Animal major metabolites

Chemical Animal Major Metabolites Identified in Reference... 

The results of metabolism studies with laboratory animals and livestock indicate that endosulfan does not bioconcentrate in fatty tissues and milk. Lactating sheep administered radiolabeled endosulfan produced milk containing less than 2% of the label. Endosulfan sulfate was the major metabolite in milk (Gorbach et al. 1968). A half-life of about 4 days was reported for endosulfan metabolites in milk from survivors of a dairy herd accidentally exposed to acutely toxic concentrations of endosulfan endosulfan sulfate accounted for the bulk of the residues detected in the milk (Braun and Lobb 1976). No endosulfan residues were detected in the fatty tissue of beef cattle grazed on endosulfan-treated pastures for 31-36 days (detection limits of 10 ppm for endosulfan, 40 ppm for endosulfan diol) the animals began grazing 7 days after treatment of the pastures. Some residues were detected in the fatty tissue of one animal administered 1.1 mg/kg/day of endosulfan in the diet for 60 days. No endosulfan residues were... 

Sulfentrazone is a broad-spectrum, pre-emergent herbicide that provides good control over broadleaf weeds, grasses and sedges in crops and turf. The metabolism of sulfentrazone in animals and plants is similar. The major plant metabolite of sulfentrazone is 3-hydroxymethyl sulfentrazone (HMS). The soybean tolerance of 0.05 mg kg includes residues of sulfentrazone plus its major metabolite, HMS. The rotational crop tolerance includes residues of sulfentrazone and its major metabolites, HMS and... 

In order to investigate whether the above glycerides are derived from the animal s diet or by biosynthesis, [2-14C]RS-mevalonic add DBED salt was injected into the digestive gland of A. montereyensis and A. odhneri spedmens, which were placed in a running sea-water aquarium for 24 h and then extracted [79]. Incorporation of the label was checked in the major metabolites of the two nudibranchs, namely 23 and 51 in A. montereyensis and 47 in A. odhneri, after HPLC purification and conversion to derivatives that were also purified via... 

Dimethylarsinic acid is the major metabolite of orally administered arsenic trioxide, and is excreted rapidly in the urine (Yamauchi and Yamamura 1985). The methylation process is true detoxification, since methanearsonates and cacodylates are about 200 times less toxic than sodium arsenite (NAS 1977). The marmoset monkey (Callithrix jacchus), unlike all other animal species studied to date, was not able (for unknown reasons) to metabolize administered As+5 to demethylarsinic acid most was reduced to As+3. Only 20% of the total dose was excreted in urine as unchanged As+5, and another 20% as As+3. The rest was bound to tissues, giving distribution patterns similar to arsenite (Vahter and Marafante 1985). Accordingly, the marmoset, like the rat, may be unsuitable for research with arsenicals. 

This parallel determination consists of measuring plasma levels of the administered agent and its major metabolites either in animals that are part of the main study or in a separate set of animals (in parallel with the main study) that are dosed and evaluated to determine just these endpoints. The purpose of these determinations is both to allow a better interpretation of the findings of the study and to encourage the... 

In addition, treatment of animals with phenobarbital not only increased overall rates of metabolism and clearance, but also shifted the metabolite patterns. One of the more common methods used for determining an exposure to (or the amount of a metabolite produced) is to determine an area under the curve (AUC) for the metabolite. Further, one of the more common methods for representing a racemically preferred metabolite is to calculate the ratio of the R to the S. For example, the 3-decholoro metabolite of ifosfamide was produced in higher amounts from the R enantiomer while the 2-decholorometabolite was the major metabolite produced from the R enantiomer in naive animals. Treatment with phenobarbital shifted the metabolism so that the 3-dechloro metabolite was no longer the major metabolite for the S enantiomer. 

Urine catecholamines may also serve as biomarkers of disulfoton exposure. No human data are available to support this, but limited animal data provide some evidence of this. Disulfoton exposure caused a 173% and 313% increase in urinary noradrenaline and adrenaline levels in female rats, respectively, within 72 hours of exposure (Brzezinski 1969). The major metabolite of catecholamine metabolism, HMMA, was also detected in the urine from rats given acute doses of disulfoton (Wysocka-Paruszewska 1971). Because organophosphates other than disulfoton can cause an accumulation of acetylcholine at nerve synapses, these chemical compounds may also cause a release of catecholamines from the adrenals and the nervous system. In addition, increased blood and urine catecholamines can be associated with overstimulation of the adrenal medulla and/or the sympathetic neurons by excitement/stress or sympathomimetic drugs, and other chemical compounds such as reserpine, carbon tetrachloride, carbon disulfide, DDT, and monoamine oxidase inhibitors (MAO) inhibitors (Brzezinski 1969). For these reasons, a change in catecholamine levels is not a specific indicator of disulfoton exposure. 

Increased levels of urinary catecholamines may also be associated with accumulation of acetylcholine that resulted from acetylcholinesterase inhibition by disulfoton. No human data were located to support this, but limited animal data provide some evidence. Disulfoton exposure caused a 173% and 313% increase in urinary noradrenaline and adrenaline levels in rats, respectively, within 72 hours (Brzezinski 1969). The major metabolite of catecholamine metabolism, HMMA, was also detected in the urine from rats given acute doses of disulfoton (Wysocka-Paruszewska 1971). 

After determining a concentration of test compound which elicits no visually detectable response or effect in the aquatic species over a period of 48 hours (Step 1), fresh animals are placed in the chamber, exposed to known concentrations of test chemical (usually 14C-labelled), and the uptake rate and major metabolites determined (Step 2). Depuration rate from the dosed animals also can be estimated at this point by transfer to untreated water. Fresh animals also can be exposed to a constant flow of test solution until an absorption-excretion equilibrium (steady state) has been established, dosed briefly with labelled compound, and release (turnover) rate determined (Step 3). 

