urinary excretion of 14C over a 72 h period. 5. Residual (72 h) tissue levels of 14C were less than 1 microgram equivalent of 14C-aminoglutethimide/g tissue in the rat, guinea-pig and rabbit. Dog tissues retained a considerable quantity of 14C at this time.     

Metabolism and excretion of di(p-aminophenyl) sulphoxide in different animals species

Rabbits, rats and guinea-pigs were treated with di(p-aminophenyl) sulphoxide and their urines examined by an analytical method which permits the simultaneous determination of this compound and of dapsone [di(p-aminophenyl) sulphone] which is a possible product of metabolic oxidation. The method gives for each drug the total of free compound plus acid-labile conjugates. All three species excreted unchanged drug together with dapsone. With rats and guinea-pigs about 33% of the excretion is dapsone, but with rabbits only 6 to 12%. The rate of combined excretion is much greater in rabbits than in the other two species. These results are discussed in relation to the significance of di(p-aminophenyl) sulphoxide as a drug in the treatment of leprosy.     

Plasma levels and urinary excretion of batroxobin and its defibrinogenating effects in various animal species

The plasma levels and urinary excretion of batroxobin administered to 6 species of animals were examined by an enzyme immunoassay method. Defibrinogenating effect of batroxobin was also studied in those species. The plasma levels of immunoreactive batroxobin disappeared exponentially in all the animals and differences in half-life were observed to occur according to species. The elimination half-life of immunoreactive batroxobin in the plasma was the largest in dogs, followed by rats, monkeys, guinea pigs, mice and rabbits. The extent of the defibrinogenating effect was also noted to vary according to the species, being greatest in dogs and then monkeys, mice, rats, guinea pigs and rabbits. Following the continuous infusion of batroxobin into dogs, its level in the plasma remained high over a considerable period of time and the defibrinogenating effect lasted in corresponding to its plasma level. The urinary excretion of immunoreactive batroxobin was quite small in these species, being 0.2-1.9% of the original dose.     

Metabolism of nabumetone (BRL 14777) by various species including man

Radiotracer methodology was used to study the metabolic fate of 4-(6-methoxy-2-naphthyl)-butan-2-one (nabumetone) after oral administration to rats, mice, rabbits, dogs, rhesus monkeys and healthy human subjects. Parent compound was not detected in plasma and urine and the major circulating metabolite in all species was identified as 6-methoxy-2-naphthylacetic acid, a compound known to possess anti-inflammatory activity. Metabolites were mainly excreted in urine from which four principal metabolites were isolated and identified by mass spectrometry and independent synthesis. Pathways involving O-demethylation, reduction of the ketone group and oxidation of the butanone side-chain to acetic acid occurred in all species, but the ratios of the metabolic end-products tended to be species dependent. In the rat about half of the administered nabumetone was oxidized to the pharmacologically active acid metabolite.     

Metabolism of meperidine in several animal species

Four new meperidine metabolites were identified by GC-MS in the urine of rats, guinea pigs, rabbits, cats, and dogs. In addition to known meperidine metabolites, 4-ethoxycarbonyl-4-phenyl-1,2,3,4-tetrapyridine (dehydronormeperidine; IV, the N-hydroxydehydro derivative of normeperidine (X), the dihydroxy derivative of meperidine (XII), and the dihydroxy derivative of normeperidine (XIII) were identified. The possible role of the N-hydroxy derivative of normeperidine (IX) in the pharmacological interaction of meperidine (I) with MAO inhibitors, seen selectively in the rabbit (and humans), is discussed. Following the administration of the p-hydroxy derivative of meperidine (VII), the major metabolite was conjugated VII. Trace amounts of the p-hydroxy derivative of normeperidine (VIII), the methoxy hydroxy derivative of meperidine (XI), XII, and XIII also were detected as metabolites of VII. The degree of N-demethylation of VII, both in vitro and in vivo, was small.     

Metabolism of gamma-glutamyl dopamide and its carboxylic acid esters

The release of dopamine (DA) from L-γ-glutamyl dopamide (GDA) during incubation with renal homogenates from the dog was catalyzed by γ-glutamyltranspeptidase. This was shown by the increased release in the presence of glycylglycine, by the formation and isolation of glutamylglycylglycine, and by the complete inhibition of release by a combination of serine and tetraborate. Cleavage was localized predominantly in the renal cortex. Carboxylic acid esters of GDA were extremely effective prodrugs for DA, as measured by the increased renal DA level following their intragastric or intraperitoneal administration to rats. There was a close correlation between the in vitro susceptibility of the esters to hydrolysis by hepatic esterase and the renal level of DA following their intragastric administration; the n-amyl, n-hexyl and benzyl esters were very active in both tests. Hydrolysis of the ester bond appeared to be the most decisive step among those that occur during the transport of DA in the form of a GDA ester in the intestine to unbound DA in the kidney. When esters were administered intraperitoneally, renal DA levels were approximately 100 times higher than after intragastric administration, and the largest increases were produced by the n-heptyl and n-octyl esters; little correlation existed between the rate of ester hydrolysis and renal DA level. Because of the intensive renal activity of γ-glutamyltranspeptidase, it is likely that most of the DA appearing in kidney from GDA and its carboxylic acid esters is released within the kidney itself and does not originate in other body organs.     

