1. Following multiple oral administration of 14C-flocoumafen to rats at 0.02 and 0.1 mg/kg per week, appreciable cellular accumulation was seen in the liver. 2. Residues in the liver increased with dose throughout the duration of the experiment (14 weeks) at the low dose, but reached a plateau after 4 weeks at the high dose. The major component was unchanged flocoumafen together with a minor polar metabolite seen also in faeces. 3. The data suggest the presence in rat liver of a saturable high-affinity binding site for flocoumafen and a second binding site of lower affinity. 4. Lethal anticoagulant action occurs only when the binding sites have become saturated. 5. A range of haematological and clinical chemistry measurements failed to predict the onset of anticoagulant toxicity seen in the high dose treatment group. 6. Flocoumafen was not extensively metabolised; at the low dose, approximately 30% of the cumulative administered dose was eliminated in the faeces within 3 days of each dosing, mainly as unchanged rodenticide. At the high dose, this value ranged from 18% after the first dose to 59% after the tenth dose. 7. Two more polar metabolites and a lipophilic compound were minor products in faeces. Amounts of the polar products increased with cumulative dosage received. The urinary route of elimination was a very minor one (less than 1.6%) at both doses.

1. 14C-Flocoumafen, administered to Japanese quail as a single oral or i.p. dose, was rapidly and extensively eliminated in excreta; most was eliminated within 24 h. Extensive metabolism of the rodenticide was seen, with at least 8 metabolites detected; unchanged flocoumafen comprised 9% dose. The elimination kinetics and metabolic profiles were qualitatively similar after oral and i.p. dosing. 2. The major metabolites (60% dose) were labile to beta-glucuronidase, liberating aglycones with identical chromatographic mobilities to those of the unchanged flocoumafen isomers. 3. Radioactivity was retained mostly in the liver; largely as unchanged flocoumafen associated with the mitochondrial and microsomal fractions. Elimination of radioactivity from most tissues was biphasic with an initially rapid depletion (5 days) followed by a slow terminal elimination phase. The elimination half life from liver was greater than 100 days. 4. Livers of quail receiving extended dietary exposure to flocoumafen at 5, 15 and 50 ppm had concentrations of flocoumafen (1.0 nmol/g) that were independent of dose, indicating a capacity-limited binding site. These hepatic concentrations were similar to those after a single oral dose and were also similar to those in rats. The data indicate the presence in quail liver of a saturable high affinity flocoumafin binding site with similar characteristics and capacity to that in the rat. 5. The selective toxicity of flocoumafen to rats (highly toxic) and quail (moderately toxic) appears to arise from differences in metabolism rather than from anticoagulant binding in the liver. When hepatic binding sites of rats are saturated anticoagulant action becomes lethal, whereas quail are able to survive and extensively metabolize the compound.

No abstract

A single oral dose of 0.14 mg kg−1 of [14C] flocoumafen to rat, which gave a transient, non‐lethal, effect, was rapidly absorbed, radioactivity appearing in the blood maximally at 4 h and falling to half maximum value by 8 h. The maximum effect on prothrombin time was at 24 h and the value returned to normal by 48 h. Elimination of radioactivity was very slow, with less than 0.5% of the dose in the urine up to 7 days after dosing, and 23‐26% in the faeces (more than half of which appeared in the first 24 h). Most of the administered radioactivity (74‐76%) was retained 7 days after dosing. Approximately half of the dose was in the liver; it was eliminated with a halflife of 220 days. At 48 h after dosing, most of the hepatic radioactivity comprised unchanged flocoumafen. Treatments of flocoumafen‐dosed rats with warfarin or with cytochrome P450‐inducing doses of phenobarbitone were without effect on the hepatic residue of flocoumafen.

1. 3-Phenoxy[14C]benzoyl-CoA has been chemically synthesized, purified and characterized by field-desorption mass spectrometry. Biological activity of the purified thioester was greater than 92%. 2. The two enzymic steps involved in the conjugation of 3-phenoxybenzoic acid (3PBA) with glycine have been investigated in hepatic and renal tissues from various mammalian species. 3. A 10- to 300-fold excess of acyl-CoA: glycine N-acyltransferase activity as compared with acyl-CoA synthetase activity was found in most tissue preparations, while the rate of the activating step matched that of the overall process. This suggests that formation of the acyl-CoA thioester (3PBA-CoA) is the rate-limiting step in the conjugation of 3PBA with glycine. 4. In most of the species tested, renal activities were higher than those of corresponding liver preparations. 5. The gerbil and ferret, which excrete 3-phenoxybenzoylglycine as the principal urinary metabolite of 3PBA, gave the highest 3PBA-CoA synthetase and glycine N-acyltransferase activities in vitro. By contrast, the hamster, which excretes only small amounts of the glycine conjugate of 3PBA, had the lowest enzymic activities in vitro. 6. In the mouse and rat there were differences between the patterns of metabolism found in vivo and in vitro, and possible reasons for this are discussed.

No abstract

In a dietary toxicity study, laying hens received a diet containing the rodenticide flocoumafen at concentrations of 1.5, 5, 10 and 50 mg kg-' for five consecutive days. The LC,, at termination following a 28-day observation period was 16.4 mg kg-'.Livers of birds which received doses of flocoumafen between 5 and 50 mg kg-l had concentrations of flocoumafen (1.5 nmol g-l) that were independent of dose. The data indicate the presence in hen liver of a saturable high-affinity flocoumafen binding site with similar characteristics and capacity to that of the quail and rat. Residues of flocoumafen in samples of breast and leg muscle were low in all exposure groups. Higher, dose-related residues were found in samples of abdominal fat and skin-associated fat and there was a clear demonstration of the transfer of dose-related residues into eggs.In a separate study in which hens were dosed with [14C]flocoumafen for five consecutive days at a daily rate of 1 and 4 mg kg-l body weight, the majority (68 %) of the daily radioactive dose was eliminated over the following 24 hours via excreta. Residues in liver at death or when killed accounted for < 1 % of the cumulative administered radioactivity. Residues in eggs were located primarily in the yolk with maximum concentrations 1.0 mg kg-' or 0.18% of the low dose; 2.1 mg kg-' or 0.06% of the high dose as ["C]flocoumafen equivalents were observed at 10 days after start of dosing. Some 40 % of the total activity in the yolk was unchanged flocoumafen.

1. Appreciable penetration of radioacticity occurred through rat skin following percutaneous administration of 14C-flocoumafen. At 7 days after dosing 12% of the administered radioactivity remained at the site of application, while 25% was located in the liver as unchanged flocoumafen. 2. Excretion of flocoumafen metabolites via the urine accounted for 10% dose over the 7 day experiment, this is some 30-fold greater than that seen after a single oral dose. 3. Unchanged flocoumafen comprised the major product detected in faeces. Biliary elimination was a very minor route of excretion and did not account for all of the unmodified flocoumafen present in faeces. 4. Considerable amounts of unchanged flocoumafen found associated with the contents of the large intestine after intraperitoneal administration to rats fitted with biliary fistulae indicates that, in the intact rat, flocoumafen enters the intestine by a non-biliary intestinal excretion mechanism.