Another challenge is how and when to consider isomers, metabolites, and the actual finished product. In general, any parent compound and its major metabolite(s) that achieve, or are suspected to achieve, systemic exposure in humans should be evaluated. Assessment of the effects of major (i.e., >25% of the parent) human-specific metabolite(s), if absent or present only at relatively low concentrations in animals, should be considered.25,52 This is of particular importance if the metabolite(s) is known to substantially contribute to the pharmacological actions of the NCE. In vitro or in vivo testing of the individual isomers should also be considered. Moreover, studies on the finished product are only necessary if the pharmacokinetics/pharmacodynamics is substantially altered in comparison to the active NCE tested previously. 

Toxicokinetics has become a critically important component of any nonclinical program (see discussion in Section 14.10). Current ICH guidelines require the determination of animal pharmacokinetics at all dose levels administered on at least 2 days (beginning and end) during a nonclinical toxicology study.5 Similarly, this requires the development of a validated analytical method for the determination of parent drug (and possible major metabolites). 

The predominant alkaloid fonnd in tobacco is (—)-nicotine other molecnles found in tissnes of smokers are either present in tobacco smoke or are metabolites of nicotine, inclnding (4-)-nicotine, (-P)-nomicotine, (—)-nomicotine and (—)-cotinine, the major metabolite (Clark et al. 1965). In animals trained to recognise the stunnlns produced by (—)-nicotine, (-P)-nicotine fully substituted for (—)-nicotine but was about one-tenth as potent. There was no stereoselectivity in responding observed with the metabolite nomicotine and both (-p) and (—)-isomers fully substituted for nicotine but again were 10-fold less potent. (—)-Cotinine also substitnted for nicotine at very high doses bnt this conld be explained by the presence of small amounts of (—)-nicotine in the sample of cotinine (Goldberg et al. 1989). 

Taxol (Paclitaxel) 137, a natural product derived from the bark of the Pacific yew, Taxus brevifolia [213-215], and the hemisynthetic analogue Docetaxel (Taxotere) 138, two recent and promising antitumour agents, have been the matter of extensive in vivo and in vitro animal metabolic studies. The major metabolites of taxol excreted in rat bile [216] were identified as a C-4 hydroxylated derivative on the phenyl group of the acyl side chain at C-13 (139), another aromatic hydroxylation product at the mefa-position on the benzoate group at C-2 (140) and a C-13 deacylated metabolite (baccatin III, 142) the structure of six minor metabolites could not be determined. The major human liver microsomal metabolite, apparently different from those formed in rat [217], has been identified as the 6a-hydroxytaxol (141) [218, 219]. A very similar metabolic pattern was... 

Dichlorophenol has been demonstrated to be the major urinary metabolite of 1,4-dichlorobenzene in both humans and animals. This metabolite is eliminated principally as a conjugate of glucuronic or... 

In general, the expected clinical route of administration should be used when feasible. Regardless of route, exposure to the parent compound and its major metabolites should be similar or greater than that observed in humans. Because safety pharmacology studies are carried out before human studies are initiated, this may have to be inferred from information derived from in vitro studies, for example, with human hepatocytes and/or from information from similar compoimds that have been used in humans. In some cases, early low-dose human studies may show that significant metabolites are formed in humans but were not formed in the animals used in safety pharmacology studies. In these circumstances, further studies will be needed in animals using isolated or chemically synthesised human metabolites. 

When a compound undergoes metabolism, the pharmacokinetics of major metabolites, particularly those that have pharmacological activity or are responsible for toxicities, should be examined. A long half-life of a metabolite may result in accumulation long after the concentration of the parent molecule has reached steady state. Much of the evaluation of the pharmacokinetics and the rates and routes of metabolism will be studied in animals using radiolabelled drug, but should be supported by cold assays. 

The toxicokinetics, in particular the peak concentrations (Cmax) and exposure (AUC) to parent drug and any major metabolites at the NOAEL and at toxic doses in the animal species tested. 

Hexanedione was found to be a major metabolite of MBK in several animal species peripheral neuropathy occurred in rats after daily subcutaneous injection of 2,5-hexanedione at a dose of 340mg/kg 5 days/ week for 19 weeks.Nonneurotoxic aliphatic monoketones, such as methyl ethyl ketone, enhance the neurotoxicity of MBK. In one rat study, the longer the carbon chain length of the nonneurotoxic monoketone, the greater the potentiating effect on MBK. It is expected that exposure to a subneurotoxic dose of MBK, plus high doses of some aliphatic monoketones, would also produce neurotoxicity. In addition, MBK itself potentiates the toxicity of other chemicals. ... 

The actions of bupropion remain poorly understood. Bupropion and its major metabolite hydroxybupropion are modest-to-moderate inhibitors of norepinephrine and dopamine reuptake in animal studies. However, these effects seem less than are typically associated with antidepressant benefit. A more significant effect of bupropion is presynaptic release of catecholamines. In animal studies, bupropion appears to substantially increase the presynaptic availability of norepinephrine and dopamine to a lesser extent. Bupropion has virtually no direct effects on the serotonin system. 

Since ciprofloxacin, the major metabolite of enrofloxacin, exhibits biological activity similar to that of the parent compound, it is also used as an individual fluoroquinolone drug. In this case, ciprofloxacin is metabolized mainly to oxociprofloxacin and desethylene ciprofloxacin (149). After oral administration to broiler chickens, ciprofloxacin was rapidly and efficiently absorbed, its metabolism being similar to that observed in other animal species. It has been reported that the mean tissue concentrations of ciprofloxacin and its metabolites that ranged between 5 and 26 ppb persisted in chickens up to 12 days after treatment (149). 

---