Metabolism of L(+)-and D(-)-tartaric acids in different animal species.

L(+)-Tartaric acid, which is the naturally occurring form, is used as a food additive in a variety of foodstuffs. Recently, there has been an increasing interest in using synthetic (D,L)-tartaric acid as a substitute. Several toxicological studies have been published on L(+)-tartaric acid, but practically nothing concerning the racemic form. The metabolism of L(+)-tartaric acid has been investigated in a variety of species including man. Species differences have been noted in the ability to excrete the acid in the urine after oral administration. The decomposition of tartaric acid by the intestinal flora has been implicated as an important factor. (Underhill et al., 1931 a,b). In the present study the metabolic fate of L(+)- and D(-)-tartaric acids is compared in different species, in vivo after oral administration and in vitro after incubation with caecal extract.     

Practolol metabolism in various small animal species.

1. The metabolism of the beta-adrenergic blocking agent practolol has been studied in a variety of small animal species, using both ring- and acetyl-14C-labelled material. After oral dosing at 100 mg/kg, elimination of 14C in urine and expired air was monitored, and urinary metabolite patterns were examined by t.l.c. 2. Marmoset was unusual in extensively deacetylating practolol (c. 57% dose). Urinary elimination was low, with only 25% being recovered in 4 days; over 30% of urinary 14C was present as desacetyl practolol, whereas less than 50% was unchanged practolol. 3. Hamster was also atypical, in its extensive hydroxylation of practolol. Urine contained 60% dose; 11% of urinary radioactivity was present as 3-hydroxypractolol, much of the polar material present (48%) appeared to be a conjugate of this, and only 35% was present as practolol. 4. For the other species studied (rat, mouse, guinea-pig and rabbit, metabolism was more limited. Deacetylation was typically about 5%, but was somewhat higher in the mouse (8--14%). Urine was the major route of elimination and practolol represented 50--90% of urinary radioactivity. 5. Despite extensive toxicity studies, both in species which metabolize practolol similarly to man and in species such as the hamster and marmoset which metabolize practolol extensively, no animal model has been found for the human adverse reactions.     

Stereoselectivity of idarubicin reduction in various animal species and humans

1. The (13S)-dihydro derivative of idarubicin, (13S)-idarubicinol, is the major urinary metabolite of idarubicin in humans. Idarubicinol epimers were quantified by h.p. 1.c. in urine from rats, mice, rabbits, dogs and man after i.v. administration of idarubicin, and in man after oral dosing. The (13R)- and (13S)-epimers of idarubicinol were determined in rat bile.

2. After i.v. injection of idarubicin. (13R)-idarubicinol was not detectable in mice and rabbit urine and no more than 0.5% of the dose was present in the urine of other species. In man, the proportion of (13R)-idarubicinol in total idarubicinol was similar after i.v. (4.1%) and oral (3.8–5.0%) administration of idarubicin; the same applies to rat bile and urine.

3. Reduction of idarubicin in vivo is dependent upon ketone reductases, and proceeds more stereoselectively than that of most ketones giving rise to the (13S)-epimer almost exclusively. The high stereospecificity in idarubicin reduction might result from chiral induction due to the presence of asymmetric centres near to the carbonyl group in idarubicin.     

Stereoselectivity of idarubicin reduction in various animal species and humans

1. The (13S)-dihydro derivative of idarubicin, (13S)-idarubicinol, is the major urinary metabolite of idarubicin in humans. Idarubicinol epimers were quantified by h.p.l.c. in urine from rats, mice, rabbits, dogs and man after i.v. administration of idarubicin, and in man after oral dosing. The (13R)- and (13S)-epimers of idarubicinol were determined in rat bile. 2. After i.v. injection of idarubicin. (13R)-idarubicinol was not detectable in mice and rabbit urine and no more than 0.5% of the dose was present in the urine of other species. In man, the proportion of (13R)-idarubicinol in total idarubicinol was similar after i.v. (4.1%) and oral (3.8-5.0%) administration of idarubicin; the same applies to rat bile and urine. 3. Reduction of idarubicin in vivo is dependent upon ketone reductases, and proceeds more stereoselectively than that of most ketones giving rise to the (13S)-epimer almost exclusively. The high stereospecificity in idarubicin reduction might result from chiral induction due to the presence of asymmetric centres near to the carbonyl group in idarubicin.     

The absorption,tissue distribution,and excretion of dodecyldimethylamine oxide (DDAO) in selected animal species and the absorption and excretion of DDAO in man

The absorption tissue distribution, and excretion pattern of [methyl-¹⁴C]DDAO and [1-dodecyl-¹⁴C]DDAO administered orally or cutaneously to rats, mice, and rabbits were investigated. The excretion pattern of radioactivity from [1-dodecyl-¹⁴C]DDAO administered orally and cutaneously to man was also investigated. An oral dose of DDAO is rapidly and extensively absorbed and excreted by rats and man. Peak tissue levels of radioactivity resulting from oral administration of [methyl-¹⁴C]DDAO to rats occur within 1 hr after dosing. Cutaneously administered DDAO is absorbed by man, rats, rabbits, and mice. In man, the rate of DDAO absorption through the skin is at least one order of magnitude less than that observed in rats, mice, and rabbits.     

Metabolism and excretion of orally administered dimethylarsinic acid in the hamster

We administered a single po dose of dimethylarsinic acid ( DMAA ) to hamsters by stomach tube and determined the in vivo accumulation of the arsenic and its excretion in the urine and feces. It was shown that a part of the DMAA was further methylated to a trimethylarsenic compound (TMA). During the 24 hr following the administration of DMAA , a total of 80% was excreted in the urine and feces: 45% in the urine (made up of 67.9% DMAA and 32.0% TMA), and 34.7% in the feces (almost completely made up of DMAA but no TMA). The findings show that DMAA and the TMA are rapidly excreted and do not accumulate in the body.     

Absorption, distribution, and excretion of ammonium perfluorooctanoate (APFO) after oral administration to various species

Male and female mice, rats, hamsters, and rabbits were treated with a single oral dose of 14C-ammonium perfluorooctanoate (APFO), and the excretion and tissue distributions were followed for 120 h (168 h in the rabbit). Substantial sex and species differences in the excretion and disposition of 14C-radioactivity derived from 14C-labeled APFO were observed in this study. The female rat and the male hamster excreted more than 99% of the original 14C activity by 120 h after dosing; conversely, the male rat and the female hamster excreted only 39% and 60% of the original 14C activity, respectively, by 120 h postdosing. The male and female rabbits excreted the 14C activity as rapidly and completely as the female rat and the male hamster, whereas male and female mice excreted only 21% of the original 14C activity by 120 h postdosing. The rapid excretors (female rat, male hamster, and male and female rabbits) contained negligible amounts of 14C in organs and tissues at sacrifice. The slow excretors exhibited the highest 14C concentrations in the blood and liver followed by the kidneys, lungs, and skin.     

Metabolism of tauromustine in liver and lung microsomes from various species

1. The cytochrome P450 (CYP)-mediated metabolism of tauromustine has been evaluated in liver and lung microsomes from various species. Liver microsomes from rat pretreated with typical CYP inducers, human liver microsomes and cDNA-expressed human CYP enzymes were used to study the enzymatic basis of the metabolism. The further metabolism of the monodemethylated product of tauromustine and that of the denitrosated product were also investigated. 2. The major routes of tauromustine metabolism were demethylation to the alkylating active compound, R2, and denitrosation to the inactive metabolite, M3. The extent of metabolism and the activity of demethylation versus denitrosation varied among the species. The highest metabolism was found in mouse (BDF strain) followed by dog, rat and the human liver. Tauromustine was also metabolized to a low extent in lung microsomes from these species. 3. The further metabolism of R2 and M3 was ~100 times lower in activity than that of tauromustine. Both the demethylation and the denitrosation of tauromustine were increased 3-fold in liver microsomes from rat pretreated with phenobarbital, whereas treatment with cyanopregnenolone enhanced the denitrosation 11-fold, indicating the involvement of CYP3A. 4. Metabolism across a panel of 10 human liver microsomal samples demonstrated a correlation with testosterone 6beta-hydroxylation of demethylation (r2= 0.86) and denitrosation of tauromustine (r2=0.79). Among the human cDNA expressed CYP enzymes, not only was tauromustine determined to be catalysed predominantly by CYP3A4, but also to some extent by CYP2C19 and CYP2D6. 5. In conclusion, the present results indicate a major role of CYP3A enzymes in the metabolism of tauromustine.